Repression of RNA polymerase III transcription by the retinoblastoma protein

Abstract

Transcription by RNA polymerase (pol) III is under cell-cycle control, being higher in S and G2 than in G0 and early G1 phases. Many transformed cell types have elevated pol III activity, presumably to sustain sufficient protein synthesis for unrestrained growth. The retinoblastoma tumour-suppressor protein (Rb) restricts cellular proliferation, and is often found mutated in transformed cells. Here we demonstrate that Rb can repress the level of transcription from pol III templates both in vitro and vivo. Analysis of Rb-deficient SAOS2 cells and primary fibroblasts from Rb-/- mice demonstrates elevated levels of pol III activity in the absence of functional Rb protein. Rb-induced repression of pol III activity is alleviated by mutations in the Rb pocket domain that occur naturally in tumours, and by viral transforming proteins that bind and inactivate Rb. These results implicate repression of pol III transcription as a mechanism for Rb-induced growth arrest, and suggest that restraining protein biosynthesis may be important in the prevention of tumour development.

Premalignant Breast Neoplasia: A Paradigm of Interlesional and Intralesional Molecular Heterogeneity and Its Biological and Clinical Ramifications

“…Repression of E2F-dependent transcriptional targets that control cell cycle arrest is assumed to be the major mechanism by which pRb exerts antitumorigenic effects. This focus on cell cycle effects and antiproliferative functions was substantiated by mutation studies showing that removal of pRb allowed accelerated entry into the G 1 -S phases of the cell cycle and that exogenously introduced unphosphorylated pRb caused cell cycle arrest (32)(33)(34)(35). This alteration in cell cycle control would be expected to manifest itself via an elevated mitotic rate, such as a higher fraction of cells expressing Ki67, and consequently, via hyperplastic morphologic alterations.…”

Mutations in the β-propeller domain of the Drosophila brain tumor (brat) protein induce neoplasm in the larval brain

“…The calibration bars in (a) and (j) indicate 100 mm, and (a ± g) and (j ± r) are of the same magni®cation. In (h) and (s) the bars indicate 50 mm, and (h,i,s) and (t) are of the same magni®cation loss of Rb and p53 function causes substantial increase in RNA polymerase I and III transcriptional activity (Nasmyth, 1996;White et al, 1996;Larminie et al, 1997;Cairns and White, 1998). It is possible that one way in which tumor cells are able to achieve an increase in cell growth is by increasing their ability to synthesize proteins through mutation of genes such as Rb and p53 that normally function to repress RNA polymerase I and III transcription (for review see Nasmyth, 1996;Larminie et al, 1998;White, 1997).…”

The HMG-box transcription factor HBP1 is targeted by the pocket proteins and E1A

“…RB can repress most RNA polymerase III (Pol III) transcribed genes in vivo (White et al, 1996) and can regulate RNA polymerase I (pol I) transcription by repressing the UBF transcription factor (Cavanaugh et al, 1995). Repression of pol I, pol III and E2F regulated pol II genes requires the pocket domain of RB (which is found mutated in tumours) and is alleviated by viral transforming proteins such as E1A binding to RB.…”