RETRACTED ARTICLE: p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation

Abstract

p14 ARF is a tumour suppressor which plays a critical role in p53-dependent or -independent cell growth control. Several studies have recently provided evidence that p14 ARF can also interfere either directly or indirectly with some components of the RB signalling pathway to mediate its antiproliferative activity. The aim of this study was to explore the existence of direct relationships between p14 ARF and RB proteins. We show that p14 ARF promotes the accumulation of a hypoacetylated RB protein, when it is upregulated in a model of stable-inducible clones or physiologically induced following cell exposure to cytotoxic agents. Looking for the mechanisms involved in this process, we demonstrate that the histone acetyl transferase Tip60 directly interacts with RB and stimulates its degradation by the proteasome through acetylation of its C-terminus. Furthermore, and consistent with p14 ARFinduced RB accumulation, we provide evidence that p14 ARF prevents Tip60-mediated RB acetylation, therefore precluding its proteasomal degradation. Overall, our results identify a novel mechanism by which p14 ARF controls the RB pathway to trigger its antiproliferative function.

Acetylation controls Notch3 stability and function in T-cell leukemia

“…Previous reports have shown that acetylation of nonhistone proteins may be linked to regulation of their stability (Hernandez-Hernandez et al, 2006;Leduc et al, 2006;Mateo et al, 2009 (Figure 2c). This observation implies that N3 IC is a substrate of HAT-dependent acetylation.…”

“…Protein acetylation has been reported to prime subsequent ubiquitin-dependent stability of target proteins (Hernandez-Hernandez et al, 2006;Leduc et al, 2006). Although we and others suggested that proteasomal degradation of Notch intracellular domain (N IC ) may be required for repressing Notch signaling, the underlying mechanisms are still to be clarified.…”

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.…”

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

“…The lysine residues targeted by Tip60 remain to be identified, but as the pRb mutant derivative K873/K874 could still be acetylated, it seems that the residues targeted by Tip60 are distinct from those acetylated by p300 and P/CAF (Leduc et al, 2006). Tip60 interacts with pRb and this triggers its degradation by the proteasome (Leduc et al, 2006). Further, through an unknown mechanism the tumour suppressor protein, p14 ARF prevents Tip60 acetylation of pRb and in turn prevents its degradation (Leduc et al, 2006).…”

“…Tip60 interacts with pRb and this triggers its degradation by the proteasome (Leduc et al, 2006). Further, through an unknown mechanism the tumour suppressor protein, p14 ARF prevents Tip60 acetylation of pRb and in turn prevents its degradation (Leduc et al, 2006).…”