Overlapping Functions of the pRb Family in the Regulation of rRNA Synthesis

Ciarmatori, Sonia; Scott, Pamela Sharkey; Sutcliffe, Josephine E.; McLees, Angela; Alzuherri, Hadi M.; Dannenberg, Jan-Hermen; Riele, Hein te; Grummt, Ingrid; Voit, Renate; White, Robert J.

doi:10.1128/mcb.21.17.5806-5814.2001

Cited by 68 publications

(50 citation statements)

References 52 publications

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“…Similarly, the hypertrophic growth of rat cardiac myocytes can be blocked by specifically preventing a 37% increase in rRNA synthesis (Brandenburger et al, 2001). The magnitude of these changes compares closely with the B40% suppression of rRNA synthesis exerted by endogenous RB and its relative p130 in embryonic fibroblasts, as determined with knockout mice (Ciarmatori et al, 2001). A similar genetic analysis found that endogenous RB suppresses tRNA levels by 2.4-fold in serum-starved mouse embryonic fibroblasts .…”

Section: Pols I and Iii May Help Mediate The Growth Control Functionsmentioning

confidence: 53%

“…Note: p53 does not interact with assembled TFIIIB and so is not detected at the pol III promoters it regulates (Crighton et al, 2003) tions). The pol I machinery is also targeted by RB and p53, both of which can reduce its output (Cavanaugh et al, 1995;Voit et al, 1997;Hannan et al, 2000a,b;Pelletier et al, 2000;Zhai and Comai, 2000;Ciarmatori et al, 2001;Sugimoto et al, 2003). It therefore appears that pols I and III are both enmeshed in a network of regulatory interactions that help to coordinate their outputs and promote balanced production of ribosomal components.…”

Section: Coordinate Regulation Of Pols I and Iiimentioning

confidence: 99%

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RNA polymerase III transcription and cancer

2004

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RNA polymerase (pol) III synthesizes a range of essential products, including tRNA, 5S rRNA and 7SL RNA, which are required for protein synthesis and trafficking. High rates of pol III transcription are necessary for cells to sustain growth. A wide range of transformed and tumour cell types have been shown to express elevated levels of pol III products. This review will summarize what is known about the mechanisms responsible for this deregulation. Some transforming agents have been shown to stimulate expression of the pol III-specific transcription factors TFIIIB or TFIIIC2. In addition, TFIIIB is bound and activated by several oncogenic proteins, including cMyc. Conversely, TFIIIB interacts in healthy cells with the tumour suppressors RB and p53. Indeed, the ability to limit pol III transcription through TFIIIB may contribute to their growth-suppression capacities. The function of p53 and/or RB is compromised in most if not all transformed cells; the resultant derepression of TFIIIB may provide an almost universal route to deregulate pol III transcription in cancers. In addition to effects on protein synthesis and growth, there is a precedent for a pol III product having oncogenic activity.

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Section: Pols I and Iii May Help Mediate The Growth Control Functionsmentioning

confidence: 53%

Section: Coordinate Regulation Of Pols I and Iiimentioning

confidence: 99%

RNA polymerase III transcription and cancer

2004

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“…All these kinases have been found overexpressed in many cancers. Several tumor suppressors have also been shown to directly interact with UBF: pRb or p130 inhibit in that way subsequent recruitment of cofactors required for rRNA transcription (Cavanaugh et al, 1995;Voit et al, 1997;Hannan et al, 2000a, b;Ciarmatori et al, 2001). p53 also interferes with Pol I activity by destabilizing the SL1-UBF complex required for transcriptional initiation on the rRNA promoter (Zhai and Comai, 2000).…”

Section: Introductionmentioning

confidence: 99%

Human tumor suppressor p14ARF negatively regulates rRNA transcription and inhibits UBF1 transcription factor phosphorylation

Ayrault¹,

Andrique²,

Fauvin³

et al. 2006

Oncogene

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The nucleolar Arf protein has been shown to regulate cell cycle through both p53-dependent and -independent pathways. In addition to the well-characterized Arf-mdm2-p53 pathway, several partners of Arf have recently been described that could participate in alternative regulation process. Among those is the nucleolar protein B23/NPM, involved in the sequential maturation of rRNA. p19 ARF can interact with B23/NPM in high molecular complexes and partially inhibit the cleavage of the 32S rRNA, whereas the human p14 ARF protein has been shown to participate in the degradation of NPM/B23 by the proteasome. These data led to define Arf as a negative regulator of ribosomal RNA maturation. Our recent finding that the human p14 ARF protein was able to specifically interact with the rRNA promoter in a p53-independent context, led us to analyse in vitro and in vivo the consequences of this interaction. Luciferase assay and pulse-chase experiments demonstrated that the rRNA transcription was strongly reduced upon p14 ARF overexpression. Investigations on potential interactions between p14 ARF and the transcription machinery proteins demonstrated that the upstream binding factor (UBF), required for the initiation of the transcriptional complex, was a new partner of the p14 ARF protein. We next examined the phosphorylation status of UBF as UBF phosphorylation is required to recruit on the promoter factors involved in the transcriptional complex. Upon p14 ARF overexpression, UBF was found hypophosphorylated, thus unable to efficiently recruit the transcription complex. Taken together, these data define a new p53-independent pathway that could regulate cell cycle through the negative control of rRNA transcription.

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“…This family of tumor suppressor genes is mutated in many types of cancers and is important in regulation of rRNA synthesis (Ruggero and Pandolfi, 2003). Several studies show a close relationship between Rb and transcription of the rDNA by RNA polymerase I (Cavanaugh et al, 1995;Hannan et al, 2000;Ciarmatori et al, 2001), and deleting Rb leads to increases in rRNA synthesis (Ciarmatori et al, 2001). Thus Whi5 and Rb have roles in both ribosome biogenesis and Start, although the regulatory connections may differ.…”

Section: K a Bernstein Et Almentioning

confidence: 99%

Ribosome Biogenesis Is Sensed at the Start Cell Cycle Checkpoint

Bernstein

Bleichert

Bean

et al. 2007

MBoC

120

122

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In the yeast Saccharomyces cerevisiae it has long been thought that cells must reach a critical cell size, called the “setpoint,” in order to allow the Start cell cycle transition. Recent evidence suggests that this setpoint is lowered when ribosome biogenesis is slowed. Here we present evidence that yeast can sense ribosome biogenesis independently of mature ribosome levels and protein synthetic capacity. Our results suggest that ribosome biogenesis directly promotes passage through Start through Whi5, the yeast functional equivalent to the human tumor suppressor Rb. When ribosome biogenesis is inhibited, a Whi5-dependent mechanism inhibits passage through Start before significant decreases in both the number of ribosomes and in overall translation capacity of the cell become evident. This delay at Start in response to decreases in ribosome biogenesis occurs independently of Cln3, the major known Whi5 antagonist. Thus ribosome biogenesis may be sensed at multiple steps in Start regulation. Ribosome biogenesis may thus both delay Start by increasing the cell size setpoint and independently may promote Start by inactivating Whi5.

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Overlapping Functions of the pRb Family in the Regulation of rRNA Synthesis

Cited by 68 publications

References 52 publications

RNA polymerase III transcription and cancer

RNA polymerase III transcription and cancer

Human tumor suppressor p14ARF negatively regulates rRNA transcription and inhibits UBF1 transcription factor phosphorylation

Ribosome Biogenesis Is Sensed at the Start Cell Cycle Checkpoint

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