Molecular Targets for Therapy (MTT)

Leukemia (2003) 17, 1263–1293. doi:10.1038/sj.leu.2402945

Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention

F Chang1, L S Steelman1, J T Lee1, J G Shelton1, P M Navolanic1, W L Blalock1,3, R A Franklin1,2 and J A McCubrey1,2

  1. 1Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
  2. 2Leo Jenkins Cancer Center, Brody School of Medicine at East Carolina University, Greenville, NC, USA

Correspondence: Dr JA McCubrey, Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA. Fax: +1 252 744 3104

3Current address: Shands Cancer Center, University of Florida, Gainesville, FL 32610, USA

Received 20 December 2002; Accepted 13 February 2003.

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Abstract

The Ras/Raf/Mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) cascade couples signals from cell surface receptors to transcription factors, which regulate gene expression. Depending upon the stimulus and cell type, this pathway can transmit signals, which result in the prevention or induction of apoptosis or cell cycle progression. Thus, it is an appropriate pathway to target for therapeutic intervention. This pathway becomes more complex daily, as there are multiple members of the kinase and transcription factor families, which can be activated or inactivated by protein phosphorylation. The diversity of signals transduced by this pathway is increased, as different family members heterodimerize to transmit different signals. Furthermore, additional signal transduction pathways interact with the Raf/MEK/ERK pathway to regulate positively or negatively its activity, or to alter the phosphorylation status of downstream targets. Abnormal activation of this pathway occurs in leukemia because of mutations at Ras as well as genes in other pathways (eg PI3K, PTEN, Akt), which serve to regulate its activity. Dysregulation of this pathway can result in autocrine transformation of hematopoietic cells since cytokine genes such as interleukin-3 and granulocyte/macrophage colony-stimulating factor contain the transacting binding sites for the transcription factors regulated by this pathway. Inhibitors of Ras, Raf, MEK and some downstream targets have been developed and many are currently in clinical trials. This review will summarize our current understanding of the Ras/Raf/MEK/ERK signal transduction pathway and the downstream transcription factors. The prospects of targeting this pathway for therapeutic intervention in leukemia and other cancers will be evaluated.

Keywords:

therapeutic intervention, small molecular weight membrane-permeable inhibitors, cytokines, oncogenes, MAPK kinase cascade, signal transduction

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Hematopoietic cytokines and the Ras/Raf/MEK/ERK signaling pathway

Hematopoietic cell proliferation, differentiation and prevention of apoptosis are finely regulated by cytokines, a group of polypeptide hormones including interleukin-3 (IL-3), granulocyte/macrophage colony stimulating factor (GM-CSF), erythropoietin and stem-cell factor (SCF, a.k.a. c-kit-L). Studies on these cytokines revealed their important regulatory functions on cell proliferation and apoptosis in hematopoietic cells of myeloid, erythroid and lymphoid lineages.1, 2, 3 IL-3 and GM-CSF are two of the first identified and best-characterized hematopoietic cytokines.4, 5

In vitro studies have shown that most nontransformed hematopoietic cell lines require cytokines such as IL-3 or GM-CSF for proliferation. These hematopoietic cytokines can induce various signaling pathways that transduce critical cell growth or anti-apoptotic signals from the cell membranes into the nucleus to modulate cell growth.4, 5, 6, 7, 8 Among the various signaling pathways triggered by hematopoietic factors is the Ras/Raf/MEK/ERK pathway, which has been shown by us as well as others to play important roles in cell proliferation and the prevention of apoptosis.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 An overview of the Ras/Raf/MEK/ERK cascade is presented in Figure 1. Many of the members of this pathway, including Ras, Raf, and their downstream transcription factor targets NF-kappaB, AP-1, c-Myc and Ets-1 were initially identified as proto-oncogenes. Aberrant activation of this pathway is commonly observed in malignantly transformed cells.4, 9, 23, 24, 25, 26, 27

Figure 1.
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Overview of Ras/Raf/MEK/ERK pathway. This figure illustrates how the Raf/MEK/ERK pathway is regulated by Ras as well as various kinases, which serve to phosphorylate S/T and Y residues on Raf. Some of these phosphorylation events serve to enhance Raf activity (shown by a black P in a white circle), whereas others serve to inhibit Raf activity (shown by a white P in a black circle. Moreover, there are phosphatases such as PP2A, which remove phosphates on certain regulatory residues. Activation of the PI3K/PDK/AKT pathway is also shown, as this pathway interacts with the Raf/MEK/ERK pathway to regulate its activity. PI3K can be activated by two mechanisms; either the p85 PI3K subunit can bind the activated IL-3Rbeta chain or Ras. Activated ERK can enter the nucleus and phosphorylate transcription factors such as Ets. The downstream transcription factors regulated by this pathway are indicated in diamond-shaped outlines.

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Ras is a small GTP-binding protein, which is the common upstream molecule of several signaling pathways including Raf/MEK/ERK, PI3K/Akt and RalEGF/Ral.28, 29, 30, 31 Different mutation frequencies have been observed between Ras genes in human cancer (Ki-Ras>Ha-Ras), and these Ras proteins show varying abilities to activate the Raf/MEK/ERK and PI3K/Akt cascades as Ki-Ras has been associated with Raf/MEK/ERK while Ha-Ras is associated with PI3K/Akt activation.31 Raf is an serine/threonine (S/T) kinase and is normally activated by a complex series of events including: (i) recruitment to the plasma membrane mediated by an interaction with Ras;31, 32, 33, 34, 35, 36 (ii) dimerization of Raf proteins;37, 38, 39, 40, 41 and (iii) phosphorylation on different domains.43, 44, 45, 46, 47 Moreover, Raf activity is modulated by adaptor proteins, including Bag1, Hsp70 and 14-3-3.48, 49 Inhibition of Ras activity hinders Raf activation. Some of the sites of potential inhibition of the Ras/Raf and downstream MEK activity, using Raf-1 as a model, are presented in Figure 2.

Figure 2.
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Sites of inhibition of Raf-1 activation/inactivation. Activation of Ras occurs after cytokine receptor ligation and results in the farnesylation of Ras and membrane translocation. Ras recruits Raf-1 to the membrane by binding the Ras-binding domain present on Raf-1. Also occurring at this time is the transient dephosphorylation of S621 present on Raf-1. The S259 present on Raf-1 is then dephosphorylated by PP2A. This allows Raf-1 to be phosphorylated and activated by other kinases (PAK, Src family kinases and potentially PKC). Raf-1 then binds ATP and phosphorylates MEK, which in turn phosphorylates ERK. Raf-1 is then inactivated by protein dephosphorylation and binds 14-3-3. This results in a conformational change and Raf-1 is translocated to the cytoplasm and is inactive. The phosphorylation/dephosphorylation events alter the configuration of Raf-1 and can result in the disassociation of the 14-3-3 protein, which unlocks the Raf-1 protein allowing it to be phosphorylated by other kinases. The binding of the chaperonin protein 14-3-3 and the subsequent conformational changes and translocation to the cytoplasm are indicated. Sites where various small molecular weight inhibitors act also indicated. Certain sites of inhibition are currently more promising than others; however, it is speculated that in the future, combinations of inhibitors may prove more effective than treatment with a single inhibitor. This figure is based in part by the models proposed by Dr Walter Kolch.59, 60, 61, 62, 63

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For Ras to be targeted to the cell membrane, it must be farnesylated by farnesyl transferase (FT). Targeting of Ras to the cell membrane occurs after IL-3 binding the IL-3 receptor and activation of Shc/Grb2/Sos. Pharmaceutical companies have developed many FT inhibitors and some are in clinical trials. The chemical structures of certain FT inhibitors are presented in Figure 3.

Figure 3.
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Chemical structures of Ras inhibitors. References documenting the use of these inhibitors in basic and clinical research are presented in Table 2.

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Chaperonin proteins such as 14-3-3 and Hsp90 regulate Raf activity.48 Moreover, Raf activity is regulated by dimerization.37, 38, 39, 40, 41 These biochemical properties allow Raf activity to be sensitive to drugs that block protein:protein interactions such as geldanamycin and coumermycin.49, 52 Geldanamycin is a nonspecific Raf inhibitor as it also affects the activity of many proteins including the BCR–ABL oncoprotein, which has a critical role in the etiology of chronic myelogenous leukemia. Geldanamycin is currently in clinical trials.50 Raf-specific iinhibitors have been developed. Raf inhibitors range from small molecular weight cell membrane-permeable drugs that bind the kinase domain to antisense RNAs.50, 51, 52, 53, 54, 55 Some of these compounds and approaches are in clinical trials. Some of the studies performed with Raf inhibitors have shown significant promise in the treatment of diverse cancers, which have been difficult to treat (eg colorectal, ovarian). The structure of some of these Raf inhibitors is presented in Figure 4.

Figure 4.
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Chemical structures of a) Raf inhibitors and b) protein destabilizers. References documenting the use of these inhibitors in basic and clinical research are presented in Table 2.

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Currently, the mammalian Raf gene family consists of Raf-1, A-Raf and B-Raf, which share three domains termed CR1, CR2 and CR3.4 Among these three domains, CR1 is the Ras-binding domain; CR2 is the regulatory domain that has recently been shown in some cells to regulate negatively Raf-1 activity by Akt or PKA phosphorylation at S259; and CR3 is the kinase domain which when phosphorylated on S338, tyrosine (Y) Y340 and Y341 positively regulates Raf-1 activity.35, 56, 57, 58, 59

There are at least 13 regulatory phosphorylation sites on Raf-1.43, 44, 45, 46, 47, 60, 61, 62, 63, 64 Some of these sites (eg S43, S259 and S621) are phosphorylated when Raf-1 is inactive. This allows the 14-3-3 chaperonin protein to bind the Raf-1 protein and confer a conformation which is inactive. Upon cell stimulation, S621 becomes transiently dephosphorylated and protein phosphatase 2A (PP2A) dephosphorylates S259.60 14-3-3 is then disassociated from Raf-1/.60, 61, 62 This allows Raf to be phosphorylated at other sites including S338, Y340, Y341 and others. A Src family kinase is likely responsible for phosphorylation at Y340 and Y341.44, 45, 46, 47, 59 The phosphatases that dephosphorylate S621 and other Raf phosphorylation sites, excluding S259, are unknown.

Y340 and Y341, the phosphorylation targets of Src family kinases, are conserved in A-Raf (Y299 and Y300), but are replaced with aspartic acid (D) at the corresponding positions in B-Raf (D492 and D493).44, 65, 66, 67 Hence, maximal activation of Raf-1 and A-Raf requires both Ras and Src activity, while B-Raf activation is Src–independent.66

A means to prevent Raf activation could be the development of specific Src family kinase inhibitors. Indeed, we have observed that Raf-responsive hematopoietic cells are very sensitive to the Src kinase inhibitor herbimycin A. Herbimycin A inhibits the c-Src kinase with an IC50 of 900 nM, whereas it inhibits other kinases (PDGF-R) at 10- to 100-fold higher concentrations. The concentrations of herbimycin A used in our study were within a 10-fold or lower range of the IC50. These hematopoietic cells proliferate in response to the introduced activated Raf oncogenes. Induction of apoptosis can be synergistically increased upon cotreatment of the Raf-responsive cells with inhibitors, which target Raf and Src or MEK and Src. The chemical structures of some Src kinase inhibitors are presented in Figure 5.

Figure 5.
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Chemical structures of Src inhibitors. The structures of the Src inhibitor herbimycin A and other Src inhibitors are presented. References documenting the use of these inhibitors in basic and clinical research are presented in Table 2.

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The S338 present in Raf-1 is conserved among the three Raf isoforms; however, in B-Raf (S445), this residue is constantly phosphorylated.47 S338 phosphorylation on Raf-1 is stimulated by Ras.46, 66, 67 This Ras-induced phosphorylation on S338 of Raf-1 is dependent on p21-activated protein kinase (PAK).67, 68, 69 Other phosphorylation regulatory residues, including S43, S339, T491, S494, S497, S499, S619 and S621, have regulatory roles on Raf-1 activity. Protein kinase C (PKC) has been shown to activate Raf activity and induce crosstalk between PKC and Raf/MEK/ERK signaling pathways.70, 71, 72, 73 S497 and S499 were identified as the target residues on Raf-1 for PKC phosphorylation.70, 71 However, other studies suggest that these sites were not necessary for Raf-1 activation.73, 74, 75 Certain PKC inhibitors may prove effective in blocking Raf-mediated growth. We have observed that the PKC inhibitors staurosporine and G06976 suppressed proliferation of Raf-responsive hematopoietic cells. The chemical structures of staurosporine and other PKC inhibitors are presented in Figure 6. UCN-01 is a modified staurosporine, whose efficacy is also being explored in clinical trials.75 Furthermore, there are PKC activators such as bryostatin-1, which are in clinical trials.76 These compounds may be useful in controlling Raf-mediated growth as while they initially activate PKC, this results in the subsequent downregulation of PKC through proteolytic cleavage of PKC.

Figure 6.
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Chemical structures of PKC a) inhibitors and b) activators. The structures of the PKC inhibitors staurosporine and UCN-01 (a) and the PKC activator bryostatin-1 (b) are presented. References documenting the use of these compounds in basic and clinical research are presented in Table 2.

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Raf activity is also negatively regulated by phosphorylation on the CR2 regulatory domain. Recently, it was shown that Akt and PKA phosphorylate S259 on Raf-1 and inhibit its activity.78, 79 Furthermore, Akt phosphorylated B-Raf on S364 and S428 to inactivate its kinase activity.80 These S-phosphorylated Rafs associate with adaptor protein 14-3-3 and become inactive.69 This inhibitory effect of Akt on Raf activity is cell-type specific and depends on the differentiation state of the cells.77 It was suggested that some differentially expressed mediators are essential for the association between Akt and Raf. Inhibitors to PI3K, Akt and PKA may modulate the activity of the Raf pathway by suppressing the phosphorylation of S259 (see Figure 2). This should increase Raf-1 activity, which may lead to p21Cip1 expression, which has been shown to regulate cell cycle progression.80 This area remains controversial, as we have observed that PI3K and Akt inhibitors inhibit Raf-responsive growth. This may be because of an autocrine component of their growth, which requires PI3K activity.

Raf activity is also regulated by dephosphorylation. As stated previously, PP2A removes the phosphate from S259, which contributes to Raf-1 activation. Undoubtedly, there are other phosphatases that remove phosphates from additional regulatory residues on Raf. Okadaic acid inhibits PP2A and theoretically could be used to inhibit Raf activity. The development of specific phosphatase inhibitors could prove beneficial in inhibiting the effects of activation of the Raf pathway. The structure of okadaic acid and other phosphatase inhibitors are presented in Figure 7.

Figure 7.
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Chemical structures of phosphatase inhibitors. The structure of okadaic acid and other phosphatase inhibitors are presented. References documenting the use of these inhibitors in basic and clinical research are presented in Table 2.

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Activated Rafs induce a signal transduction cascade, which includes the Mitogen-activated protein kinase/ERK kinase (MEK), extracellular-signal-regulated kinase (ERK), ribosomal S6 kinase (RSK) and a set of transcription factors including NF-kappaB, cyclic AMP-responsive element-binding protein (CREB), Ets, AP-1 and c-Myc. MEK is a Y- and S/T-dual specificity protein kinase.82 Its activity is positively regulated by Raf phosphorylation on S residues in the catalytic domain, for example, S218 and S222 of mouse MEK1.32, 82, 83, 84, 85, 86, 87, 88, 89 All three Raf family members are able to phosphorylate and activate MEK, but different biochemical potencies have been observed (B-Raf>Raf-1double greater thanA-Raf).84, 85, 86 Specific inhibitors to MEK have been developed (PD98059 and UO126). Interestingly and controversially, it has recently been proposed that B-Raf is the major activator of MEK1 and that Raf-1 may require B-Raf to become activated. Furthermore, B-Raf may be temporally activated before Raf-1. There may be different subcellular localizations of B-Raf and Raf-1 within the cell that exert different roles in signaling and apoptotic pathways.85, 86 Second-generation MEK inhibitors such as PD184352 have been developed and are currently in clinical trials.88, 89 The structures of certain MEK inhibitors are presented in Figure 8.

Figure 8.
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Chemical structures of MEK inhibitors. The structures of PD98059, U0126 and second-generation MEK inhibitors are presented. References documenting the use of these inhibitors in basic and clinical research are presented in Table 2.

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ERKs are S/T kinases and their activity is positively regulated by phosphorylation mediated by MEK1 and MEK2. MEKs can phosphorylate ERK1 on T202, and Y204 and ERK2 on T185 and Y187 to activate their kinase activities.90 ERKs can directly phosphorylate a set of transcription factors including Ets-1, c-Jun and c-Myc. ERK can also phosphorylate and activate RSK, which then leads to the activation of the transcription factor CREB.90 Moreover, by an indirect mechanism, ERK can lead to transcription factor Nuclear Factor immunoglobulin kappa chain enhancer-B cell (NF-kappaB) activation by phosphorylating and activating its regulator inhibitor kappaB Kinase (IKK) (see below). ERK1 and ERK2 are differentially regulated in certain cells. ERK2 has been associated with proliferation while ERK1 may inhibit the effects of ERK2 in certain cells.91

The localization of the different Rafs and the downstream kinases present in this cascade remains an intense area of research. While it was initially thought that the activated Rafs were present at the cytoplasmic membrane, recent evidence has demonstrated that some Rafs (Raf-1 and A-Raf) may carry out important antiapoptotic functions in the mitochondrion (eg phosphorylation and inactivation of Bad and regulation of VDAC channels).86, 92 Moreover, there may be temporal distributions of different Rafs in different lipid Rafts in the cells, which occur during mitogen stimulation.86 Downstream ERK and p90Rsk also have different subcellular localizations (cytoplasmic vs nuclear), which determine their effects on phosphorylation and nuclear translocation of key kinases (Cdk2), cyclins (cyclin E) transcription factors (Elk, c-Myc and CREB) involved in cell growth.92 An important caveat that must be considered with many of these studies is that they deal with overexpression of activated, fluorescent-tagged or even organelle-localization-tagged constructs that have been introduced into the cells by transfection. In these studies, the overexpressed or altered protein may be artificially localized to certain compartments of the cells, hence making the results difficult to interpret.

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Proliferative and antiproliferative effects of Ras/Raf/MEK/ERK signaling

Amplification of ras proto-oncogenes and activating mutations that lead to the expression of constitutively active Ras proteins are observed in approximately 30% of all human cancers.93, 94, 95 The effects of Ras on proliferation and tumorigenesis have been documented in immortal cell lines.96 However, antiproliferative responses of oncogenic Ras have also been observed in nontransformed cells including primary rat Schwann cells and primary fibroblast cells of human and murine origins.95, 96, 97, 98, 99, 100, 101 This p15Ink4b/p16Ink4a or p21Cip1-mediated premature G1 arrest and subsequent senescence is dependent on the Raf/MEK/ERK pathway.97, 102

Overexpression of activated Raf proteins is associated with such divergent responses as cell growth, cell cycle arrest or even apoptosis.103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114 Ectopic overexpression of Raf proteins is associated with cell proliferation in cells including human hematopoietic cells,111, 112, 113, 114 human erythroid progenitor cells,103 and A10 smooth muscle cells.107 However, overexpression of activated Raf proteins is associated with cell cycle arrest in cell lines including rat Schwann cells, mouse PC12 cells, human promyelocytic leukemia HL-60 cells and small cell lung cancer cell lines.107, 108, 109 Depending on the Raf isoform, overexpression of Raf can lead to cell proliferation or cell growth arrest in NIH-3T3 and mouse FDC-P1 cells. It is not clear why overexpression of the Raf gene can lead to such conflicting results, but it has been suggested that the opposite outcomes may be determined by the amount or activity of the Raf oncoprotein.81, 111

NIH-3T3 cells have been transfected with the three different Raf genes. The introduced A-Raf molecule was able to upregulate the expression of cyclin D1, cyclin E, Cdk2, and Cdk4 and downregulate the expression of Cdk inhibitor p27Kip1.81 These changes induced the cells to pass through G1 phase and enter S phase. However, in B-Raf- and Raf-1-transfected NIH-3T3 cells, there was also a significant induction of p21Cip1, which led to G1 arrest. Using FDC-P1 hematopoietic cells transfected with conditional mutant Raf-1, A-Raf and B-Raf genes as a model, we have demonstrated that moderate Raf activation, including A-Raf and Raf-1, led to cell proliferation, which was associated with the induction of cyclin expression and Cdks activity. However, ectopic expression of B-Raf led to apoptosis.113, 114

An alternative explanation for the diverse proliferative results obtained with the three Raf genes is the different biological effects of A-Raf, B-Raf and Raf-1. The individual functions of these three different Raf proteins are not fully understood. Even though it has been shown that all three Raf proteins are activated by oncogenic Ras,30, 66, 115, 116, 117, 118, 119 target the same downstream molecules, that is, MEK1 and MEK2,24, 61, 80, 120 and use the same adapter proteins 14-3-3 for conformational stabilization,119, 120, 121, 122, 123, 124, 125 different biological and biochemical properties among them have been reported and their functions are noncompensatable.24, 69, 104 For instance, the distribution of Raf proteins in mice is very different. The Raf-1 protein is expressed ubiquitously in almost all tissues examined, while A-Raf is predominately expressed in urogenital tissues and B-Raf in neuronal tissues.126, 127 Knockout mice with a homologous deletion of these Raf genes have revealed very different phenotypes.25, 128, 129 B-Raf-/- mice died embryonically with serious defects in vascular endothelial cell survival and differentiation indicated by an increased number of endothelial cell precursors and apoptotic cells in vascular endothelium.128 A-Raf-/- mice showed gastro-intestinal and neurological defects and died shortly after birth.25 Raf-1-/- mice also died embryonically and showed defects in the development of skin, lung and placenta.129 However, both A-Raf-/- and Raf-1-/- mice showed no sign of defects in apoptosis.130 Finally, it has recently been shown that the B-Raf gene is frequently mutated in certain cancers, especially melanomas. It may be easier for B-Raf mutations to contribute to tumor progression, as a single missense mutation may result in B-Raf activity, whereas multiple mutations may be required for Raf-1 or A-Raf activity to be detected.26

The abilities of the Ras isoforms to activate the three Raf molecules are different.66, 115, 118, 131, 132 In murine cells, Ras and Src stimulate the kinase activity of both Raf-1 and A-Raf. However, B-Raf kinase activity is controlled by Ras and other members of the small G protein family such as Rap1 in PC12 cells66, 131, 132, 133 or TC21 in NIH-3T3 cells.66, 133 Raf-isoform-specific interaction partners have been identified using three different Raf molecules as bait in yeast two-hybrid screens. For instance, the PA28alpha, a subunit of the 11 S regulator of proteasomes, was found to bind specifically to B-Raf but not Raf-1 or A-Raf.134 Both CK2beta (the regulatory subunit of protein kinase CK2) and pyruvate kinase M2 have been shown to be A-Raf-specific interaction partners.119, 130 Thus, important subtleties exist among the functions of Raf-1, A-Raf and B-Raf as well as their regulation.

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Downstream transcription factor targets of the Ras/Raf/MEK/ERK pathway and their regulation of cell proliferation

The Ras/Raf/MEK/ERK signaling pathway can exert proliferative or antiproliferative effects through downstream transcription factor targets including NF-kappaB, CREB, Ets-1, AP-1 and c-Myc. ERKs can directly phosphorylate Ets-1, AP-1 and c-Myc, which lead to their activation. Alternatively, ERKs can phosphorylate and activate a downstream kinase target RSK, which then phosphorylates and activates transcription factors, such as CREB. Moreover, instead of a direct phosphorylation, ERKs can lead to transcription factor NF-kappaB activation by phosphorylating and activating its positive regulator IKK (see below). These transcription factors induce the expression of genes important for cell cycle progression, for example, Cdks, cyclins, growth factors, and apoptosis prevention, for example, antiapoptotic Bcl-2 and cytokines. However, under certain circumstances, strong Raf signaling has been shown to result in the inactivation of downstream transcription factors, including NF-kappaB and c-Myc, which may account for the Raf-induced antiproliferative responses observed in some studies.

Raf signaling and NF-kappaB

NF-kappaB is a dimeric transcription factor comprising members of the Rel gene family of DNA-binding proteins. NF-kappaB can modulate the expression of its target genes encoding cytokines, growth factors, other transcription factors, and regulators of cell proliferation and apoptosis by binding to the kappaB cis-acting element contained in their promoter regions.135, 136, 137, 138 Many target genes of NF-kappaB play important roles in proliferation, prevention of apoptosis, angiogenesis, metastasis, and immune responses.139, 140, 141, 142

So far, five members of the Rel family have been identified, which include RelA, RelB, c-Rel, p105/NF-kappaB1 and p100/NF-kappaB2.143 p105/NF-kappaB1 and p100/NF-kappaB2 are inactive precursors, which are processed into their active forms of p50 and p52, respectively, before dimerization. NF-kappaB is a collective name of homo- or heterodimers comprised of different combinations of two Rel proteins. Different subunit combinations have diverse functions in regulating transcription. The heterodimer comprising p50/NF-kappaB1 and RelA is the most frequently observed NF-kappaB complex. It is a potent activator of gene expression from kappaB sites because of the presence of two transactivating domains in the C-terminal region of RelA, and was defined as the classic NF-kappaB transcription factor complex.144, 145 This classic NF-kappaB was also used for most studies examining the activity of transcription factor NF-kappaB.

Before stimulation, NF-kappaB is normally sequestered in the cell cytoplasm by binding to IkappaBalpha, IkappaBbeta and IkappaBalt epsilon inhibitors.146 This binding masks the nuclear localization signal on NF-kappaB, thereby preventing nuclear translocation of NF-kappaB (Figure 9). The inhibitory effects of IkappaBs on NF-kappaB can be eliminated by the multisubunit IkappaB kinase cascades.147, 148, 149, 150 IKK core complex contains four IKK subunits: one IKKalpha, one IKKbeta and two IKKitalic gammas. IKKalpha and IKKbeta are the catalytic subunits, both of which can phosphorylate IkappaBs at specific S residues in the NH2-terminal domain. For instance, they can phosphorylate IkappaBalpha on S32 and S36 or IkappaBbeta on S19 and S23.151, 152 Phosphorylated IkappaBs can be recognized by the IkappaB-E3 ubiquitin ligase SCF (Skp1-Cullin-F-box protein ligase complexes), and degraded through the proteosomes pathway.149, 153 IKKitalic gamma is required for stabilization of the IKK complex.154 Proteosome inhibitors may prove useful in inhibiting NF-kappaB activity in response to activation of the Raf/MEK/ERK cascade.

Figure 9.
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Raf signaling-induced NF-kappaB activation. Raf induces kinases (MEKK1 and NIK) that phosphorylate and activate IKK. IKK in turn phosphorylates I-kappaB, leading to its ubiquitination. This allows NF-kappaB to become phosphorylated by MSK1, PKA, IKK and CKII. Phosphorylated NF-kappaB forms a heterodimer with CBP, which stimulates gene expression in the nucleus.

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Kinases including NF-kappaB-inducing Kinase (NIK) and Mitogen-activated protein kinase/ERK Kinase Kinase-1 (MEKK1) phosphorylate subunits of IKK complex and modulate its activity.155, 156, 157 Even though NIK and MEKK1 can activate both IKKalpha and IKKbeta, NIK preferentially activates IKKalpha by phosphorylation on S176,155, 156, 157 while MEKK1 preferentially activates IKKbeta by phosphorylation on S177 and S181.158 These results indicate that NIK and MEKK1 independently phosphorylate and activate the IKK complex, and therefore differentially regulate NF-kappaB activity.155, 156, 157 NF-kappaB transcriptional activity is also regulated by its own phosphorylation by kinases including Casein kinase II (CKII) and IKK on the C-terminal transactivation domain159, 160, 161 as well as the N-terminal domain by PKA and Mitogen- and Stress-activated protein Kinase (MSK1).147, 162 PKA and MSK1 phosphorylate p65 on S276, which lead to the association of NF-kappaB with its transcriptional coactivator CBP/p300.147, 162 CK II and IKK phosphorylate p65 on the C-terminal transactivation domain at S529 and S536, respectively.159, 160, 161 These phosphorylation events regulate NF-kappaB activity by modulating its DNA binding, transactivation properties and interactions between transcription factor and regulatory proteins.147

Raf activation induces the expression of reporter genes driven by the NF-kappaB promoter.141, 163 Raf activates NF-kappaB through two pathways. (1) Raf can activate NF-kappaB in a rapid and direct fashion, which involves the activation of MEKK1 and IKKbeta.164, 165, 166 (2) Raf may also activate NF-kappaB through an autocrine loop in some cell types.164, 167, 168, 169 Earlier work had suggested a possible role of RSK in the activation of NF-kappaB, since in vitro studies have shown that RSK could phosphorylate IkappaB on S32, which would lead to IkappaB degradation.170, 171 Further studies indicated that Raf-mediated NF-kappaB activation is independent of the MEK/ERK/RSK pathway, but dependent on MEKK1.165 Raf-induced MEKK1 preferentially activates IKKbeta and has little effect on IKKalpha.151, 165 This activation is possibly through direct phosphorylation.157 However, potent Raf inhibits NF-kappaB activity in the human glioblastoma cell line, T98G, through the MEK/ERK pathway. So, the Raf/MEK/ERK pathway may in some circumstances exert a negative regulatory role in NF-kappaB activity.172

Regulation of NF-kappaB activity is a key therapeutic target. Some inhibitors of NF-kappaB are presented in Figure 10. Moreover, the inhibitor of NF-kappaB (I-kappaB) is also a therapeutic target. Overexpression of protease-resistant forms of IkappaB (aka super-repressor) inactivates NF-kappaB activity in certain cells.4, 173 They have been introduced into cells by adenoviral and retroviral vectors.

Figure 10.
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Chemical structure of NF-kappaB inhibitors. References documenting the use of these inhibitors in basic and clinical research are presented in Table 2.

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Raf Signaling and CREB

CREB was initially identified as the transcription factor that functions as a regulatory effector of the cAMP signaling pathway. Further investigation revealed that CREB also plays important roles in signal transduction initiated by Ca2+, growth factors and stress signals.174, 175 CREB has been shown to regulate angiotensins, long-term memory and immune functions. The CREB/ATF is a gene family of basic leucine zipper DNA-binding proteins, including CREB, CREM, ATF-1, ATF-2, ATF-3 and ATF-4, that can form homodimers, heterodimers or even in some cases cross-family heterodimers with the other leucine zipper DNA-binding transcription factors in the Jun family.176, 177, 178

Genes regulated by the CREB/ATF transcription factors include cyclin A,178, 179 cyclin D1,180 c-Fos,181, 182 and Bcl-2.183, 184, 185 The cell cycle arrest effect caused by TGF-beta is mediated through the downregulation of cyclin A. Djaborkhel et al179 showed that this downregulation occurred by CREB inactivation. TGF-beta reduced CREB protein levels and induced its dephosphorylation. c-Fos expression was rapidly and transiently activated as part of a mitogenic response. Transcription factors including CREB, serum response factors (SRFs) and Elk-1 contribute to the c-Fos induction mediated by growth factors.186 The ternary complex factor (TCF) formed by two molecules of SRF and one molecule of Elk-1 binds to the serum response element (SRE) at position -300, while the CREB/ATF dimer binds to the CRE centered at position -60 of c-Fos promoter to induce its expression.181, 187 c-Fos is a component of the AP-1 transcription factor whose activity is important for cell proliferation. An outline of the effects of Raf signaling on CREB activation is presented in Figure 11.

Figure 11.
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Raf signaling-induced CREB activation. Possible mechanisms of phosphorylation of the CREB transcription factor by the Raf/MEK/ERK/Rsk, PKA, MSK1, CaMKIV pathways are indicated. The association of CBP with phosphorylated CREB and ATF allows the complex to induce the transcription of CREB-responsive genes. Rsk and MSK1 can phosphorylate CREB in the nucleus.

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Activation of CREB is regulated by phosphorylation by several kinases and is mediated by coactivators such as CREB-binding protein (CBP) and p300.188 CREB/ATF, when associated with the adaptor protein CBP, recognize the CRE region in the promoter of its target genes (Figure 11). CBP provides the bridge between CREB/ATF and the general transcription factors such as RNA polymerase II.189, 190, 191 Furthermore, since CBP also possess a histone acetyltransferase activity, it may play regulatory roles in chromatin structure by modifying the acetylation state of histones.192 It may be possible to target the effects of Raf-mediated CREB activity by drugs, which inhibit histone deacetylation. The structures of some drugs, which inhibit histone deacetylation, are shown in Figure 12. Many of these drugs are in clinical trials.

Figure 12.
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Chemical structures of histone deacetylase inhibitors. The structures of various histone deacetylase inhibitors used in clinical trials are presented. References documenting the use of these inhibitors in basic and clinical research are presented in Table 2.

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Protein kinases including PKA, Ca2+-calmodulin-dependent kinase IV (CaMKIV), MSK, p70S6K and RSK phosphorylate CREB.188, 193, 194, 195, 196, 197 All these kinases target CREB on S133 to activate CREB. Raf signaling activates CREB in several cell types with different treatments that lead to a mitogenic effect.7, 181, 198 This is believed to result from the direct phosphorylation of CREB by RSKs. RSK2 was shown to mediate growth factor induction of phosphorylation of CREB on S133 both in vivo and in vitro.173, 194, 199, 200, 201

Raf signaling and Ets-1

Ets is a family of transcription factors, which include Ets-1, Ets-2, Elk-1, SAP1, SAP2, E1AF, PEA3, PU1 and others.202 They share an 85 amino-acid sequence called the ETS DNA-binding domain. The Ets transcription factors regulate many genes including: transcription factor genes (p53,203, 204, 205 c-Fos204 and NF-kappaB205); cell cycle regulation genes (cyclin D1,206, Rb207 and p21Cip1208); apoptosis-related genes (Bcl-2,209 Bcl-XL,210 and Fas211); cytokine genes (GM-CSF212 and IL-3213); and growth factor genes (platelet-derived growth factor (PDGF)214 and heparin-binding epidermal growth factor (HB-EGF)168).

Ets proteins usually associate with other transcription factors to transactivate their target genes (Figure 13). Ets proteins can be classified into three major subgroups according to the cis-acting elements they recognize, the transcription cofactors they bind to and their transactivating activity.202, 214, 215, 216, 217, 218 The first subgroup includes Ets-1 and Ets-2, which associate with other transcription factors such as AP-1 or NF-kappaB and bind to the Ets/AP-1 or Ets/NF-kappaB sites to induce gene expression. The second subgroup consists of Elk-1, SAP1 and SAP2. They are collectively named TCFs. They form a ternary complex by associating with a dimer of SRF and bind to the SRE to activate gene expression. The third subgroup is unique in that they function as transcriptional repressors. This ETS2 repressor factor (ERF) group includes ERF, NET, YAN and TEL.218, 219 In addition to an ETS DNA-binding domain, transcriptional repression domains were also identified in these repressor factors.220, 221 The molecular mechanisms of ERF-mediated repression are not clear.

Figure 13.
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Raf signaling-induced Ets activation. ERK can phosphorylate Ets and ELK, which lead to their ability to associate functionally with Ap-1 and SRF cis-acting elements and induce gene transcription.

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Raf signaling regulates all three Ets subgroups through direct phosphorylation by the downstream ERK molecules.132, 189, 222, 223 Ets-1 and Ets-2 are phosphorylated by ERKs on T38 and T72, respectively, which lead to Ets activation.168, 216 In NIH-3T3 cells, activated Ets-2 cooperates with AP-1 and this heterodimer binds to the Ets/AP-1 site on the promoter of HB-EGF and induces its expression. Autocrine HB-EGF expression has been postulated to be involved in the transformation of NIH-3T3 cells by oncogenic Raf.168 The TCF Elk-1 is a target for all three MAPK pathways, that is, p38MAPK, JNK and ERK pathways, but through different residues.216, 217 ERK can bind to Elk-1 in the D-domain, which is located N-terminal from the C-terminal transcriptional domain (C-domain), and phosphorylate S383 and S389 in this domain.44, 224, 225, 226, 227 ERK-induced Elk-1 phosphorylation leads to enhanced DNA-binding and TCF-mediated transcriptional activation.186, 216, 217, 228 One of the best-characterized target genes for Elk-1 is c-Fos. Elk-1, after phosphorylation by ERK, binds to the SRE cis-acting element in the promoter region of c-fos and induces its transcription.182, 229, 230 ERK can physically associate with ERF and phosphorylate ERF on multiple sites, including S161, S246, S251 and T526.219, 222 Phosphorylated ERF is then exported from the nucleus into the cytoplasm and becomes inactive. This transportation inactivation of ERF is eliminated when ERK activity is inhibited.222 Furthermore, ERF mutants with the ERK phosphorylation sites mutated to alanine (A) are insensitive to ERK activation and block Ras-induced transformation of NIH-3T3 cells.222

Ets-binding sequences have been identified in the promoter regions of cytokines and growth factor genes including GM-CSF, IL-3, PDGF and HB-EGF. This suggests that the autocrine loop induced by Raf signaling may be mediated by Ets transcription factors. However, Ets binding sequences have also been identified in the promoter regions of genes that may inhibit cell cycle progression such as the Cdk kinase inhibitors (CKI) p21Cip1 and p16Ink4a,208, 231, 232, 233 and the tumor suppressor gene p53.203 This latter observation may account for the Raf-induced cell cycle arrest observed in some cell types.

Raf signaling and AP-1

The AP-1 transcription factor is comprised of homodimers and heterodimers of Jun and Fos gene family members.234, 235, 236 Their transactivating activity has been associated with cell proliferation, differentiation and apoptosis.234-238 Their activity is finely regulated, both by protein levels and post-translational modification. This regulation occurs during the cell cycle, which suggests important regulatory roles that they play in cell proliferation. Genes such as cyclin D1, cyclin A, p53, p16Ink4a, IL-2, IL-3 and GM-CSF are under AP-1 control through the putative cis-acting AP-1 sites in their promoter and enhancer regions.235, 236, 237, 238, 239, 240, 241

The Jun gene family consists of c-Jun, JunB and JunD, which can form homodimers or heterodimers with Fos proteins. The Fos gene family consists of c-Fos, FosB, Fra1 and Fra2, which do not form homodimers but can heterodimerize with Jun. Both Jun and Fos proteins also dimerize with other transcription factors including members of the ATF/CREB or Maf/Nrl families of proteins to transactivate gene expression under certain circumstances.242, 243, 244, 245 For instance, JunD can dimerize with ATF2 to transactivate cyclin A expression.178

Owing to the different AP-1 molecules formed by dimerization of the many AP-1 components as well as with other bZIP transcription factors, it has been difficult to clarify the precise role of individual AP-1 members in cell cycle progression. The most significant findings about AP-1 transcription factors on cell cycle regulation come from studies on Jun genes. In cycling cells, c-Jun protein levels remain high and they are activated by phosphorylation on the transactivating domain by kinases including ERKs (see below). In contrast, JunB protein levels remain low in cycling cells234 and are phosphorylated by the Cdk1/cyclin B kinase complexes during G2/M phase, which lead to JunB proteolysis.239

Fibroblast cells derived from c-Jun knockout mice display a severe proliferation defect, which was associated with low levels of cyclin D1 protein and Cdk4/6 activity.241 Moreover, fibroblasts carrying c-Jun alleles with S63 and S73 mutated to A also displayed a proliferation defect.246 On the contrary, fibroblasts that overexpressed JunB proteins had reduced proliferation because of an extended G1 phase and undergo premature senescence.237 Furthermore, hematopoietic cells derived from JunB knockout mice exhibited an increased proliferation rate.247 Similar to JunB, overexpressed JunD in fibroblast cells also inhibited proliferation.248

AP-1 sites have been identified in the promoter region of cyclin D1,239, 241 which suggests regulation of cyclin D1 by AP-1 transcription factors. It appears that c-Jun plays positive while JunB and JunD play negative regulatory roles on cell cycle progression.239, 240, 241 In normal fibroblast cells, c-Jun dimerizes with c-Fos and the c-Jun/c-Fos transcription factor then binds to the AP-1 site in the promoter of cyclin D1 to induce its expression.239, 240, 241, 324 JunB can compete with c-Fos to dimerize with c-Jun. JunB/c-Jun is an inactive AP-1 heterodimer in terms of its ability to transactivate cyclin D1. Cyclin D1 is therefore downregulated by the effects of JunB.239 Similar inhibitory effects of JunD on cyclin D1 expression were observed.239, 248, 249 c-Jun-deficient fibroblast cells also accumulated increased levels of p53, which led to an accumulation of p21Cip1 whose function has been associated with cell cycle arrest in fibroblast cells.240 These results suggest that c-Jun has an inhibitory effect on p53 expression, which was eliminated in c-Jun knockout cells. Furthermore, JunB is a positive transactivator for p16Ink4a gene transcription.237 JunB protein levels increased in primary fibroblast cells and they bound to the three AP-1 sites in the promoter region of the p16Ink4a gene to induce its transcription.

Regulation of c-Fos activity by Raf signaling is mainly at the transcriptional level through the activation of transcription factors Elk-1 and CREB. Elk-1 can be phosphorylated and activated by ERKs, while CREB can be phosphorylated and activated by RSKs. Phosphorylated Elk-1 binds to the SRE cis-acting element, while phosphorylated CREB binds to the CRE cis-acting element in the promoter of c-fos to induce its transcription.159, 229, 230

Regulation of c-Jun activity by Raf signaling occurs at both the transcriptional and post-translational levels. Cytokine induction of c-jun transcription is ERK-dependent.250, 251, 252 c-Fos, whose expression is also positively regulated by Raf signaling, can form heterodimers with c-Jun and bind the AP-1 site on the c-jun promoter region inducing its transcription.250 c-Jun activity is regulated by phosphorylation on the amino-terminal A1 transactivating domain and the carboxyl-terminal DNA-binding domain. Phosphorylation on the carboxyl-terminal domain at T231, S243 and S249 significantly reduces its DNA-binding ability and therefore inactivates c-Jun transactivation ability. On the other hand, phosphorylation at S63 and S73 in the A1 transactivation domain at the amino-terminal activates c-Jun. Protein kinases including glycogen synthase kinase 3beta (GSK-3beta) and CKII were shown to phosphorylate this domain to inactivate c-Jun activity.253, 254 Activation of c-Jun by phosphorylation of S63 and S73 by Jun N-terminal kinase (JNK) has been well documented.255, 256 Interestingly, the Raf signaling pathway also phosphorylates Jun at S63 and S73 in the transactivating domain, and also S243 in the carboxyl DNA-binding domain of c-Jun to regulate positively or negatively AP-1 activity.254, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261 ERK can directly phosphorylate these S residues.261, 262, 263, 264

Raf signaling and c-Myc

c-Myc is a transcription factor that regulates a distinct set of target genes whose functions are associated with cell proliferation or apoptosis.265, 266, 267, 268, 269, 270, 271 Deregulated expression of c-Myc is sufficient to drive continuous cell proliferation or apoptosis in response to growth-promoting or -inhibitory signals, respectively.265, 269 Moderate c-Myc expression modulates important proliferation-associated gene expression and leads to cell cycle progression.265, 268, 271 However, strong c-Myc expression induces apoptotic gene expression and leads to apoptosis.265, 268, 269

c-Myc induces cell proliferation by promoting an increase in cell mass as well as modulating the expression of genes that control cell cycle progression. Constitutive expression of a c-Myc transgene resulted in an increase in the size of B lymphocytes.270, 271, 272 This c-Myc-induced cell growth is independent of cell cycle phase and correlates with an increase in protein synthesis.271, 272 c-Myc also directly targets and modulates the expression of genes that regulate cell cycle progression, which include cyclin D1, cyclin D2, cyclin A, cyclin E, Cdk1, Cdk4, p15Ink4b, p21Cip1 and p27Kip1 (Table 1).273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285c-Myc heterodimerizes with Max and binds to the cis-acting E box element in the promoter of their target genes to transactivate its expression (Figure 14). However, c-Myc has also been shown to function as a transrepressor to inhibit transcription of specific genes.214, 286 by binding to the initiator (Inr)-like element, which is a consensus transcriptional initiation motif for transcription factor II-1 (TFII-1), found in certain promoter regions.269, 286, 287, 288 TFII-1 binds to the Inr element, and with additional transcription factors can either induce or repress gene expression. Binding of TFII-I with c-Myc in the Inr element prohibits additional binding of general factors and abolishes transcription.

Figure 14.
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Raf signaling-induced c-Myc activation. The Raf/MEK/ERK pathway can regulate c-Myc by phosphorylation of certain residues. ERK can phosphorylate c-Myc in the nucleus. Phosphorylated Myc forms heterodimers with MAX to regulate the transcription of c-Myc-responsive genes.

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c-Myc directly activates transcription of cyclin D1, cyclin D2 and Cdk4, and leads to Cdk 4/6 activation,273, 274, 280, 285 which is associated with cell cycle progression. c-Myc activation is also associated with increased cyclin E/Cdk 2 activity.289 This effect comes from two events. (1) Cyclin D induced by c-Myc can sequestrate the Cdk2 inhibitor p27Kip1 from the cyclin E/Cdk2 complex90, 290, 291, 292 to eliminate its inhibitory effect. (2) Cyclin E is a target gene of c-Myc, which also leads to Cdk2 activation.277

c-Myc also directly represses transcription of Cdk kinase inhibitors including p27Kip1, p21Cip1, p15Ink4b and p16Ink4a281, 282, 283, 284 in many cases. Activation of c-Myc is associated with the downregulation of p27Kip1285, 289, 293, 294 Recently, it was shown that c-Myc/Max can function as a transrepressor and reduce p27Kip1 transcription through the Inr element identified in the p27Kip1 promoter region.282 Binding with Max facilitates c-Myc's binding and represses p27Kip1 promoter activity through these sites.282 Downregulation of p27Kip1 induced by c-Myc also contributes to the activation of cyclin E/Cdk 2 since p27Kip1 can specifically target cyclin E/Cdk 2 and inhibit its activity.277 Furthermore, c-Myc activation can also promote the degradation of p27Kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase SCFSKP2.295, 296

p21Cip1 is another CKI, whose expression is controlled by c-Myc. Oligonucleotide microarray analysis revealed that p21Cip1 expression was repressed by c-Myc activation in primary human fibroblasts.285 Recently, it was shown that c-Myc can downregulate p21Cip1 by sequestering its transcriptional activator Sp1.281 TGF-beta could induce the cell cycle arrest at G1 phase in epithelial cells. This G1 arrest was accompanied by a downregulation of the proto-oncogene c-Myc and an upregulation of the Cdk inhibitor p15Ink4b. These two events were not independent and downregulation of c-Myc expression by TGF-beta is required for the activation of p15Ink4b, since ectopically overexpressed c-Myc abolished the p15Ink4 induction by TGF-beta.297 Further investigation revealed the negative regulatory role of c-Myc on p15Ink4b expression. c-Myc/Max dimers could complex with the Myc-associated transcriptional factor Miz-1 at the p15 initiator and inhibit transcription activation by Miz-1.283, 284

The ability of c-Myc to trigger actively apoptosis in response to apoptosis stimulation was first shown by Askew et al.298 They observed that G1 arrest induced by cytokine withdrawal in myeloid 32D cells was abolished in clones that harbor an exogenous copy of c-Myc and constitutively express high levels of c-Myc. These c-Myc clones rapidly and actively induced apoptosis upon cytokine withdrawal without going through a G1 arrest. This resulted from the simultaneous induction of G1 progression and apoptosis by high dosage of c-Myc. Similar results were observed in primary rodent embryo fibroblasts and established Rat1 fibroblast cells.299 It was therefore suggested that in addition to inducing cell proliferation, C-Myc could also induce apoptosis. c-Myc is essential for the apoptotic effects induced by diverse agents including TNF-alpha, taxol, etoposide, doxorubicin and C2-ceramide.300, 301, 302, 303 The apoptosis induced by c-Myc is a protective mechanism to control tumor development and has therefore attracted a lot of attention because of its possible therapeutic importance. Recently, it was shown that the c-Myc-mediated cell apoptosis is through its ability to stimulate the proapoptotic molecule Bax activity in the mitochondria, which leads to cytochrome-C release and eventually apoptosis in response to apoptosis-inducing agents.303 In a c-myc null fibroblast cell line, Bax is not activated and cytochrome-C is not released into the cytoplasm after treatment with the apoptosis-inducing agent taxol. However, when a C-myc gene was reintroduced into these cells, both phenotypes were restored and associated with cellular apoptosis.303 Other apoptosis-associated genes including p53,304, 305 and tumor necrosis factor receptor-associated protein-1 (TRAP1),285 are also c-Myc targets. c-Myc, when overexpressed in fibroblast cells, is an essential negative regulator of PDGFbeta-receptor expression.306 This may also account for the apoptosis induced by strong c-Myc activation.

The ability of c-Myc to modulate gene transcription is regulated by stoichiometry of the Myc, Max and Mad proteins, and the phosphorylation state of c-Myc.307 Eisenman and co-workers have proposed the Myc–Max–Mad network model to explain the regulation of c-Myc activity.308, 309 In this model, Max functions as the central molecule, which forms transactivating complexes when it dimerizes with c-Myc, or transrepressor complexes when it dimerizes with Mad or Mnt.308 Therefore, the levels of Myc–Max–Mad determine if the target genes are activated or repressed.

c-Myc can be phosphorylated on the central acidic domain and carboxyl-terminal domain by CK-II310, 311, 312, 313 and the amino-terminal transactivation domain by GSK-3beta, EGF receptor T-669 (ERT) protein kinase and ERK260, 314, 315, 316, 317 (Figure 14). The function of CK-II-induced phosphorylation of c-Myc is not clear but it is biologically important and may be involved in dimerization.312, 318, 319, 320 Two critical amino-acid residues in the amino-terminal transactivating domain, that is, T58 and S62, were identified to be phosphorylation targets for GSK-3beta,264, 315 ERT protein kinase260, 315, 316 and ERK.264, 315 Mutagenesis of T58 to A induced focus formation, whereas mutagenesis of S62 to A significantly inhibited cell transformation, and mutation of both residues restored wild-type activity.264, 315 It was therefore suggested that phosphorylation of S62 positively, while phosphorylation of T58 negatively, regulate c-Myc-mediated cell growth.264 Raf signaling has been shown to induce c-Myc activity in many cell types.169, 314, 321, 322

ERK can phosphorylate c-Myc on S62, which leads to increased c-Myc transactivation activity.260, 315, 316, 317 Phosphorylation of T58 by ERK was also observed.260 It was suggested that T58 phosphorylation facilitates rapid c-Myc proteolysis through the ubiquitin–proteosome pathway,309, 323 but phosphorylation on S62 significantly increases the c-Myc half-life.324 T58 phosphorylation is also essential for the sequestration of c-Myc by microtubulins.325 c-Myc binds with alpha-tubulin in the cytoplasm. This c-Myc–alpha-tubulin interaction prevents c-Myc from functioning as a transcription factor in the nucleus. In mitotic cells, this interaction is disrupted and c-Myc translocates to the nucleus to modulate gene expression. In the T58A mutant, c-Myc does not bind with alpha-tubulin and is a constitutively active transcription factor that induces cell proliferation.325 In summary, ERK phosphorylates c-Myc at S62 or T58 to regulate positively or negatively its transactivation activity. A summary of the growth-related targets of Raf-induced transcription factors is presented in Table 1.

Targeting the Ras/Raf/MEK/ERK pathway for therapeutic intervention

A goal of this review has been to introduce various sites, which have been targeted for therapeutic intervention. To this end, these therapeutic opportunities were mentioned when they were initially discussed, since we wanted the reader to be aware of these possibilities and to keep them in mind when they were reading the rest of the review. Some of these sites may be currently more attractive and significant than others. However, as this field matures, other sites, which may have initially appeared unattractive or impossible to target, may turn into key sites.

Mutations at three different Ras codons (12,13 and 61) convert the Ras protein into a constitutively active protein.93 These point mutations can be induced by environmental mutagens. Given the high level of mutations that have been detected at Ras, this pathway has always been considered a key target for therapeutic intervention. Ras mutations are frequently observed in certain hematopoietic malignancies including myelodysplastic syndromes.95 Ras mutations are often one step in tumor progression, and mutations at other genes (chromosomal translocations, gene amplification, tumor suppressor gene inactivation) have to occur for full-blown malignant phenotype to be manifested. Pharmaceutical companies have developed many FT inhibitors, which suppress the farnesylation of Ras, precluding it from localizing to the cell membrane. Some FT inhibitors were depicted earlier in Figure 3. Some of these FT inhibitors have shown great promise in clinical trials.348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375 A listing of clinical and scientific studies to evaluate the usefulness of small molecular inhibitors is presented in Table 2.348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545


There are three different Ras genes: Ki-Ras, Ha-Ras and N-Ras. The biochemical differences between these Ras proteins have remained elusive. Ki-Ras mutations have been more frequently detected in human neoplasia than Ha-Ras mutations.546 Ras has been shown to activate both the Raf/MEK/ERK and the PI3K/Akt pathways. Thus, mutations at Ras should theoretically activate both pathways simultaneously. Ras mutations have a key role in malignant transformation as both of these pathways can prevent apoptosis as well as regulate cell cycle progression. Recently, it was shown that there is specificity in terms of the ability of Ki-Ras and Ha-Ras to induce the Raf/MEK/ERK and PI3K/Akt pathways.31 Ki-Ras preferentially activates the Raf/MEK/ERK pathway while Ha-Ras preferentially activates the PI3K/Akt pathway.31 Therefore, if Ras inhibitors could be developed which would specifically inhibit one particular Ras protein, it might be possible to inhibit one of the downstream pathways. This might under certain circumstances be advantageous, as Raf has cell cycle inhibitory effects under certain conditions. Furthermore, decreases in ERK expression may affect differentiation responses. Thus in certain tumors, one might desire to inhibit the effects Ras has on the PI3K/Akt pathway as opposed to the effects Ras has on Raf. Targeting of Ha-Ras as opposed to Ki-Ras might inhibit apoptosis suppression by Ha-Ras, but not inhibit the effects Ki-Ras has on inhibition of cell cycle progression or differentiation. A diagram illustrating the interactions between the Raf/MEK/ERK and PI3K/Akt cascades and potential sites of inhibition by small molecular weight inhibitors is presented in Figure 15.

Figure 15.
Figure 15 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Interactions between Raf/MEK/ERK and PI3K/Akt pathways and potential sites for intervention. Regulatory signals are transduced to either or both Ki-Ras and Ha-Ras, which results in the activation of Raf or PI3K or both. Akt can regulate the activity of both Raf-1 and B-Raf. This can result in the inactivation of both of these kinases, which would suppress their effects on p53 and p21Cip1, and the induction of cell cycle arrest. In normal cells, cell proliferation is tightly balanced with apoptosis. Uncontrolled cell proliferation and prevention of apoptosis results in the breakdown of this balance. Some of the sites targeted by small molecular weight inhibitors are illustrated.

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Overexpression of the Raf/MEK/ERK cascade has been frequently observed in human neoplasia. A prime consequence of this activation may be the increased expression of growth factors, which can potentially further activate this cascade by an autocrine loop. Many cytokine and growth factor genes contain transcription-factor-binding sites, which are bound by transcription factors whose activity are often activated by the Raf/MEK/ERK cascade. Identification of the mechanisms responsible for the activation of this cascade has remained elusive. Genetic mutations at Raf, MEK or ERK were thought to be relatively rare in human neoplasia. For many years, it was felt that the activation of the Raf/MEK/ERK cascade was mainly because of mutations at Ras; however, this opinion has recently changed.

While mutations at the Raf gene in human neoplasia have been detected, they have not until recently gained the clinical importance that Ras mutations readily achieved. Owing to more innovative, high throughput DNA sequencing, scientists have recently discovered that the B-Raf gene is frequently mutated in certain cancers. Approximately 60% of the melanomas surveyed in one study were observed to have mutations at B-Raf.26 This result provides relevance to investigating signal transduction pathways as by understanding how B-Raf is activated, one Ras-dependent and one Ras-independent event, scientists could predict why a single missense mutation in B-Raf permitted ligand-independent activation, whereas similar mutation events would not be predicted to result in either Raf-1 or A-Raf activation because they required multiple activation events.

Raf inhibitors have been developed and some are being used in clinical trials.50, 51, 52, 53, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412. As stated previously Raf has at least 13 regulatory phosphorylation residues. Inhibition of Raf is a tricky affair as certain phosphorylation events stimulate Raf activity while others inhibit Raf activity and promote Raf association with 14-3-3 proteins, which render it inactive and present in the cytoplasm. Certain Raf inhibitors were developed, which inhibit the Raf kinase activity as determined by assays with purified Raf proteins and substrates (MEK). These inhibitors (eg L-779,450, ZM 336372, Bay 43-9006) bind the Raf kinase domain and therefore prevent its activity. Some Raf inhibitors may affect a single Raf isoform (eg Raf-1), others may affect Raf proteins, which are more similar (Raf-1 and A-Raf), while still other Raf inhibitors may affect all three Raf proteins (Raf-1, A-Raf and B-Raf). We have observed that the L-779,450 inhibitor suppresses the effects of A-Raf and Raf-1 more than the effects of B-Raf. Knowledge of the particular Raf gene mutated or overexpressed in certain tumors may provide critical information regarding how to treat the patient. Inhibition of certain Raf genes might prove beneficial while inhibition of other Raf genes under certain circumstances might prove detrimental. Thus, the development of unique and broad-spectrum Raf inhibitors may prove useful in human cancer therapy.

As stated previously, prevention of Raf activation by targeting kinases (eg Src, PKC, PKA, PAK or Akt) and phosphatases (eg PP2A) involved in Raf activation may be a mechanism to inhibit/regulate Raf activity. It is worth noting that some of these kinases normally inhibit Raf activation (Akt, PKA). A major limitation of this approach would be that these kinases and phosphatases could result in the activation or inactivation of other proteins and would have other effects on cell physiology.413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464

Dimerization of Raf proteins is critical for their activity. We often think of a single Raf protein carrying out its biochemical activity. However, different Raf isoforms dimerize with itself and other Raf isoforms to become active. Drugs such as coumermycin, which inhibit Raf dimerization, and others such as geldanmycin, which prevent interaction of Raf with 14-3-3 proteins, suppress Raf activity. Various Raf isoforms may dimerize and result in chimeric molecules, which may have different biochemical activities. Little is known about the prevention of heterodimerization of Raf proteins. Moreover Raf interacts with chaperonin proteins. Drugs such as geldanamycin that block protein:protein interactions, strongly inhibit Raf activation.50, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412

Downstream of Raf lies MEK. Currently, it is believed that MEK1 is not frequently mutated in human cancer. However, aberrant expression of MEK1 has been detected in many different types of cancer, and mutated forms of MEK1 will transform fibroblast, hematopoietic and other cell types. Useful inhibitors to MEK have been developed that display high degrees of specificity.465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485 The successful development of MEK inhibitors may be because of the relatively few phosphorylation sites on MEK involved in activation/inactivation. MEK inhibitors are in clinical trials.

Downstream of MEK lies ERK. To our knowledge no small molecular weight ERK inhibitors have been developed yet: however, inhibitors to ERK could prove very useful as ERK can phosphorylate many targets (Rsk, c-Myc, Elk, etc.), which have growth-promoting effects. There are at least two ERK molecules regulated by the Raf/MEK/ERK cascade, ERK1 and ERK2. Little is known about the different in vivo targets of ERK1 and ERK2. However, ERK2 has been postulated to have proproliferative effects while ERK1 has antiproliferative effects.92, 548, 549, 550 Development of specific inhibitors to ERK1 and ERK2 might eventually prove useful in the treatment of certain diseases. The MAP kinase phosphatase-1 (MKP-1) removes the phosphates from ERK. MKP-1 is mutated in certain tumors and could be considered a tumor suppressor gene.92, 551, 552, 553, 554, 555, 556 An inhibitor to this phosphatase has been developed (Ro-31-8220).

Phosphatases and small molecular weight inhibitors aside, a number of other novel strategies exist for purposes of inhibiting the kinases responsible for signaling through the Raf/MEK/ERK pathway. For example, dominant-negative (DN) inhibitors function in such a manner that they inhibit the catalytic function of the endogenous protein of the same variety. For example, DN Ras inhibitors have been generated to inhibit endogenous Ras activity by blocking its ability to hydrolyze GTP or by sequestering Ras away from the membrane where it initiates signaling.557, 558 Antisense RNAs are yet another tool that is currently under exploration for the inhibition of kinase signaling. These oligonucleotides are synthesized so that their nucleotide sequence is complementary to the mRNAs of the target kinase. Consequently, the endogenous mRNAs are unable to be translated into functional protein, thereby affecting the overall kinetics of signals transduced by that kinase. Retroviral and plasmid vectors, as well as liposomal-based synthetic antisense oligonucleotides, are methods that are currently being explored effectively to utilize this avenue of inhibition.559, 560 The primary limitation of this therapeutic strategy has been the inability to deliver specifically these molecules to tumor cells in the clinic; however, because of the tremendous potential of such therapies, a number of pharmaceutical firms are extensively developing more effective means of administration. Furthermore, RNA interference (RNAi) is an extension of this antisense technology. RNAi employs the use of double-stranded RNA molecules that target cognate mRNAs for purposes of inhibition.560 Augmenting the argument for the use of RNAi in cancer therapy are a number of recent manuscripts outlining the effectiveness of such endeavors.562, 563 Lastly, aptamers are nucleic acids that are generated for purposes of binding to and inhibiting the function of specific kinases. Over several rounds of selective processing, minor nucleotide modifications are made and subsequent selection for a specific molecule leads to the generation of a high-affinity aptamer. This unique technology has generated inhibitory molecules against ERK2, a kinase responsible for many of the signaling events described in this review.564 It is important to note that the strategies outlined in this paragraph are in various stages of early development; given this, it is imperative that these potential therapies are further developed for effective translation into clinical settings.

Although the Raf/MEK/ERK pathway is a major effector of Ras's biological effects, Ras also elicits cellular responses via Raf-independent signaling pathways. The Rho family of small GTPases mediate some of the Raf-independent effects of Ras.565 DN inhibitors of Rho have been shown in some instances to prevent Ras-induced transformation.566 The Rho family of GTPases is proposed to have a role in cytoskeleton regulation and consists of Rho, Rac and cdc42.567 Rac has been shown to induce the activation of Rho; and Rho activation has been shown to lead to the activation of the JNK pathway.568 Rac resides downstream of cdc42; however, Ras activation has also been shown to lead to Rac activation independent of cdc42.565 The mechanism by which Ras activates Rac has been proposed to occur via the ability of Ras to activate PI3K,565, 568, 569 but may also occur via the convergence of the Ras and PI3K pathways.564

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Summary

This review has concentrated on the mechanisms by which the Raf/MEK/ERK cascade is activated and how this pathway transmits its signals from membrane receptors to transcription factors, which regulate gene transcription. Owing to advances in the past decade, we have a better understanding of how signals are transmitted from cytokines to their receptors and the downstream Raf/MEK/ERK cascade by phosphorylation/dephosphorylation. This knowledge has permitted the isolation and development of specific inhibitors, which may prevent these phosphorylation/dephosphorylation events. Furthermore, it is now realized that the subcellular location of a protein is important in terms of the proteins activity/inactivity. The Ras proteins, whose activity are regulated by farnesylation, document this as inhibition of farnesylation prevents Ras translocation to the membrane and activity. Active Ras can bind Raf proteins and result in their translocation to the cellular membrane. By inhibiting Ras farnesylation, activation of the Raf/MEK/ERK pathway is suppressed. Furthermore, the different Raf proteins may have different subcellular localization patterns, which alter their activities. The prospects of inhibiting certain components of this pathway by DN genes are very attractive and may be easier in certain types of tumors than others. However, a key problem will be the successful delivery of the DN gene to the tumor cell. An area that is still in its infancy is the inhibition of transcription factors, which are induced by the Raf/MEK/ERK and other signal transduction cascades. As more information about these pathways and how they are regulated becomes available, it may be possible to develop better methods to inhibit them and understand why certain drugs may work while others may fail. Our scientific quest should never end, as and when we think we have a specific inhibitor, we may learn that the cell has developed mechanisms by which it can become resistant to that inhibitor. A prime example is the drug Gleevec (Imatinib). While this drug shows great promise in the treatment of chronic myelogenous leukemia, clinicians have documented resistance to this drug in certain patients. Thus, additional research to combat resistance to this and additional drugs must be performed for us to be ultimately successful in combating leukemia.

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Acknowledgements

This work has been supported in part by grants from the NIH (RO1CA51025) and NIH (R01CA98195) to JAM.