Abstract #SY15-4: Functions of p53 in cell senescence and survival

The p53 protein is an important tumor suppressor that activates a number of different responses, including cell cycle arrest, senescence and apoptosis. While the induction of apoptosis and senescence both play important roles in the tumor suppressive response to p53, there is evidence that these might represent separable responses to p53 - resulting from the activation of distinct sets of p53 target genes (1). Certain point mutations in the DNA binding domain of p53 can distinguish the cell cycle arrest and apoptotic responses, and post-translational modification of p53 or association with other proteins can also contribute to the choice of response. Interestingly, different tumor types can respond differently to p53 activation, although it seems clear that both apoptosis and senescence can be effective therapeutic outcomes (2-4). The ASPP family of proteins have been identified as important modulators of the p53 response, with full length ASPP1 and ASPP2 contributing to the ability of p53 to induce apoptosis (5). We have been investigating the role of the p53 binding protein ASPP1 in the regulation of outcome to p53 activation and this work will be discussed. Interestingly, ASPP1 expression can be regulated by the E2F transcription factors (6-8) and stress signals that activate E2F - such as oncogene activation and DNA damage - result in an up-regulation of ASPP1 expression. We are presently investigating the effect of modulating ASPP1 expression on tumor growth and the response to therapy. Although the ability of p53 to negatively regulate cell growth through apoptosis or senescence has been understood for some time, more recently several additional activities of p53 have been described, including the ability to function as an antioxidant and to contribute to the regulation of metabolism (9). In several cases these activities of p53 can act to promote survival, an apparent contradiction to the well understood apoptotic role of p53. The induction of survival signals appears to be a rapid response to p53 activation and may be limited to situations of mild or transient stress. It is possible that p53\#8217;s contribution to cell survival is accompanied by attempts to resolve moderate DNA damage, and it is known that p53 can directly contribute to DNA repair pathways. The emerging model suggests that only irreparable damage or sustained stress would switch the p53 response to eliminate cells through mechanisms such as apoptosis or senescence (10). However, these dual functions of p53 bring the possibility that p53 activities designed to protect cells from death to allow repair would be counterproductive when the apoptotic pathway is engaged. Indeed, there is evidence that the pro-survival response to p53 is switched off as the apoptotic response becomes activated. p53 can activate the expression of a number of proteins with antioxidant activities such as TIGAR, a protein that shows similarity to the bisphosphatase domain of the bifunctional enzyme PFK-2/FBPase-2, which is one of the principal regulators of glycolysis (11). Expression of TIGAR drives the pentose phosphate pathway, resulting in enhanced NADPH production and so restoring reduced glutathione levels. This helps to lower intracellular ROS levels and we have shown that TIGAR expression helps to protect the cell from ROS-associated apoptosis. More recently we have been investigating a role of TIGAR in the regulation of autophagy and senescence. These responses may protect from tumor development if they prevent genotoxic damage or assist in its repair. However, the modulation of ROS and other metabolic pathways by TIGAR might also contribute to tumor cell growth and survival, if not tightly regulated. 1.%9Vousden KH, Lu X. Live or let die: the cell's response to p53. Nature Reviews Cancer 2002;2:594-604. 2.%9Martins CP, Brown-Swigart L, Evan GI. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 2006;127:1323-34. 3.%9Ventura A, Kirsch DG, McLaughlin ME, et al. Restoration of p53 function leads to tumour regression in vivo. Nature 2007;445:661-5. 4.%9Xue W, Zender L, Miething C, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007;445:656-60. 5.%9Sullivan A, Lu X. ASPP: a new family of oncogenes and tumour suppressor genes. British journal of cancer 2007;96(2):196-200. 6.%9Fogal V, Kartasheva NN, Trigiante G, et al. ASPP1 and ASPP2 are new transcriptional targets of E2F. Cell Death Differ 2005;12:369-76. 7.%9Zhu Z, Ramos J, Kampa K, et al. Control of ASPP2/(53BP2L) protein levels by proteasomal degradation modulates p53 apoptotic function. J Biol Chem 2005;280(41):34473-80. 8.%9Chen D, Padiemos E, Ding F, Lossos IS, Lopez CD. Apoptosis-stimulating protein of p53-2 (ASPP2/53BP2L) is an E2F target gene. Cell Death Differ 2005;12:358-68. 9.%9Bensaad K, Vousden KH. p53: new roles in metabolism. Trends Cell Biol 2007;17:286-91. 10.%9Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol 2007;8(4):275-83. 11.%9Bensaad K, Tsuruta A, Selak MA, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 2006;126:107-20.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr SY15-4.