The target of rapamycin (TOR) signal-transduction pathway is an important mechanism by which eucaryotic cells adjust their protein biosynthetic capacity to nutrient availability. Both in yeast and in mammals, the TOR pathway regulates the synthesis of ribosomal components, including transcription and processing of pre-rRNA, expression of ribosomal proteins and the synthesis of 5S rRNA. Expression of the genes encoding the numerous constituents of ribosomes requires transcription by all three classes of nuclear RNA polymerases. In this review, we summarize recent advances in understanding the interplay among nutrient availability, transcriptional control and ribosome biogenesis. We focus on transcription in response to nutrients, detailing the relevant downstream targets of TOR in yeast and mammals. The critical role of TOR in linking environmental queues to ribosome biogenesis provides an efficient means by which cells alter their overall protein biosynthetic capacity.
Cells are sensitive to external signals, such as the presence of growth factors, cytokines, pharmacological agents or different types of stress, which result in the activation of signaling pathways that rapidly alter patterns of gene expression. As many, if not all, organisms control growth in response to nutrients, much research in the signal-transduction field has focused on the identification of relevant targets of such pathways. It has long been known that starvation or lack of nutrients inhibits signaling events that require the mammalian target of rapamycin (mTOR) (also known as FRAP, RAFT and RAPT). Proteins in the mTOR family are conserved from yeast to man; they all have a C-terminal kinase domain which phosphorylates serine and threonine residues. mTOR signaling controls diverse readouts, all of which are related to cell growth, including transcription, translation, protein kinase C (PKC) signaling, protein degradation, membrane traffic or actin organization (reviewed by Gingras et al., 2001; Proud, 2002). The number and diversity of growth-related readouts controlled by mTOR indicate that this functionally conserved kinase may not be simply part of a single, linear growth-controlling pathway, but can be regarded as a central player that integrates cell physiology and environment to elicit balanced growth.
Based on experiments using rapamycin, an immunosuppressive macrolide that inhibits the phosphoinositol 3-kinase (PI3K)-like kinases TOR1 and TOR2 (target of rapamycin) in yeast, and mTOR in mammals, it is clear that mTOR coordinates nutrient availability with cellular protein biosynthetic activity. Amino acids, especially leucine, positively regulate mTOR signaling (Hara et al., 1998; Kimball et al., 1999; Xu et al., 2001), thereby relieving inhibition of translation by the repressor protein 4EBP1, which regulates the translation factor eIF4E, and activating ribosomal S6 kinase1 (S6K1) which regulates translation elongation. TOR signaling also regulates transcription of c-myc and is involved in the activation of signal transducer and activator of transcription 3, PKCα and PKCδ.
Rapamycin treatment or TOR depletion also inhibits cell cycle progression by arresting cells at the G1/S boundary and causes several physiological changes that are characteristic of starved (G0) cells, including reduced nucleolar size (Zaragoza et al., 1998). This indicates that the TOR kinases play a critical role in a signaling pathway that activates eIF4E-dependent protein synthesis and, thereby, induce G1 progression. The striking similarities between starved and rapamycin-treated cells established the concept that the TOR signaling pathway controls cell growth in response to nutrients. Under favorable growth conditions and in the presence of growth factors, TOR kinase is active and promotes protein synthesis and inhibits protein degradation. Upon unfavorable conditions, TOR is inactive, leading to a reduction in protein synthesis and upregulation of protein degradation. Thus, TOR maintains a balance between protein synthesis and degradation such that the cell can rapidly adjust mass accumulation to a level appropriate for nutrient supply.
Contribution of mTOR signaling to the regulation of ribosome biogenesis
A hallmark of growth regulation in both prokaryotic and eucaryotic cells is the tight coupling between extracellular conditions and the synthesis of ribosomes. When nutrient concentrations change, particularly those of essential amino acids, protein synthesis is decreased. Upregulation of ribosome synthesis occurs in response to favorable conditions and allows a cell to grow faster, but only if all components of the ribosome are available. Ribosome synthesis is a complex process that is one of the major energy consuming processes of the cell. A proliferating HeLa cell produces about 7500 ribosomes/min, a process that requires transcription of 150–200 rRNA genes, the synthesis of ∼300 000 ribosomal proteins (RPs), and numerous interactions with assembly factors, endo- and exoribonucleases, RNA helicases and small nucleolar ribonucleoprotein particles. Thus, to conserve resources, cells must limit the production of ribosomes under conditions in which the demand for protein synthesis is reduced, such as occurs when nutrients are limiting.
As a central controller of cell growth, TOR regulates several growth-related processes, including ribosome biogenesis. Studies in yeast and mammals have demonstrated that TOR signaling couples nutrient availability to the regulation of ribosome biogenesis (Schmelzle and Hall, 2000; Kim et al., 2003). mTOR controls ribosome biogenesis by at least two mechanisms: by promoting the translation of mRNAs for RPs and by affecting ribosomal RNA (rRNA) synthesis. Ribosome biogenesis accounts for a large segment of total energy consumption by the cell. In yeast, the synthesis of rRNA represents ∼60% of total transcriptional activity and the synthesis of mRNAs encoding RPs accounts for ∼60% of all Pol II transcription initiation events (Warner, 1999).
Ribosome synthesis requires the coordinated activities of all three nuclear RNA polymerases, that is, Pol I for the synthesis of rRNA, Pol II for transcription of RP genes and Pol III for the synthesis of 5S RNA (see Figure 1). The control of ribosome biosynthesis by the TOR pathway is surprisingly complex. Inhibition of (m)TOR signaling by rapamycin treatment leads to a rapid and pronounced downregulation of rRNA gene transcription and pre-rRNA processing (Mahajan, 1994; Hardwick et al., 1999; Powers and Walter, 1999; Zaragoza et al., 1998; Claypool et al., 2003; Hannan et al., 2003). Moreover, TOR regulates transcription of genes encoding RPs (Cardenas et al., 1999; Hardwick et al., 1999; Powers and Walter, 1999) and controls tRNA and 5S RNA synthesis (Zaragoza et al., 1998). Inhibition of mTOR signaling also inhibits translation, however, more slowly and less pronounced than transcription of ribosomal components (Cardenas et al., 1999; Hardwick et al., 1999). The fact that TOR signaling controls ribosome biogenesis at many levels, including transcription by Pol I, II and III, rRNA processing and translation, underscores the involvement of TOR in linking nutrient availability to the biosynthesis of ribosomes.
mTOR-dependent regulation of Pol I transcription
Production of rRNA is a limiting step in ribosome synthesis, and therefore growing cells need to maintain high rates of Pol I transcription to sustain the level of ribosomes required for protein synthesis. Conditions that impair cell growth and proliferation, such as growth factor deprivation, amino-acid withdrawal, cell confluence or inhibition of protein synthesis, downregulate Pol I transcription. Transcription initiation by Pol I requires at least three basal factors, termed Transcription Initiation Factor I (TIF-I) A, TIF-IB/SL1 and Upstream Binding Factor (UBF) (reviewed by Grummt, 2003). Significantly, the activity of all three factors can be modulated by different signaling pathways to ensure fine tuning of Pol I transcription according to growth factor and nutrient availability and during cell cycle progression (Figure 2). The key player that mediates growth- and nutrient-dependent regulation of rRNA gene (rDNA) transcription is the basal factor TIF-IA, the mammalian homolog of S. cerevisiae Rrn3p (Bodem et al., 2000; Moorefield et al., 2000). TIF-IA was initially identified as an activity that complements transcriptionally inactive extracts from starved or growth-arrested cells (Buttgereit et al., 1985). Later studies have shown that TIF-IA is phosphorylated at multiple sites and phosphorylation by different pathways that are important for cell proliferation adapts TIF-IA activity to cell growth. TIF-IA interacts with both Pol I and the TBP-containing promoter selectivity factor TIF-IB/SL1, thereby recruiting Pol I to the rDNA promoter and facilitating transcription complex formation (Miller et al., 2001; Cavanaugh et al., 2002; Yuan et al., 2002).
Early studies have established that rRNA synthesis in mammalian cells is regulated by the availability of nutrients, especially amino acids. Withdrawal of essential amino acids, in particular the absence of leucine, leads to a rapid decrease in Pol I transcription, half of the maximum inactivation occurring within 30 min (Grummt et al., 1976). This finding, together with the observation that rDNA transcription is rapamycin-sensitive, indicated that rRNA synthesis is controlled by mTOR (Mahajan, 1994). Inhibition of rDNA transcription by rapamycin was observed in both proliferating NIH3T3 cells and non-proliferating cardiac muscle cells (Hannan et al., 2003). Nuclear extracts from rapamycin-treated cells were transcriptionally inactive, and transcriptional repression was overcome by exogenous TIF-IA (Mayer et al., 2004). Moreover, rapamycin-dependent transcriptional repression was rescued by exogenous mTOR or S6K1, but not by a kinase-deficient S6K1 mutant, indicating that either S6K1 itself or S6K1-dependent enzymes regulate TIF-IA activity. Indeed, both in yeast and mammals, TOR controls Pol I transcription via the transcription factor Rrn3p/TIF-IA (Claypool et al., 2003; Mayer et al., 2004). Inhibition of mTOR signaling inactivates TIF-IA by decreasing phosphorylation at serine 44 (S44) and enhancing phosphorylation at serine 199 (S199). Phosphorylation of S44 and S199 affects TIF-IA activity in opposite ways. Whereas S44 phosphorylation is required for TIF-IA activity, phosphorylation at S199 inactivates TIF-IA. This indicates that mTOR-responsive kinase(s) and phosphatase(s) modulate the activity of TIF-IA in different ways and implies that antagonizing phosphorylations may play a key role in mTOR-dependent regulation of Pol I transcription. Importantly, rapamycin treatment abolishes the association of TIF-IA with both Pol I and TIF-IB/SL1, thereby impairing formation of the transcription initiation complex. Likewise, upon rapamycin treatment Rrn3p (the yeast homolog of TIF-IA) dissociates from Pol I and rDNA promoters (Claypool et al., 2003). Thus, both in yeast and in mammals, TOR regulates the recruitment of Pol I to TIF-IB/SL1 bound to the rDNA promoter, thereby modulating transcription complex formation. Thus, by facilitating recruitment of Pol I to rDNA, mTOR signaling may be a key event in the complex pathways the cell uses to regulate the assembly of transcription complexes and to adapt Pol I activity to nutrient availability.
Interestingly, mTOR signaling does not only control the activity but also the intracellular localization of TIF-IA. Once inactivated by rapamycin treatment, a significant part of TIF-IA translocates from the nucleus into the cytoplasm. mTOR-sensitive sequestration of TIF-IA in the cytoplasm is reminiscent of studies in yeast which have shown that the TOR signaling pathway broadly controls nutrient metabolism by sequestering several transcription factors in the cytoplasm (Di Como and Arndt, 1996; Beck and Hall, 1999; Jiang and Broach, 1999). Together, these results demonstrate that inhibition of mTOR signaling downregulates Pol I transcription by three inter-related mechanisms, which involve hypophosphorylation of S44, hyperphosphorylation of S199 and shuttling of TIF-IA from the nucle(ol)us into the cytoplasm. The functional interplay of these mechanisms may provide a mechanistic explanation of the possible role of TOR in regulating rRNA synthesis in response to environmental queues.
Two other studies showed that another basal Pol I-specific factor, UBF, is also regulated by mTOR in an S6K1-dependent manner (Hannan et al., 2003). Mitogen-induced activation of S6K1 phosphorylates UBF in its C-terminal region, and this phosphorylation is required for the interaction between UBF and TIF-IB/SL1. Expression of a constitutively active mutant of S6K1 rescued rapamycin-induced inhibition of Pol I transcription. In another study, mTOR was shown to enhance rRNA synthesis in hypertrophic skeletal muscle by activating CDK4/cyclinD (Nader et al., 2005). Together, these results suggest that mTOR signaling leads to a cyclin D1-dependent increase in CDK4 activity, followed by phosphorylation-mediated dissociation of pRb from UBF with a concominant increase in UBF availability. Finally, a complex signaling network downstream of insulin-like growth factor-1, involving branches of PI3K as well as mTOR and mitogen-activated protein kinase cascade modules, was shown to regulate rRNA synthesis by inhibiting binding of the TBP-containing factor TIF-IB/SL1 to the rDNA promoter, thereby impairing pre-initiation complex formation (James and Zomerdijk, 2004). Together, TOR signaling targets several Pol I-specific transcription factors to regulate and finetune rRNA synthesis according to cellular demands. These results underscore the central role of mTOR in cell proliferation and imply that common mechanisms control cellular growth in both the proliferative and differentiated state.
TOR regulates transcription of RP genes
Mammalian ribosomes contain 79 different proteins, all of them being encoded by single-copy genes. RP genes are located on different chromosomes and are expressed in all tissues. Interestingly, all functional RP genes as well as many proteins implicated in rRNA processing and ribosome assembly are transcriptionally co-regulated as ‘Ribi regulons’ by the same set of cis- and/or trans-acting factors. Members of the ‘Ribi regulon’ share a polypyrimidine tract, termed 5′TOP (‘terminal oligopyrimidines’ or ‘track of pyrimidines’) sequence at the 5′ end of their mRNA. Analysis of gene expression in yeast cells exposed to rapamycin using DNA arrays representing the whole yeast genome revealed that inhibiting TOR has profound effects on the transcription of many yeast genes, including enhanced expression of nitrogen-source utilization genes and global repression of the majority of RP genes (Cardenas et al., 1999; Preiss et al., 2003).
In yeast, two TOR-dependent transcription factors have been shown to regulate RP gene transcription in response to environmental cues. The transcription factor SFP1, previously described as a regulator of cell size, controls RP gene expression in response to nutrients and stress by binding to and regulating RP gene promoters in a TOR-dependent manner. Under optimal growth conditions, SFP1 is localized in the nucleus and is associated with RP gene promoters. In the presence of rapamycin, stress or amino-acid starvation, SFP1 is inactivated and RP gene transcription is downregulated (Jorgensen et al., 2004; Marion et al., 2004). TOR also controls the expression of RP genes via the forkhead transcription factor FHL1 together with its co-activator IFH1 and its co-repressor CRF1 (Martin et al., 2004; Schawalder et al., 2004; Rudra et al., 2005). Under favorable conditions, FHL1 binds to the promoter and activates RP gene transcription. TOR, via protein kinase A (PKA), maintains the co-repressor CRF1 in the cytoplasm. Upon unfavorable growth conditions, CRF1 accumulates in the nucleus and binds FHL1, leading to repression of RP gene transcription. Thus, TOR-mediated control of ribosome biogenesis involves nutrient-dependent changes of subcellular localization of transcription factors through regulated nuclear import and/or cytoplasmic retention (Beck and Hall, 1999; Rohde et al., 2001).
Apart from affecting components of the transcriptional machinery, other effectors have been implicated in TOR-dependent regulation of RP gene expression by chromatin-based mechanisms. Two histone H4 modifying enzymes, for example, ESA1, a histone acetyltransferase, and RPD3, a histone deacetylase subunit of the SIN3 complex, are implicated in the activation and repression of RP genes, respectively. Under good nutrient conditions, TOR signaling activates the expression of RP genes by promoting maintenance of the ESA1 complex to RP gene promoters. Upon starvation or rapamycin treatment, ESA1 is rapidly released from RP genes (Rohde and Cardenas, 2003). Conversely, RPD3 binds and inhibits RP genes in a TOR-dependent manner, indicating that nutrient availability affects the chromatin structure of RP genes. In support of this, deletion of RPD3 confers rapamycin resistance to RP gene expression, and chromatin immunoprecipitation experiments have demonstrated that rapamycin inhibits binding of ESA1 to RP gene promoters while enhancing the association of RPD3 (Humphrey et al., 2004). Thus, complex and dynamic protein–protein interactions, many of which are positively or negatively affected by TOR signaling, regulate transcription at RP gene promoters.
5′TOP mRNAs – a short side-trip to translational control
Aside from being regulated at the transcriptional level, RP gene expression is most notably controlled at the level of translation, via the 5′TOP sequence. In quiescent cells, a large proportion of RP mRNAs are stored in the cytoplasm as inactive ribonucleoprotein (mRNP) particles. Upon stimulation with growth factors, 5′TOP mRNAs become recruited to and translated by polysomes (Warner, 1999). Concomitantly, phosphorylation of rpS6 and the activity of S6K1, one of the two protein kinases responsible for rpS6 phosphorylation, rapidly increases. These findings, together with the observation that rapamycin-insensitive mutants of S6K1 impair mitogen-induced translation of 5′TOP mRNAs (Jefferies et al., 1997), suggested that ribosomes with the highest proportion of phosphorylated rpS6 would have a selective affinity towards 5′TOP mRNAs. According to this view, phosphorylation of rpS6 is the ‘gatekeeper’ of 5′TOP mRNA translation and S6K1 activity is translating nutritional cues into the required biosynthetic output (Volarevic and Thomas, 2001). However, recent studies have shown that rpS6 phosphorylation by S6K1 does not play a major role in the control of 5′TOP mRNA translation. Overexpression of a dominant-negative S6K1 mutant that abolished rpS6 phosphorylation did not affect translation of 5′TOP mRNAs (Tang et al., 2001). Moreover, translation was repressed in differentiating mouse embryonic lymphoid cells in the absence of changes in rpS6 phosphorylation (Barth-Baus et al., 2002). In S6K1-deficient cells, translation was enhanced in a rapamycin-dependent manner upon mitogenic stimulation (Pende et al., 2004), demonstrating that mTOR-dependent translational regulation of 5′TOP mRNAs requires neither active S6K1 nor phosphorylation of rpS6. The mechanism by which translation of 5′TOP mRNAs are controlled either directly or indirectly by TOR remains to be elucidated.
Control of Pol III transcription by TOR
Compared to what is known about the role of TOR in the regulation of Pol I and Pol II transcription, there is very little information concerning the impact of TOR signaling on Pol III transcription. In S. cerevisae, rapamycin treatment induces many aspects of the normal response to nutrient limitation, including the induction of G0-specific Pol II genes and repression of transcription initiation by Pol I and Pol III (Zaragoza et al., 1998). Downregulation of Pol III transcription was observed both in extracts from a temperature-sensitive mutant of TOR and an isogenic wild-type strain, demonstrating that transcriptional repression of 5S rRNA and tRNALeu genes is direct and independent of TOR effects on translation. Biochemical analysis of the transcription defect in extracts from cells treated with rapamycin revealed that TOR signaling regulates Pol III transcription by modulating the activity of Pol III and the TBP-containing transcription initiation factor TFIIIB. The results suggest that TOR signaling regulates the phosphorylation status and therefore the transcriptional activity of Pol III.
Similar studies in mammalian cells have demonstrated that inhibition of mTOR signaling attenuates Pol III transcription (White, 2005). Transcriptional repression was accompanied by decreased association of the Pol III-specific transcription factors TFIIIB and TFIIIC with 5S rRNA genes, indicating that TOR signaling regulates recruitment of Pol III to its target genes in lower and higher eucaryotes (Graham, White and Scott; unpublished observations).
Nutrient-dependent co-regulation of Pol I, Pol II and Pol III transcription
Despite great efforts, the individual steps by which the nutrient status impinges on ribosome biogenesis are far from being understood. In particular, it is not known whether and how transcription by all three nuclear RNA polymerases and post-transcriptional events are coordinated to ensure an equimolar supply of ribosomal components. The nutrient-mediated coordinated change in the abundance of ribosome constituents could mean that TOR signaling on its own is sufficient to co-regulate the activity of all three transcription machineries. Alternatively, regulation of transcription in response to nutrients could be mediated by different signaling pathways, and the crosstalk between members of different signaling networks ensures transcriptional co-regulation. For example, there is ample evidence of crosstalk between the PI3K-Akt/PKB-mTOR signaling pathway and the pathway leading to activation of extracellular signal-regulated kinase (ERK). In fact, both the ERK and mTOR pathways cooperate to control transcription by Pol I (James and Zomerdijk, 2004) and possibly Pol III (White, 2005).
Alternatively, there could be communication between the three nuclear machineries that synthesize ribosome components. In the simplest case, co-regulation of all three transcription machineries could be achieved by a factor that targets a common subunit of all three RNA polymerases. In support of this, a genome-wide analysis of the nutrient-sensitive transcriptional program in S. cerevisiae indicates that the unconventional prefoldin URI could be such a hypothetical target (Gstaiger et al., 2003). Prefoldins are small molecular weight proteins that assemble into molecular chaperone complexes and interact with other prefoldins. Interestingly, URI interacts with RPB5, a shared subunit of all three nuclear RNA polymerases, and URI is a bona fide target of nutrient signaling that participates in mTOR-dependent control of gene expression. Other potential regulatory targets of TOR signaling could be nuclear actin or myosin which have been shown to be involved in transcription by Pol I, Pol II and Pol III (reviewed by Grummt, 2006). Conditions that activate mTOR pathways lead to actin polymerization, indicating that mTOR signals to the actin cytoskeleton (Jacinto et al., 2004). Although it might be far fetched, it is tempting to speculate that growth factor and nutrient cues may also regulate actin function in the nucleus and contribute to transcriptional control.
Finally, an alluring possibility to achieve coordinated transcription by Pol I, II and III is that one class of RNA polymerases serves as a ‘master regulator’ that coordinates the activity of the other transcription machineries. In support of this, a genetic study in yeast suggests that Pol I might serve such a role. Carles and collaborators have used a yeast strain that expresses a constitutively active Pol I to investigate the in vivo co-regulation of the three nuclear transcription machineries (Laferté et al., personal communication). They found that attenuation of rapamycin-mediated repression of Pol I transcription leads to concomitant de-repression of transcription of 5S rRNA by Pol III and RP protein mRNA by Pol II. This study indicates that regulation of Pol I plays a predominant role in the communication network that controls the activity of the three nuclear RNA polymerases to synthesize ribosome constituents.
The last few years have seen several important advances in our understanding of transcriptional control by nutrients, and have unraveled a causal link between aberrant mTOR signaling and tumor formation. However, as is often the case, even more questions are raised than answered. Many of the components of the mTOR signaling pathway have been characterized and the advent of proteomics will undoubtedly identify more target proteins that are regulated by TOR. There is increasing appreciation of the requirement of a cell to control the maintenance of a balanced ribosome supply. The growing list of TOR- as well as ribosome-related diseases underscores the need for further studies. Finally, mTOR signaling components are frequently activated in human cancers, indicating that mTOR-mediated activation of transcription and ribosome synthesis contributes to tumorigenesis. Indeed, mTOR-dependent transcription of a number of genes is associated with the development of neoplasia (Ruggero and Pandolfi, 2003), and changes in ribosome biogenesis correlate with the development of a number of pathological processes, including cancer (Holland et al., 2004). In accordance with this, overexpression of RPs seems to be frequently associated with tumorigenesis (Ferrari et al., 1990). Deregulated expression of the rpS3a, an endonuclease that cleaves DNA in response to ultraviolet irradiation, induced transformation of NIH3T3 cells (Naora et al., 1998). Studies elucidating novel functions of RPs apart from their role as ribosome constituents and their control by mTOR signaling may provide insights into the role of ribosomal components in cancer. Such studies should not only answer some longstanding basic questions, such as the mechanism and the nature of the machinery by which mammalian cells sense amino acids, but also hold in store the potential discovery of novel therapeutic targets.
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We apologize to those whose work was not cited or discussed because of space limitations. Work in the authors' laboratory is supported by the Deutsche Forschungsgemeinschaft (SFB/Transregio 5, SP, Epigenetics'), the EU-Network ‘Epigenome’ and the Fonds der Chemischen Industrie.
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Mayer, C., Grummt, I. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene 25, 6384–6391 (2006). https://doi.org/10.1038/sj.onc.1209883
- RNA polymerase
- ribosome biogenesis
- ribi regulon
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