RNA polymerase III transcription: its control by tumor suppressors and its deregulation by transforming agents.
The level of RNA polymerase (pol) III transcription is tightly linked to the rate of growth; it is low in resting cells and increases following mitogenic stimulation. When mammalian cells begin to proliferate, maximal pol III activity is reached shortly before the G1/S transition; it then remains high throughout S and G2 phases. Recent data suggest that the retinoblastoma protein RB and its relatives p107 and p130 may be largely responsible for this pattern of expression. During G0 and early G1 phase, RB and p130 bind and repress the pol III-specific factor TFIIIB; shortly before S phase they dissociate from TFIIIB, allowing transcription to increase. At the end of interphase, when cells enter mitosis, pol III transcription is again suppressed; this mitotic repression is achieved through direct phosphorylation of TFIIIB. Thus, pol III transcription levels fluctuate as mammalian cells cycle, being high in S and G2 phases and low during mitosis and early G1. In addition to this cyclic regulation, TFIIIB can be bound and repressed by the tumor suppressor p53. Conversely, it is a target for activation by several viruses, including SV40, HBV, and HTLV-1. Some viruses also increase the activity of a second pol III-specific factor called TFIIIC. A large proportion of transformed and tumor cell types express abnormally high levels of pol III products. This may be explained, at least in part, by the very high frequency with which RB and p53 become inactivated during neoplastic transformation; loss of function of these cardinal tumor suppressors may release TFIIIB from key restraints that operate in normal cells.
Brown
T R
TR
Institute of Biomedical and Life Sciences, Division of Biochemistry and Molecular Biology, University of Glasgow, UK.
Scott
P H
PH
Stein
T
T
Winter
A G
AG
White
R J
RJ
D000818:Animals; D002453:Cell Cycle; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D008322:Mammals; D012320:RNA Polymerase III / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D035361:Transcription Factor TFIIIB; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016160:Retinoblastoma Protein; D035361:Transcription Factor TFIIIB; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D012320:RNA Polymerase III