RB: mitotic implications of a tumour suppressor

Abstract

RB, a well known tumour suppressor that functions in the control of cell cycle progression and proliferation, has recently been shown to have additional functions in the maintenance of genomic stability, such that inactivation of RB family proteins promotes chromosome instability (CIN) and aneuploidy. Several studies have provided potential explanations for these phenomena that occur following RB loss, and they suggest that this new function of RB may contribute to its role in tumour suppression.

Figure 1. Mechanisms of CIN

Recent papers from several groups have proposed three different mechanisms to explain how the corruption of the RB pathway can promote chromosome segregation errors, chromsome instability (CIN) and aneuploidy.

Figure 2. pRB-mediated effects on progression of S through M phase

The RB/E2F pathway has well characterized roles in the regulation of quiescence, senescence and S phase entry. RB also regulates the expression of genes that act at later stages of the cell cycle and has been shown to physically interact with proteins that function during these stages ^{, -, , , -}. As a result, the functional inactivation of pRB does not simply affect G1 regulation, but influences cell cycle events that occur later in the cell cycle. Changes that occur at any of these steps can be detrimental to genomic stability.

Figure 3. The CINful path

Previous models to explain CIN and aneuploidy when pRB is inactivated have proposed that specific cellular changes (green), such as changes in the expression of mitotic proteins, changes in chromatin structure, or defects in replication fork progression ultimately cause defects during mitosis (blue). This figure illustrates the fact that these different aspects of the pRB-loss of function phenotype do not exist in isolation, but are highly interconnected and are likely to influence one another. We suggest that changes in chromosome segregation and genome stability seen when pRB-proteins are inactivated represent the combined effect of mutiple defects.