Diversity within the pRb pathway: is there a code of conduct?

Abstract

The failure of cell proliferation to be properly regulated is a hallmark of tumourigenesis. The retinoblastoma protein (pRb) pathway represents a key component in the regulation of the cell cycle and tumour suppression. Recent findings have revealed new levels of complexity reflecting a repertoire of post-translational modifications that occur on pRb together with its key effector E2F-1. Here we provide an overview of the modifications and consider the possibility of a 'code' that endows pRb with the ability to function in diverse physiological settings.

JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

“…23 In addition, methylation of RB have been shown to affect its function. 25 Therefore, we intended to determine whether JMJD3 interacted with RB. First, we examined the relationship between JMJD3 and RB by using the co-immunoprecipitation (CoIP) assay, and the results showed that the ectopically expressed His-JMJD3 and Flag-RB in HEK-293T cells (Figure 4a), as well as the endogenous JMJD3 and RB in WI38 cells (Figure 4b), were co-precipitated.…”

“…25 The truncated peptide RB(659-840) shown to interact with JMJD3 described above comprises the K810 residue, and this encouraged us to speculate that K810 may be the site JMJD3 demethylates the RB protein. Set7/9 is a methyltransferase reported to methylate the K810 and K873 sites at the C-terminal region of RB.…”

“…Multiple sites of phosphorylation of RB have been identified, and the increased level of RB phosphorylation at S807/811 results in dissociation of E2F from RB and activates the transcription of genes required for DNA synthesis and cell cycle progression. 25 Apart from the phosphorylation, methylation of RB has emerged as an important modification in recent years; for example, three lysine residues (K810, K873 and K860) within the C-terminal domain of RB have been reported to be methylated. [25][26][27] Particularly, the methylation of K810 residue has been found to bring about variable effects on the function of RB.…”

“…25 Apart from the phosphorylation, methylation of RB has emerged as an important modification in recent years; for example, three lysine residues (K810, K873 and K860) within the C-terminal domain of RB have been reported to be methylated. [25][26][27] Particularly, the methylation of K810 residue has been found to bring about variable effects on the function of RB. For instance, methylation of K810 by SET domain containing protein 7 (Set7/9) retains the hypophosphorylated status of RB and suppresses the cellular growth in U2OS cells.…”

RB1: a prototype tumor suppressor and an enigma

“…The idea that pRB's binding activity is tailored by phosphorylation is only part of the story. Evidence that pRB is both acetylated and methylated in specific contexts (Chan et al 2001;Nguyen et al 2004;Leduc et al 2006;Munro et al 2010;Saddic et al 2010), evidence of interplay between different post-translational modifications (Carr et al 2011;Macdonald and Dick 2012;Munro et al 2012;Kim et al 2015), and evidence that pRB interacts with specific partners in response to cellular cues (MacLellan et al 2000;Miyake et al 2000;Dick and Dyson 2003;Nguyen et al 2004;Carr et al 2014) all suggest additional levels of diversity. Collectively, these observations raise several intriguing possibilities: (1) There may be multiple pools of pRB that perform different functions.…”