Direct Regulation of RNA Polymerase III Transcription by RB, p53 and c-Myc

Felton-Edkins, Zoë A.; Kenneth, Niall S.; Brown, T.R.P.; Daly, Nicole L.; Gomez-Roman, Natividad; Grandori, Carla; Eisenman, Robert N.; White, Robert J.

doi:10.4161/cc.2.3.375

Cited by 105 publications

(118 citation statements)

References 54 publications

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“…This region is necessary and sufficient for RB to bind TFIIIB and repress pol III transcription (White et al, 1996;Chu et al, 1997;Larminie et al, 1997). Accordingly, this function is ablated by substitutions or small deletions in the pocket that arose naturally in tumours (White et al, 1996;Brown et al, 2000;Felton-Edkins et al, 2003b). (Figure 2).…”

Section: Derepression Of Tfiiibmentioning

confidence: 99%

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: Derepression Of Tfiiibmentioning

confidence: 99%

RNA polymerase III transcription and cancer

2004

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“…In untransformed cells, TFIIIB is bound and repressed by both RB and p53 (Felton-Edkins et al, 2003). Inactivation of either of these tumour suppressors can cause elevated rates of pol III transcription in vivo (Felton-Edkins et al, 2003). For example, neutralizing RB with the E7 oncoprotein of HPV16 can stimulate expression of a pol III reporter in transfected fibroblasts, but this response is abolished by mutations that prevent the RB/E7 interaction (Larminie et al, 1999;Sutcliffe et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Deregulation of RNA polymerase III transcription in cervical epithelium in response to high-risk human papillomavirus

et al. 2004

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RNA polymerase (pol) III transcription is a major determinant of biosynthetic capacity, providing essential products such as tRNA and 5S rRNA. It is controlled directly by the tumour suppressors RB and p53. High-risk types of human papillomavirus (HPV), such as HPV16, express the oncoproteins E6 and E7 that can inactivate p53 and RB, respectively. Accordingly, both E6 and E7 stimulate pol III transcription in cultured cells. HPV16-positive cervical biopsies express elevated levels of tRNA and 5S rRNA when compared to biopsies that test negative for HPV or are infected with the lower risk HPV11. Integration of viral DNA into the host cell genome stimulates expression of E6 and E7 and correlates with induction of tRNA and 5S rRNA. Expression of mRNA encoding the pol III-specific transcription factor Brf1 also correlates with the presence of integrated HPV16. Brf1 levels are limiting for tRNA and 5S rRNA synthesis in cervical cells. Furthermore, pol III-transcribed genes that do not use Brf1 are not induced in HPV16-positive biopsies. Three complementary mechanisms may therefore allow high-risk HPV to stimulate production of tRNA and 5S rRNA: E6-mediated removal of p53; E7-mediated neutralization of RB; and induction of Brf1. The resultant increase in biosynthetic capacity may contribute to deregulated cell growth.

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“…14,15 The c-Myc protein bound to TFIIIB, a RNA polymerase III-specific general transcription factor, directly activates pol III transcription, thereby stimulating ribosomal RNA production. 16,17 The tumor suppressors p53 and pRB repress TFIIIB expression. 17 The c-Myc protein itself is assumed to be necessary for c-Myc expression.…”

Section: Conformational Cycle Of Hsp90 Chaperonementioning

confidence: 99%

“…16,17 The tumor suppressors p53 and pRB repress TFIIIB expression. 17 The c-Myc protein itself is assumed to be necessary for c-Myc expression. 18 The c-Myc expression is under self-control.…”

Section: Conformational Cycle Of Hsp90 Chaperonementioning

confidence: 99%

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

et al. 2011

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Heat-shock protein 90 (Hsp90) inhibitor downregulates c-Myc expression and upregulates the expression of tumor repressor proteins such as p53 and pRB, inhibiting the G1/S transition and causing G2/M arrest during cell cycle progression. The cycle progression is extensively controlled by the pRB/E2F signaling pathway. E2F is released from the pRB/E2F complex with the phosphorylation of pRB by cyclin-cyclin-dependent kinase (CDK) complexes. The released E2F promotes the transcription of target genes involved in cell cycle progression. The pRB/E2F signaling pathway is controlled by DNA methyltransferase-1 (Dnmt-1). The elevated expression of Dnmt-1 has been reported in carcinomas of the colon, lung and prostate. A defect of pRB expression in RbÀ/À cancer cells is caused by the aberrant methylation of CpG in the Rb promoter. The Hsp90 inhibitor disrupts the Dnmt-1/Hsp90 association and upregulates pRB expression. In this review, the Hsp90 inhibitors that show promise for cancer therapy are summarized.

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Direct Regulation of RNA Polymerase III Transcription by RB, p53 and c-Myc

Cited by 105 publications

References 54 publications

RNA polymerase III transcription and cancer

RNA polymerase III transcription and cancer

Deregulation of RNA polymerase III transcription in cervical epithelium in response to high-risk human papillomavirus

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

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