Abstract
The Ras-dependent extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein (MAP) kinase pathway plays a central role in cell proliferation control. In normal cells, sustained activation of ERK1/ERK2 is necessary for G1- to S-phase progression and is associated with induction of positive regulators of the cell cycle and inactivation of antiproliferative genes. In cells expressing activated Ras or Raf mutants, hyperactivation of the ERK1/2 pathway elicits cell cycle arrest by inducing the accumulation of cyclin-dependent kinase inhibitors. In this review, we discuss the mechanisms by which activated ERK1/ERK2 regulate growth and cell cycle progression of mammalian somatic cells. We also highlight the findings obtained from gene disruption studies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Abbott DW, Holt JT . (1999). Mitogen-activated protein kinase kinase 2 activation is essential for progression through the G2/M checkpoint arrest in cells exposed to ionizing radiation. J Biol Chem 274: 2732–2742.
Adhikary S, Eilers M . (2005). Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol 6: 635–645.
Albanese C, Jonhson J, Watanabe G, Eklund N, Vu D, Arnold A et al. (1995). Transforming p21ras mutants and 2c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J Biol Chem 270: 23589–23597.
Ang XL, Harper JW . (2004). Interwoven ubiquitination oscillators and control of cell cycle transitions. Sci STKE 2004: pe31.
Arabi A, Wu S, Ridderstrale K, Bierhoff H, Shiue C, Fatyol K et al. (2005). c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription. Nat Cell Biol 7: 303–310.
Arber N, Sutter T, Miyake M, Kahn SM, Venkatraj VS, Sobrino A et al. (1996). Increased expression of cyclin D1 and the Rb tumor suppressor gene in c-K-ras transformed rat enterocytes. Oncogene 12: 1903–1908.
Bagui TK, Mohapatra S, Haura E, Pledger WJ . (2003). p27Kip1 and p21Cip1 are not required for the formation of active D cyclin-cdk4 complexes. Mol Cell Biol 23: 7285–7290.
Balmanno K, Cook SJ . (1999). Sustained MAP kinase activation is required for the expression of cyclin D1, p21Cip1 and a subset of AP-1 proteins in CCL39 cells. Oncogene 18: 3085–3097.
Bottazzi ME, Zhu X, Bohmer RM, Assoian RK . (1999). Regulation of p21(cip1) expression by growth factors and the extracellular matrix reveals a role for transient ERK activity in G1 phase. J Cell Biol 146: 1255–1264.
Bouchard C, Thieke K, Maier A, Saffrich R, Hanley-Hyde J, Ansorge W et al. (1999). Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27. EMBO J 18: 5321–5333.
Boucher MJ, Jean D, Vezina A, Rivard N . (2004). Dual role of MEK/ERK signaling in senescence and transformation of intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 286: G736–G746.
Bourcier C, Jacquel A, Hess J, Peyrottes I, Angel P, Hofman P et al. (2006). p44 mitogen-activated protein kinase (extracellular signal-regulated kinase 1)-dependent signaling contributes to epithelial skin carcinogenesis. Cancer Res 66: 2700–2707.
Bracken AP, Ciro M, Cocito A, Helin K . (2004). E2F target genes: unraveling the biology. Trends Biochem Sci 29: 409–417.
Brondello JM, McKenzie FR, Sun H, Tonks NK, Pouysségur J . (1995). Constitutive MAP kinase phosphatase (MKP-1) expression blocks G1 specific gene transcription and S-phase entry in fibroblasts. Oncogene 10: 1895–1904.
Brunet A, Pagès G, Pouysségur J . (1994). Constitutively active mutants of MAP kinase kinase (MEK1) induce growth factor-relaxation and oncogenicity when expressed in fibroblasts. Oncogene 9: 3379–3387.
Cardozo T, Pagano M . (2004). The SCF ubiquitin ligase: insights into a molecular machine. Nat Rev Mol Cell Biol 5: 739–751.
Carrano AC, Eytan E, Hershko A, Pagano M . (1999). SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1: 193–199.
Cha H, Hancock C, Dangi S, Maiguel D, Carrier F, Shapiro P . (2004). Phosphorylation regulates nucleophosmin targeting to the centrosome during mitosis as detected by cross-reactive phosphorylation-specific MKK1/MKK2 antibodies. Biochem J 378: 857–865.
Chen D, Heath V, O'Garra A, Johnston J, McMahon M . (1999). Sustained activation of the raf-MEK-ERK pathway elicits cytokine unresponsiveness in T cells. J Immunol 163: 5796–5805.
Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM et al. (1999). The p21(Cip1) and p27(Kip1) CDK ’inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J 18: 1571–1583.
Cheng M, Sexl V, Sherr CJ, Roussel MF . (1998). Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1). Proc Natl Acad Sci USA 95: 1091–1096.
Claassen GF, Hann SR . (2000). A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor beta -induced cell-cycle arrest. Proc Natl Acad Sci USA 97: 9498–9503.
Cobrinik D . (2005). Pocket proteins and cell cycle control. Oncogene 24: 2796–2809.
Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M et al. (2005). Tumour biology: senescence in premalignant tumours. Nature 436: 642.
Coller HA, Grandori C, Tamayo P, Colbert T, Lander ES, Eisenman RN et al. (2000). Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc Natl Acad Sci USA 97: 3260–3265.
Conlon I, Raff M . (1999). Size control in animal development. Cell 96: 235–244.
Cook SJ, Aziz N, McMahon M . (1999). The repertoire of fos and jun proteins expressed during the G1 phase of the cell cycle is determined by the duration of mitogen-activated protein kinase activation. Mol Cell Biol 19: 330–341.
Cook SJ, McCormick F . (1996). Kinetic and biochemical correlation between sustained p44ERK1 (44 kDa extracellular signal-regulated kinase 1) activation and lysophosphatidic acid-stimulated DNA synthesis in Rat-1 cells. Biochem J 320 (Part 1): 237–245.
Cooper JA, Sefton BM, Hunter T . (1984). Diverse mitogenic agents induce the phosphorylation of two related 42, 000-dalton proteins on tyrosine in quiescent chick cells. Mol Cell Biol 4: 30–37.
Corradetti MN, Guan KL . (2006). Upstream of the mammalian target of rapamycin: do all roads pass through mTOR? Oncogene 25: 6347–6360.
Cowley S, Paterson H, Kemp P, Marshall CJ . (1994). Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77: 841–852.
Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KL . (2005). eIF4E promotes nuclear export of cyclin D1 mRNAs via an element in the 3′UTR. J Cell Biol 169: 245–256.
Delmas C, Manenti S, Boudjelal A, Peyssonnaux C, Eychene A, Darbon JM . (2001). The p42/p44 mitogen-activated protein kinase activation triggers p27Kip1 degradation independently of CDK2/cyclin E in NIH 3T3 cells. J Biol Chem 276: 34958–34965.
DeSilva DR, Jones EA, Favata MF, Jaffee BD, Magolda RL, Trzaskos JM et al. (1998). Inhibition of mitogen-activated protein kinase kinase blocks T cell proliferation but does not induce or prevent anergy. J Immunol 160: 4175–4181.
Dever TE . (2002). Gene-specific regulation by general translation factors. Cell 108: 545–556.
Dey A, She H, Kim L, Boruch A, Guris DL, Carlberg K et al. (2000). Colony-stimulating factor-1 receptor utilizes multiple signaling pathways to induce cyclin D2 expression. Mol Biol Cell 11: 3835–3848.
Diehl JA, Yang W, Rimerman RA, Xiao H, Emili A . (2003). Hsc70 regulates accumulation of cyclin D1 and cyclin D1-dependent protein kinase. Mol Cell Biol 23: 1764–1774.
Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR . (1995). A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA 92: 7686–7689.
Ebisuya M, Kondoh K, Nishida E . (2005). The duration, magnitude and compartmentalization of ERK MAP kinase activity: mechanisms for providing signaling specificity. J Cell Sci 118: 2997–3002.
Edelmann HM, Kuhne C, Petritsch C, Ballou LM . (1996). Cell cycle regulation of p70 S6 kinase and p42/p44 mitogen-activated protein kinases in Swiss mouse 3T3 fibroblasts. J Biol Chem 271: 963–971.
Evans DR, Guy HI . (2004). Mammalian pyrimidine biosynthesis: fresh insights into an ancient pathway. J Biol Chem 279: 33035–33038.
Fanton CP, McMahon M, Pieper RO . (2001). Dual growth arrest pathways in astrocytes and astrocytic tumors in response to Raf-1 activation. J Biol Chem 276: 18871–18877.
Filmus J, Robles AI, Shi W, Wong MJ, Colombo LL, Conti CJ . (1994). Induction of cyclin D1 overexpression by activated ras. Oncogene 9: 3627–3633.
Fingar DC, Blenis J . (2004). Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 23: 3151–3171.
Fischer AM, Katayama CD, Pages G, Pouyssegur J, Hedrick SM . (2005). The role of erk1 and erk2 in multiple stages of T cell development. Immunity 23: 431–443.
Flynn A, Proud CG . (1996). Insulin and phorbol ester stimulate initiation factor eIF-4E phosphorylation by distinct pathways in Chinese hamster ovary cells overexpressing the insulin receptor. Eur J Biochem 236: 40–47.
Fukunaga R, Hunter T . (1997). MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J 16: 1921–1933.
Galaktionov K, Chen X, Beach D . (1996). Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 382: 511–517.
Ganoth D, Bornstein G, Ko TK, Larsen B, Tyers M, Pagano M et al. (2001). The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)- mediated ubiquitinylation of p27. Nat Cell Biol 3: 321–324.
Geng Y, Yu Q, Sicinska E, Das M, Bronson RT, Sicinski P . (2001). Deletion of the p27Kip1 gene restores normal development in cyclin D1-deficient mice. Proc Natl Acad Sci USA 98: 194–199.
Gomez-Cambronero J . (1999). p42-MAP kinase is activated in EGF-stimulated interphase but not in metaphase-arrested HeLa cells. FEBS Lett 443: 126–130.
Gotoh I, Fukuda M, Adachi M, Nishida E . (1999). Control of the cell morphology and the S phase entry by mitogen- activated protein kinase kinase. A regulatory role of its n-terminal region. J Biol Chem 274: 11874–11880.
Grandori C, Gomez-Roman N, Felton-Edkins ZA, Ngouenet C, Galloway DA, Eisenman RN et al. (2005). c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat Cell Biol 7: 311–318.
Graves LM, Guy HI, Kozlowski P, Huang M, Lazarowski E, Pope RM et al. (2000). Regulation of carbamoyl phosphate synthetase by MAP kinase. Nature 403: 328–332.
Greulich H, Erikson RL . (1998). An analysis of Mek1 signaling in cell proliferation and transformation. J Biol Chem 273: 13280–13288.
Gysin S, Lee SH, Dean NM, McMahon M . (2005). Pharmacologic inhibition of RAFMEKERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. Cancer Res 65: 4870–4880.
Han J, Tsukada Y, Hara E, Kitamura N, Tanaka T . (2005). Hepatocyte growth factor induces redistribution of p21(CIP1) and p27(KIP1) through ERK-dependent p16(INK4a) up-regulation, leading to cell cycle arrest at G1 in HepG2 hepatoma cells. J Biol Chem 280: 31548–31556.
Harbour JW, Dean DC . (2000). The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev 14: 2393–2409.
Harding A, Giles N, Burgess A, Hancock JF, Gabrielli BG . (2003). Mechanism of mitosis-specific activation of MEK1. J Biol Chem 278: 16747–16754.
Hatano N, Mori Y, Oh-hora M, Kosugi A, Fujikawa T, Nakai N et al. (2003). Essential role for ERK2 mitogen-activated protein kinase in placental development. Genes Cells 8: 847–856.
Hay N, Sonenberg N . (2004). Upstream and downstream of mTOR. Genes Dev 18: 1926–1945.
Hayne C, Tzivion G, Luo Z . (2000). Raf-1/MEK/MAPK pathway is necessary for the G2/M transition induced by nocodazole. J Biol Chem 275: 31876–31882.
Hayne C, Xiang X, Luo Z . (2004). MEK inhibition and phosphorylation of serine 4 on B23 are two coincident events in mitosis. Biochem Biophys Res Commun 321: 675–680.
Herber B, Truss M, Beato M, Muller R . (1994). Inducible regulatory elements in the human cyclin D1 promoter. Oncogene 9: 2105–2107.
Hermeking H, Rago C, Schuhmacher M, Li Q, Barrett JF, Obaya AJ et al. (2000). Identification of CDK4 as a target of c-MYC. Proc Natl Acad Sci USA 97: 2229–2234.
Hill CS, Treisman R . (1995). Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell 80: 199–211.
Hsu JY, Reimann JD, Sorensen CS, Lukas J, Jackson PK . (2002). E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1). Nat Cell Biol 4: 358–366.
Jones SM, Kazlauskas A . (2001). Growth-factor-dependent mitogenesis requires two distinct phases of signalling. Nat Cell Biol 3: 165–172.
Jorgensen P, Tyers M . (2004). How cells coordinate growth and division. Curr Biol 14: R1014–R1027.
Kahan C, Seuwen K, Meloche S, Pouyssegur J . (1992). Coordinate, biphasic activation of p44 mitogen-activated protein kinase and S6 kinase by growth factors in hamster fibroblasts. Evidence for thrombin-induced signals different from phosphoinositide turnover and adenylylcyclase inhibition. J Biol Chem 267: 13369–13375.
Karpova AY, Abe MK, Li J, Liu PT, Rhee JM, Kuo WL et al. (1997). MEK1 is required for PDGF-induced ERK activation and DNA synthesis in tracheal myocytes. Am J Physiol 272: L558–L565.
Kawada M, Yamagoe S, Murakami Y, Suzuki K, Mizuno S, Uehara Y . (1997). Induction of p27Kip1 degradation and anchorage independence by Ras through the MAP kinase signaling pathway. Oncogene 15: 629–637.
Kerkhoff E, Rapp UR . (1997). Induction of cell proliferation in quiescent NIH 3T3 cells by oncogenic c-Raf-1. Mol Cell Biol 17: 2576–2586.
Kerkhoff E, Rapp UR . (1998). High-intensity Raf signals convert mitotic cell cycling into cellular growth. Cancer Res 58: 1636–1640.
Knauf JA, Ouyang B, Knudsen ES, Fukasawa K, Babcock G, Fagin JA . (2006). Oncogenic RAS induces accelerated transition through G2/M and promotes defects in the G2 DNA damage and mitotic spindle checkpoints. J Biol Chem 281: 3800–3809.
Kohno M . (1985). Diverse mitogenic agents induce rapid phosphorylation of a common set of cellular proteins at tyrosine in quiescent mammalian cells. J Biol Chem 260: 1771–1779.
Kohno M, Pouyssegur J . (1986). Alpha-thrombin-induced tyrosine phosphorylation of 43,000- and 41,000-Mr proteins is independent of cytoplasmic alkalinization in quiescent fibroblasts. Biochem J 238: 451–457.
LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS et al. (1997). New functional activities for the p21 family of CDK inhibitors. Genes Dev 11: 847–862.
Ladha MH, Lee KY, Upton TM, Reed MF, Ewen ME . (1998). Regulation of exit from quiescence by p27 and cyclin D1-CDK4. Mol Cell Biol 18: 6605–6615.
Lai HK, Borden KL . (2000). The promyelocytic leukemia (PML) protein suppresses cyclin D1 protein production by altering the nuclear cytoplasmic distribution of cyclin D1 mRNA. Oncogene 19: 1623–1634.
Lavoie JN, L'Allemain G, Brunet A, Muller R, Pouyssegur J . (1996). Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem 271: 20608–20616.
Lenferink AE, Simpson JF, Shawver LK, Coffey RJ, Forbes JT, Arteaga CL . (2000). Blockade of the epidermal growth factor receptor tyrosine kinase suppresses tumorigenesis in MMTV/Neu + MMTV/TGF-alpha bigenic mice. Proc Natl Acad Sci USA 97: 9609–9614.
Lewis TS, Shapiro PS, Ahn NG . (1998). Signal transduction through MAP kinase cascades. Adv Cancer Res 74: 49–139.
Li Y, Jenkins CW, Nichols MA, Xiong Y . (1994). Cell cycle expression and p53 regulation of the cyclin-dependent kinase inhibitor p21. Oncogene 9: 2261–2268.
Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW . (1998). Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev 12: 3008–3019.
Lips DJ, Bueno OF, Wilkins BJ, Purcell NH, Kaiser RA, Lorenz JN et al. (2004). MEK1–ERK2 signaling pathway protects myocardium from ischemic injury in vivo. Circulation 109: 1938–1941.
Liu JJ, Chao JR, Jiang MC, Ng SY, Yen JJ, Yang-Yen HF . (1995). Ras transformation results in an elevated level of cyclin D1 and acceleration of G1 progression in NIH 3T3 cells. Mol Cell Biol 15: 3654–3663.
Liu X, Yan S, Zhou T, Terada Y, Erikson RL . (2004). The MAP kinase pathway is required for entry into mitosis and cell survival. Oncogene 23: 763–776.
Liu Y, Martindale JL, Gorospe M, Holbrook NJ . (1996). Regulation of p21WAF1/CIP1 expression through mitogen-activated protein kinase signaling pathway. Cancer Res 56: 31–35.
Lloyd AC . (1998). Ras versus cyclin-dependent kinase inhibitors. Curr Opin Genet Dev 8: 43–48.
Lloyd AC, Obermuller F, Staddon S, Barth CF, McMahon M, Land H . (1997). Cooperating oncogenes converge to regulate cyclin/cdk complexes. Genes Dev 11: 663–677.
Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP . (2005). Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121: 179–193.
Macleod KF, Sherry N, Hannon G, Beach D, Tokino T, Kinzler K et al. (1995). p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. Genes Dev 9: 935–944.
Maekawa M, Nishida E, Tanoue T . (2002). Identification of the anti-proliferative protein Tob as a MAPK substrate. J Biol Chem 277: 37783–37787.
Malumbres M, Barbacid M . (2001). To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1: 222–231.
Malumbres M, Perez De Castro I, Hernandez MI, Jimenez M, Corral T, Pellicer A . (2000). Cellular response to oncogenic ras involves induction of the Cdk4 and Cdk6 inhibitor p15(INK4b). Mol Cell Biol 20: 2915–2925.
Mamane Y, Petroulakis E, Rong L, Yoshida K, Ler LW, Sonenberg N . (2004). eIF4E – from translation to transformation. Oncogene 23: 3172–3179.
Manning BD, Cantley LC . (2003). Rheb fills a GAP between TSC and TOR. Trends Biochem Sci 28: 573–576.
Mayer C, Grummt I . (2006). Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene 25: 6384–6391.
Meloche S . (1995). Cell cycle reentry of mammalian fibroblasts is accompanied by the sustained activation of p44mapk and p42mapk isoforms in the G1 phase and their inactivation at the G1/S transition. J Cell Physiol 163: 577–588.
Meloche S, Seuwen K, Pages G, Pouyssegur J . (1992). Biphasic and synergistic activation of p44mapk (ERK1) by growth factors: correlation between late phase activation and mitogenicity. Mol Endocrinol 6: 845–854.
Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM et al. (2005). BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436: 720–724.
Michieli P, Chedid M, Lin D, Pierce JH, Mercer WE, Givol D . (1994). Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res 54: 3391–3395.
Mirza AM, Gysin S, Malek N, Nakayama K, Roberts JM, McMahon M . (2004). Cooperative regulation of the cell division cycle by the protein kinases RAF and AKT. Mol Cell Biol 24: 10868–10881.
Morgan DO . (2007). The Cell Cycle: Principles of Control. New Science Press Ltd: London, UK.
Morley SJ, McKendrick L . (1997). Involvement of stress-activated protein kinase and p38/RK mitogen-activated protein kinase signaling pathways in the enhanced phosphorylation of initiation factor 4E in NIH 3T3 cells. J Biol Chem 272: 17887–17893.
Murphy LO, MacKeigan JP, Blenis J . (2004). A network of immediate early gene products propagates subtle differences in mitogen-activated protein kinase signal amplitude and duration. Mol Cell Biol 24: 144–153.
Murphy LO, Smith S, Chen RH, Fingar DC, Blenis J . (2002). Molecular interpretation of ERK signal duration by immediate early gene products. Nat Cell Biol 4: 556–564.
Nakamura KD, Martinez R, Weber MJ . (1983). Tyrosine phosphorylation of specific proteins after mitogen stimulation of chicken embryo fibroblasts. Mol Cell Biol 3: 380–390.
Nakayama K, Nakayama K . (1998). Cip/Kip cyclin-dependent kinase inhibitors: brakes of the cell cycle engine during development. BioEssays 20: 1020–1029.
Noda A, Ning Y, Venable SF, Pereira-Smith OM, Smith JR . (1994). Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 211: 90–98.
Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V et al. (1995). Role of the ubiquitin–proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269: 682–685.
Pages G, Guerin S, Grall D, Bonino F, Smith A, Anjuere F et al. (1999). Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science 286: 1374–1377.
Pages G, Lenormand P, L'Allemain G, Chambard JC, Meloche S, Pouyssegur J . (1993). Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc Natl Acad Sci USA 90: 8319–8323.
Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K et al. (2001). Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22: 153–183.
Pelengaris S, Khan M, Evan G . (2002). c-MYC: more than just a matter of life and death. Nat Rev Cancer 2: 764–776.
Peters JM . (2002). The anaphase-promoting complex: proteolysis in mitosis and beyond. Mol Cell 9: 931–943.
Piatelli MJ, Doughty C, Chiles TC . (2002). Requirement for a hsp90 chaperone-dependent MEK1/2–ERK pathway for B cell antigen receptor-induced cyclin D2 expression in mature B lymphocytes. J Biol Chem 277: 12144–12150.
Ptacek J, Devgan G, Michaud G, Zhu H, Zhu X, Fasolo J et al. (2005). Global analysis of protein phosphorylation in yeast. Nature 438: 679–684.
Pumiglia KM, Decker SJ . (1997). Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway. Proc Natl Acad Sci USA 94: 448–452.
Ravi RK, Weber E, McMahon M, Williams JR, Baylin S, Mal A et al. (1998). Activated Raf-1 causes growth arrest in human small cell lung cancer cells. J Clin Invest 101: 153–159.
Rivard N, Boucher MJ, Asselin C, L'Allemain G . (1999). MAP kinase cascade is required for p27 downregulation and S phase entry in fibroblasts and epithelial cells. Am J Physiol 277: C652–C664.
Roberts EC, Shapiro PS, Nahreini TS, Pages G, Pouyssegur J, Ahn NG . (2002). Distinct cell cycle timing requirements for extracellular signal-regulated kinase and phosphoinositide 3-kinase signaling pathways in somatic cell mitosis. Mol Cell Biol 22: 7226–7241.
Roovers K, Assoian RK . (2000). Integrating the MAP kinase signal into the G1 phase cell cycle machinery. BioEssays 22: 818–826.
Roovers K, Davey G, Zhu X, Bottazzi ME, Assoian RK . (1999). Alpha5beta1 integrin controls cyclin D1 expression by sustaining mitogen-activated protein kinase activity in growth factor-treated cells. Mol Biol Cell 10: 3197–3204.
Roper E, Weinberg W, Watt FM, Land H . (2001). p19ARF-independent induction of p53 and cell cycle arrest by Raf in murine keratinocytes. EMBO Rep 2: 145–150.
Rosenwald IB, Kaspar R, Rousseau D, Gehrke L, Leboulch P, Chen JJ et al. (1995). Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. J Biol Chem 270: 21176–21180.
Rossant J, Cross JC . (2001). Placental development: lessons from mouse mutants. Nat Rev Genet 2: 538–548.
Rossomando AJ, Payne DM, Weber MJ, Sturgill TW . (1989). Evidence that pp42, a major tyrosine kinase target protein, is a mitogen-activated serine/threonine protein kinase. Proc Natl Acad Sci USA 86: 6940–6943.
Rossomando AJ, Sanghera JS, Marsden LA, Weber MJ, Pelech SL, Sturgill TW . (1991). Biochemical characterization of a family of serine/threonine protein kinases regulated by tyrosine and serine/threonine phosphorylations. J Biol Chem 266: 20270–20275.
Rousseau D, Kaspar R, Rosenwald I, Gehrke L, Sonenberg N . (1996). Translation initiation of ornithine decarboxylase and nucleocytoplasmic transport of cyclin D1 mRNA are increased in cells overexpressing eukaryotic initiation factor 4E. Proc Natl Acad Sci USA 93: 1065–1070.
Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J . (2004). Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci USA 101: 13489–13494.
Saba-El-Leil MK, Vella FD, Vernay B, Voisin L, Chen L, Labrecque N et al. (2003). An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development. EMBO Rep 4: 964–968.
Sakakibara K, Kubota K, Worku B, Ryer EJ, Miller JP, Koff A et al. (2005). PDGF-BB regulates p27 expression through ERK-dependent RNA turn-over in vascular smooth muscle cells. J Biol Chem 280: 25470–25477.
Sale EM, Atkinson PG, Sale GJ . (1995). Requirement of MAP kinase for differentiation of fibroblasts to adipocytes, for insulin activation of p90 S6 kinase and for insulin or serum stimulation of DNA synthesis. EMBO J 14: 674–684.
Scheper GC, Proud CG . (2002). Does phosphorylation of the cap-binding protein eIF4E play a role in translation initiation? Eur J Biochem 269: 5350–5359.
Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR . (2000). Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 14: 2501–2514.
Sebolt-Leopold JS, Dudley DT, Herrera R, Van Becelaere K, Wiland A, Gowan RC et al. (1999). Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 5: 810–816.
Sebolt-Leopold JS, Herrera R . (2004). Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4: 937–947.
Seger R, Seger D, Reszka AA, Munar ES, Eldar-Finkelman H, Dobrowolska G et al. (1994). Overexpression of mitogen-activated protein kinase kinase (MAPKK) and its mutants in NIH 3T3 cells. Evidence that MAPKK involvement in cellular proliferation is regulated by phosphorylation of serine residues in its kinase subdomains VII and VIII. J Biol Chem 269: 25699–25709.
Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW . (1997). Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88: 593–602.
Servant MJ, Giasson E, Meloche S . (1996). Inhibition of growth factor-induced protein synthesis by a selective MEK inhibitor in aortic smooth muscle cells. J Biol Chem 271: 16047–16052.
Seufferlein T, Withers DJ, Rozengurt E . (1996). Reduced requirement of mitogen-activated protein kinase (MAPK) activity for entry into the S phase of the cell cycle in Swiss 3T3 fibroblasts stimulated by bombesin and insulin. J Biol Chem 271: 21471–21477.
Sewing A, Wiseman B, Lloyd AC, Land H . (1997). High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol Cell Biol 17: 5588–5597.
Shapiro PS, Vaisberg E, Hunt AJ, Tolwinski NS, Whalen AM, McIntosh JR et al. (1998). Activation of the MKK/ERK pathway during somatic cell mitosis: direct interactions of active ERK with kinetochores and regulation of the mitotic 3F3/2 phosphoantigen. J Cell Biol 142: 1533–1545.
Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE . (1997). Cyclin E–CDK2 is a regulator of p27Kip1. Genes Dev 11: 1464–1478.
Sheikh MS, Li XS, Chen JC, Shao ZM, Ordonez JV, Fontana JA . (1994). Mechanisms of regulation of WAF1/Cip1 gene expression in human breast carcinoma: role of p53-dependent and independent signal transduction pathways. Oncogene 9: 3407–3415.
Sherr CJ . (2000). The Pezcoller lecture: cancer cell cycles revisited. Cancer Res 60: 3689–3695.
Shinohara M, Mikhailov AV, Aguirre-Ghiso JA, Rieder CL . (2006). Extracellular signal-regulated kinase 1/2 Activity is not required in mammalian cells during late G2 for timely entry into or exit from mitosis. Mol Biol Cell 17: 5227–5240.
Spruck C, Strohmaier H, Watson M, Smith AP, Ryan A, Krek W et al. (2001). A CDK-independent function of mammalian Cks1. Targeting of SCF(Skp2) to the CDK inhibitor p27(Kip1). Mol Cell 7: 639–650.
Stefanovsky VY, Pelletier G, Hannan R, Gagnon-Kugler T, Rothblum LI, Moss T . (2001). An immediate response of ribosomal transcription to growth factor stimulation in mammals is mediated by ERK phosphorylation of UBF. Mol Cell 8: 1063–1073.
Strudwick S, Borden KL . (2002). The emerging roles of translation factor eIF4E in the nucleus. Differentiation 70: 10–22.
Sun H, Tonks NK, Bar-Sagi D . (1994). Inhibition of Ras-induced DNA synthesis by expression of the phosphatase MKP-1. Science 266: 285–288.
Sutterluty H, Chatelain E, Marti A, Wirbelauer C, Senften M, Muller U et al. (1999). p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol 1: 207–214.
Suzuki T, J KT, Ajima R, Nakamura T, Yoshida Y, Yamamoto T . (2002). Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation. Genes Dev 16: 1356–1370.
Takenaka K, Moriguchi T, Nishida E . (1998). Activation of the protein kinase p38 in the spindle assembly checkpoint and mitotic arrest. Science 280: 599–602.
Takuwa N, Takuwa Y . (1997). Ras activity late in G1 phase required for p27kip1 downregulation, passage through the restriction point, and entry into S phase in growth factor-stimulated NIH 3T3 fibroblasts. Mol Cell Biol 17: 5348–5358.
Talarmin H, Rescan C, Cariou S, Glaise D, Zanninelli G, Bilodeau M et al. (1999). The mitogen-activated protein kinase kinase/extracellular signal-regulated kinase cascade activation is a key signalling pathway involved in the regulation of G(1) phase progression in proliferating hepatocytes. Mol Cell Biol 19: 6003–6011.
Tamemoto H, Kadowaki T, Tobe K, Ueki K, Izumi T, Chatani Y et al. (1992). Biphasic activation of two mitogen-activated protein kinases during the cell cycle in mammalian cells. J Biol Chem 267: 20293–20297.
Tang D, Wu D, Hirao A, Lahti JM, Liu L, Mazza B et al. (2002). ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53. J Biol Chem 277: 12710–12717.
Tetsu O, McCormick F . (2003). Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 3: 233–245.
Tombes RM, Auer KL, Mikkelsen R, Valerie K, Wymann MP, Marshall CJ et al. (1998). The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic. Biochem J 330 (Part 3): 1451–1460.
Tong W, Pollard JW . (2001). Genetic evidence for the interactions of cyclin D1 and p27(Kip1) in mice. Mol Cell Biol 21: 1319–1328.
Topisirovic I, Capili AD, Borden KL . (2002). Gamma interferon and cadmium treatments modulate eukaryotic initiation factor 4E-dependent mRNA transport of cyclin D1 in a PML-dependent manner. Mol Cell Biol 22: 6183–6198.
Topisirovic I, Ruiz-Gutierrez M, Borden KL . (2004). Phosphorylation of the eukaryotic translation initiation factor eIF4E contributes to its transformation and mRNA transport activities. Cancer Res 64: 8639–8642.
Treinies I, Paterson HF, Hooper S, Wilson R, Marshall CJ . (1999). Activated MEK stimulates expression of AP-1 components independently of phosphatidylinositol 3-kinase (PI3-kinase) but requires a PI3-kinase signal to stimulate DNA synthesis. Mol Cell Biol 19: 321–329.
Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H . (1999). p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27. Curr Biol 9: 661–664.
Ueda T, Watanabe-Fukunaga R, Fukuyama H, Nagata S, Fukunaga R . (2004). Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth or development. Mol Cell Biol 24: 6539–6549.
Vantaggiato C, Formentini I, Bondanza A, Bonini C, Naldini L, Brambilla R . (2006). ERK1 and ERK2 mitogen-activated protein kinases affect Ras-dependent cell signaling differentially. J Biol 5: 14.
Vlach J, Hennecke S, Amati B . (1997). Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27. EMBO J 16: 5334–5344.
Waskiewicz AJ, Flynn A, Proud CG, Cooper JA . (1997). Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J 16: 1909–1920.
Waskiewicz AJ, Johnson JC, Penn B, Mahalingam M, Kimball SR, Cooper JA . (1999). Phosphorylation of the cap-binding protein eukaryotic translation initiation factor 4E by protein kinase Mnk1 in vivo. Mol Cell Biol 19: 1871–1880.
Weber JD, Hu W, Jefcoat Jr SC, Raben DM, Baldassare JJ . (1997a). Ras-stimulated extracellular signal-related kinase 1 and RhoA activities coordinate platelet-derived growth factor-induced G1 progression through the independent regulation of cyclin D1 and p27. J Biol Chem 272: 32966–32971.
Weber JD, Raben DM, Phillips PJ, Baldassare JJ . (1997b). Sustained activation of extracellular-signal-regulated kinase 1 (ERK1) is required for the continued expression of cyclin D1 in G1 phase. Biochem J 326 (Part 1): 61–68.
Weinberg RA . (1995). The retinoblastoma protein and cell cycle control. Cell 81: 323–330.
Whitmarsh AJ, Davis RJ . (1996). Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med 74: 589–607.
Widmann C, Gibson S, Jarpe MB, Johnson GL . (1999). Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 79: 143–180.
Willard FS, Crouch MF . (2001). MEK, ERK, and p90RSK are present on mitotic tubulin in Swiss 3T3 cells: a role for the MAP kinase pathway in regulating mitotic exit. Cell Signal 13: 653–664.
Williams DH, Wilkinson SE, Purton T, Lamont A, Flotow H, Murray EJ . (1998). Ro 09-2210 exhibits potent anti-proliferative effects on activated T cells by selectively blocking MKK activity. Biochemistry 37: 9579–9585.
Winston JT, Coats SR, Wang YZ, Pledger WJ . (1996). Regulation of the cell cycle machinery by oncogenic ras. Oncogene 12: 127–134.
Woods D, Parry D, Cherwinski H, Bosch E, Lees E, McMahon M . (1997). Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol 17: 5598–5611.
Wright JH, Munar E, Jameson DR, Andreassen PR, Margolis RL, Seger R et al. (1999). Mitogen-activated protein kinase kinase activity is required for the G(2)/M transition of the cell cycle in mammalian fibroblasts. Proc Natl Acad Sci USA 96: 11335–11340.
Wullschleger S, Loewith R, Hall MN . (2006). TOR signaling in growth and metabolism. Cell 124: 471–484.
Yamamoto T, Ebisuya M, Ashida F, Okamoto K, Yonehara S, Nishida E . (2006). Continuous ERK activation downregulates antiproliferative genes throughout G1 phase to allow cell-cycle progression. Curr Biol 16: 1171–1182.
Yan Y, Spieker RS, Kim M, Stoeger SM, Cowan KH . (2005). BRCA1-mediated G2/M cell cycle arrest requires ERK1/2 kinase activation. Oncogene 24: 3285–3296.
Yang HY, Zhou BP, Hung MC, Lee MH . (2000). Oncogenic signals of HER-2/neu in regulating the stability of the cyclin-dependent kinase inhibitor p27. J Biol Chem 275: 24735–24739.
Yao Y, Li W, Wu J, Germann UA, Su MS, Kuida K et al. (2003). Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation. Proc Natl Acad Sci USA 100: 12759–12764.
Yoon S, Seger R . (2006). The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24: 21–44.
Yoshida Y, Nakamura T, Komoda M, Satoh H, Suzuki T, Tsuzuku JK et al. (2003). Mice lacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev 17: 1201–1206.
Zecevic M, Catling AD, Eblen ST, Renzi L, Hittle JC, Yen TJ et al. (1998). Active MAP kinase in mitosis: localization at kinetochores and association with the motor protein CENP-E. J Cell Biol 142: 1547–1558.
Zeller KI, Jegga AG, Aronow BJ, O'Donnell KA, Dang CV . (2003). An integrated database of genes responsive to the myc oncogenic transcription factor: identification of direct genomic targets. Genome Biol 4: R69.
Zezula J, Sexl V, Hutter C, Karel A, Schutz W, Freissmuth M . (1997). The cyclin-dependent kinase inhibitor p21cip1 mediates the growth inhibitory effect of phorbol esters in human venous endothelial cells. J Biol Chem 272: 29967–29974.
Zhu J, Woods D, McMahon M, Bishop JM . (1998). Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev 12: 2997–3007.
Acknowledgements
S Meloche holds a Canada Research Chair in Cellular Signaling. Work in the author's laboratory was supported by grants from the National Cancer Institute of Canada, Canadian Institutes for Health Research and Cancer Research Society to SM, and by the Centre National de la Recherche Scientifique, Centre A Lacassagne, Ministère de l'Education, de la Recherche et de la Technologie, Ligue Nationale Contre le Cancer (Equipe labellisée) and Association pour la Recherche sur le Cancer to JP.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Meloche, S., Pouysségur, J. The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 26, 3227–3239 (2007). https://doi.org/10.1038/sj.onc.1210414
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1210414
Keywords
This article is cited by
-
TRIM22 promotes the proliferation of glioblastoma cells by activating MAPK signaling and accelerating the degradation of Raf-1
Experimental & Molecular Medicine (2023)
-
An Insight on Synergistic Anti-cancer Efficacy of Biochanin A and Sulforaphane Combination Against Breast Cancer
Applied Biochemistry and Biotechnology (2023)
-
Non-phosphorylatable cyclin D1 mutant potentiates endometrial hyperplasia and drives carcinoma with Pten loss
Oncogene (2022)
-
The extracellular matrix molecule tenascin-C modulates cell cycle progression and motility of adult neural stem/progenitor cells from the subependymal zone
Cellular and Molecular Life Sciences (2022)
-
Cannabidiol induces autophagy via ERK1/2 activation in neural cells
Scientific Reports (2021)