The retinoblastoma protein and cell cycle control

RA Weinberg - cell, 1995 - Elsevier
cell, 1995Elsevier
Whitehead Institute for Biomedical Research Massachusetts Institute of Technology
Cambridge, Massachusetts 02142 pRB, the product of the retinoblastoma tumor suppressor
gene, operates in the midst of the cell cycle clock apparatus. Its main role is to act as a signal
transducer connecting the cell cycle clock with the transcriptional machinery. In this role,
pRB allows the clock to control the expression of banks of genes that mediate advance of
the cell through a critical phase of its growth cycle. Loss of pRB function deprives the clock …
Whitehead Institute for Biomedical Research Massachusetts Institute of Technology Cambridge, Massachusetts 02142 pRB, the product of the retinoblastoma tumor suppressor gene, operates in the midst of the cell cycle clock apparatus. Its main role is to act as a signal transducer connecting the cell cycle clock with the transcriptional machinery. In this role, pRB allows the clock to control the expression of banks of genes that mediate advance of the cell through a critical phase of its growth cycle. Loss of pRB function deprives the clock and thus the cell of an important mechanism for braking cell proliferation through modulation of gene expression. pRB and the G1 Restriction Point pRB exerts most and perhaps all of its effects in a defined window of time in the first two thirds of the G1 phase of the cell cycle. As demonstrated by Pardee almost two decades ago, this is the time window during which the mammalian cell makes most of its decisions about growth versus quiescence. Cells entering G1 from mitosis require serum mitogens continuously until several hours before the onset of S phase; thereafter, they become relatively serum independent. This transition from a serum-dependent to serum-independent state is demarcated by a discrete point in time, which he termed the R (restriction) point (Pardee, 1989). By passing through the R point, the cell commits itself to traverse the remainder of its growth cycle through M, barring major misadventure such as DNA damage or metabolic disturbance. Such a commitment decision represents a transition in the life of the cell that is as important as the much-studied G0/G1 emergence of the cell from quiescence. pRB undergoes a readily discernible alteration at a time close to and perhaps contemporaneous with the R point transition. Through the preceding hours of G 1, pRB is found in an underphosphorylated form. The bulk of pRB prepared from cells during the last several hours of G1 is, in contrast, hyperphosphorylated, pRB maintains this hyperphosphorylated configuration throughout the remainder of the cell cycle, losing its multiple phosphate groups only upon emergence from M.
Several lines of evidence indicate that this phosphorylation causes the inactivation of the growth inhibitory functions of pRB. First, oncoproteins made by three classes of DNA tumor viruses eliminate pRB function by binding and sequestering hypophosphorylated pRB, ignoring hyperphosphorylated forms. Second, the hypophosphorylated form binds and ostensibly controls a number of other cellular proteins (see below); the hyperphosphorylated form appears to have lost the ability to interact with these proteins. Third, conditions that cause pRB phosphorylation favor cell proliferation (reviewed by Cobrinik et al., 1992).
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