Differential effects on p53-mediated cell cycle arrest vs. apoptosis by p90

Abstract

p53 functions as a central node for organizing whether the cell responds to stress with apoptosis or cell cycle arrest; however, the molecular events that lead to apoptotic responses are not completely understood. Here, we identified p90 (also called Coiled-Coil Domain Containing 8) as a unique regulator for p53. p90 has no obvious effects on either the levels of p53 or p53-mediated cell cycle arrest but is specifically required for p53-mediated apoptosis upon DNA damage. Notably, p90 is crucial for Tip60-dependent p53 acetylation at Lys120, therefore facilitating activation of the proapoptotic targets. These studies indicate that p90 is a critical cofactor for p53-mediated apoptosis through promoting Tip60-mediated p53 acetylation.T he p53 tumor suppressor acts as the major sensor for a regulatory circuit that monitors signaling pathways from diverse sources, including DNA damage, oncogenic events, and other abnormal cellular processes (1, 2). p53 monitors and responds to a multitude of stress signals by coordinating cell growth arrest or apoptosis (3-5). Central to p53 regulation of these cellular processes is its activity as a transcription factor, although transcription-independent functions of p53 are also critical under some biological settings. The activation of p53 transcription activity requires multiple steps, including sequence-specific DNA binding, antirepression and acquirement of combinations of posttranslational modifications, and recruitment of corepressors/coactivators in a promoter-specific manner (6). To suppress tumor growth, p53 induces either cell growth arrest or apoptosis depending on the cellular context. The molecular mechanisms that govern the choice between growth arrest and apoptosis are extremely important but not well understood (4, 7). As a key player in the stress response, p53 demands an exquisitely complicated network of control and fine-tuning mechanisms to ensure correct, differentiated responses to the various stress signals encountered by cells (2,5,(8)(9)(10).p53 was the first nonhistone protein known to be regulated by acetylation and deacetylation (11,12). There is accumulating evidence indicating that acetylation of p53 plays a major role in activating p53 function during stress responses (2, 13, 14). Following our early findings of C terminus p53 acetylation, we and others recently showed that p53 is also acetylated by Tip60 (also known as KAT5)/MOF (human ortholog of males absent on the first) at residue Lys120 (K120) within the DNA-binding domain (15-17). K120 acetylation is crucial for p53-mediated apoptosis but has no obvious effect on p21 expression, an essential target of p53-mediated growth arrest. Notably, although Tip60 is required for K120 acetylation of p53 in vivo, the levels of K120 acetylation are dynamically regulated in vivo and the interaction between p53 and Tip60 is not very stable, indicating that additional regulators may play a role in controlling K120 acetylation and subsequent p53-mediated apoptotic response (18)(19)(20). Through biochemical pur...

Ankyrin Repeats of ANKRA2 Recognize a PxLPxL Motif on the 3M Syndrome Protein CCDC8

“…CUL7 stimulates ubiquitination of p53, insulin receptor substrate 1, and the hominoid-specific TBC1D3 oncoprotein (Andrews et al, 2006;Kong et al, 2012;Xu et al, 2008). Related to the interaction of CUL7 with p53, CCDC8 was recently reported to bind p53 (Dai et al, 2011). Our results indicate that ANKRA2 does not affect p53 ubiquitination (data not shown).…”

Structural Basis for p53 Lys120-Acetylation-Dependent DNA-Binding Mode

“…Similar effect was found in a mouse knock-in model carrying the K117R mutation (analogous to K120 in human) [28]. The biochemical processes that regulate Lys120 acetylation-as well as deacetylationhave been studied by several groups [24,27,[29][30][31][32], but less is known about the molecular mechanism downstream of Lys120 acetylation and how this acetylation event directly affects the transcriptional activity of p53 and its interaction with the DNA.…”

Caspase-3 and RasGAP: a stress-sensing survival/demise switch

“…Only strong and sustained ER stress allows the accumulation of proapoptotic labile proteins such as the transcription factor CHOP [66,67]. Similarly, distinct post-translational modifications (e.g., acetylation of lysine 150 or phosphorylation of serine 46) generated by various degrees of DNA damage determine whether p53 preferentially stimulates a repair pathway versus a cell-death response [68][69][70] one could propose a general paradigm where cellular stress is sensed by molecules and pathways that stimulate either cell survival or apoptosis based on the extent of their stimulation (as in the case of the UPR) or as a result of stressmediated differential post-translational modifications (e.g., cleavage of RasGAP, acetylation/phosphorylation of p53). Hence, cells may use the same set of sensor proteins to finetune an appropriate cellular response resulting in either cell survival or cellular demise, rather than relying on separate sensors for either response.…”