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Oncogene (2006) 25, 6384–6391
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REVIEW
Ribosome biogenesis and cell growth: mTOR coordinates transcription by
all three classes of nuclear RNA polymerases
C Mayer and I Grummt
Division of Molecular Biology of the Cell II, German Cancer Research Center, Heidelberg, Germany
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 cues to
ribosome biogenesis provides an efficient means by which
cells alter their overall protein biosynthetic capacity.
Oncogene (2006) 25, 6384–6391. doi:10.1038/sj.onc.1209883
Keywords: transcription; RNA polymerase; mTOR;
ribosome biogenesis; ribi regulon
Introduction
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
Correspondence: Dr I Grummt, Division of Molecular Biology of the
Cell II, German Cancer Research Center, Im Neuenheimer Feld 581,
Heidelberg D-69120, Germany.
E-mail: [email protected]
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 growthrelated 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 phosphatidylinositide 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, PKCa and PKCd.
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 rapamycintreated 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.
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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
B300 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 B60% of total transcriptional activity and
the synthesis of mRNAs encoding RPs accounts for
B60% 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
Figure 1 TOR coordinates ribosome biogenesis in S. cerevisiae by controlling transcription by Pol I, Pol II and Pol III. Known targets
of TOR signaling are indicated in colors. Black arrows indicate either transport or processing steps.
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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 rapamycinsensitive, 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 TIFIA activity. Indeed, both in yeast and mammals, TOR
controls Pol I transcription via the transcription factor
Oncogene
Figure 2 Nutrients and growth factors control mammalian rRNA
synthesis via mTOR. Arrows indicate activation; bars indicate
repression. Question marks reflect the uncertainty as to whether a
given protein is controlled by a kinase directly. Solid lines represent
known interactions, whereas dashed lines indicate that uncertainty
exists as to how these signals may feed into the pathway. Colors
indicate the grouping of factors into pathways; (blue) cell cyclerelated proteins; (red) Pol I transcription machinery; (orange)
factors upstream of mTOR and (green) core factors of the
rapamycin-sensitive mTOR pathway.
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
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C Mayer and I Grummt
6387
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 TIFIA. 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 Ispecific 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 50 TOP (‘terminal
oligopyrimidines’ or ‘track of pyrimidines’) sequence at
the 50 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, TORmediated 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
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C Mayer and I Grummt
6388
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.
50 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 50 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, 50 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 50 TOP mRNAs (Jefferies et al., 1997), suggested that ribosomes with the
highest proportion of phosphorylated rpS6 would have
a selective affinity towards 50 TOP mRNAs. According
to this view, phosphorylation of rpS6 is the ‘gatekeeper’
of 50 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 50 TOP
mRNA translation. Overexpression of a dominantnegative S6K1 mutant that abolished rpS6 phosphorylation did not affect translation of 50 TOP mRNAs
(Tang et al., 2001). Moreover, translation was repressed
in differentiating mouse embryonic lymphoid cells in the
absence of changes in rpS6 phosphorylation (BarthBaus 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
50 TOP mRNAs requires neither active S6K1 nor
phosphorylation of rpS6. The mechanism by which
translation of 50 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 temperatureOncogene
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 coregulation. 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
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C Mayer and I Grummt
6389
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 coregulation 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.
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 mTORmediated activation of transcription and ribosome
synthesis contributes to tumorigenesis. Indeed, mTORdependent 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.
Concluding remarks
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
Acknowledgements
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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