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Coping with Stress: Multiple Ways to Activate P53

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Coping with Stress: Multiple Ways to Activate P53 Oncogene (2007) 26, 1306–1316 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Coping with stress: multiple ways to activate p53 HF Horn and KH Vousden The Beatson Institute for Cancer Research, Glasgow, UK Over the years, p53 has been shown to sit at the centre of Srivastava et al., 1990). Furthermore, mouse studies an increasingly complexweb of incoming stress signals have corroborated the importance of p53 in tumour and outgoing effector pathways. The number and diversity development; p53 null mice can develop normally but of stress signals that lead to p53 activation illustrates the nearly all develop cancer before 6 months of age breadth of p53’s remit – responding to a wide variety of (Donehower et al., 1992; Jacks et al., 1994; Purdie potentially oncogenic insults to prevent tumour develop- et al., 1994). Taken together, a role for p53 as a key ment. Interestingly, different stress signals can use player in the inhibition of tumour development is different and independent pathways to activate p53, and beyond doubt. However, there is growing evidence that there is some evidence that different stress signals can p53 also contributes to other pathologies beyond cancer mediate different responses. How each of the responses to – including a possible contribution in determining p53 contributes to inhibition of malignant progression is longevity – making it unlikely that the high degree of beginning to be clarified, with the hope that identification interest in p53 will wane. of responses that are key to tumour suppression will allow a more focused and effective search for new therapeutic targets. In this review, we will highlight some recently identified roles for p53 in tumour suppression, and discuss The downstream response to p53 activation some of the numerous mechanisms through which p53 can be regulated and activated. The p53 protein is a transcription factor that regulates Oncogene (2007) 26, 1306–1316. doi:10.1038/sj.onc.1210263 the expression of a large number of target genes (Vogelstein et al., 2000). Through this mechanism p53 Keywords: p53; tumour suppression; MDM2; ubiquiti- can induce a number of differentresponses, ranging nation; apoptosis from the induction of cell cycle arrest, cell death and senescence to protective antioxidant activities, DNA repair and the control of mitochondrial respiration. One of the first transcriptional targets of p53 to be identified was the cyclin dependent kinase (CDK) Waf1/Cip1 Introduction inhibitor p21 (El-Deiry et al., 1994). CDKs play an important role in regulating progression through the cell Waf1/Cip1 Since its discovery over a quarter of a century ago, work cycle, and the inhibition of CDK activity by p21 on the tumour suppressor protein p53 has produced results in a cell cycle arrest (reviewed in Sherr and nearly 40 000 publications. This vast amount of work on Roberts, 1999). Thus, p53 can effectively cause cells to one protein is arguably justified by the importance of stop proliferating, which – among other things – allows p53 in cancer biology, as illustrated by the frequency for the repair of any damaged DNA, preventing muta- with which p53 function is lost during tumour develop- tions from being passed on to daughter cells. Interest- ment. Approximately 50% of all malignancies carry a ingly, a directrole for p53 in DNA repair has also been p53 mutation, and of those tumours that do not have demonstrated (reviewed in Gatz and Wiesmuller (2006)). mutated p53, a large proportion have inactivated p53 Recently, other activities of p53 that can inhibit the function by another mechanism (Hainaut and Hollstein, acquisition of potentially oncogenic mutations have 2000; Bykov and Wiman, 2003). Taken together, p53 been described. Several studies have shown an anti- function is lost in almost all tumours. The importance oxidant role for p53 resulting from the expression of of p53 as a tumour suppressor is illustrated by target genes that reduce intracellular reactive oxygen the observation that many individuals affected by Li species (ROS) levels and so preventgenotoxic damage Fraumeni syndrome – and so displaying an abnormally (Budanov et al., 2004; Yoon et al., 2004; Sablina et al., high and early incidence of tumour development – suffer 2005; Bensaad et al., 2006). This function of p53 appears a germline mutation in p53 (Malkin et al., 1990; to be important even in the absence of acute, high levels of stress – and probably reflects a response to lower levels of constitutive stress that accompany everyday life Correspondence: Professor KH Vousden, The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 of complex multicellular organisms (Sablina et al., 1BD, UK. 2005). These antioxidant functions of p53 are linked E-mail: [email protected] with enhanced survival of cells expressing p53, and so Activation of p53 HF Horn and KH Vousden 1307 seem to be at odds with another important activity of suggesting that both transcriptional and non-transcrip- p53, which is to induce cell death through apoptosis or tional activities of p53 are important for the induction of autophagy. Why would p53 induce repair of a cell that it cell death (reviewed in Yee and Vousden, 2005). then targets for destruction? While some of the answer clearly lies in cell-type dependent differences, an interesting model is emerging where p53 behaves Regulation of p53 function differently depending on the severity of the stress (Bensaad and Vousden, 2005). In response to low, The anti-proliferative activities of p53 play an important constitutive stress, p53 activates expression of genes that role in tumour suppression, but require strong negative drive a temporary cell cycle arrest, allowing for the regulation to allow for normal growth and development. removal of intracellular ROS and repair of any damage Not surprisingly, this regulation of p53 takes many that may have occurred. But when the stress-induced forms, including the regulation of expression, protein damage is too severe for the cell to recover, p53 initiates stability and protein activity. Many post-transcriptional programmed cell death – so eliminating cells that may modifications of p53 have been described including have acquired irreparable and potentially oncogenic phosphorylation, acetylation, methylation, glycosyla- alterations. The transcriptional targets of p53 include a tion, ribosylation and, most recently, O-GlcNAcylation number of pro-apoptotic proteins such as the BH3 only (Bode and Dong, 2004; Yang et al., 2006c). However, proteins Puma and Noxa (Oda et al., 2000; Nakano and in vivo models have suggested that these modifications Vousden, 2001; Yu et al., 2001). These proteins function play only very subtle, modulatory roles in regulating by inducing the loss of inner mitochondrial membrane p53 function (Toledo and Wahl, 2006). The interaction potential, leading to the release of cytochrome C and of p53 with proteins that control p53 function, either other apoptogenic factors and the activation of the directly or through the regulation of p53 stability, caspase cascade that results in apoptotic cell death appears to be key in turning on and off the p53 (Jeffers et al., 2003; Villunger et al., 2003; Yu et al., 2003 response. and reviewed in Danial and Korsmeyer, 2004). Activa- tion of autophagy by the p53-induced protein DRAM (damage-regulated autophagy modulator) has also Regulation of p53 protein stability been described to be an important contributor of the p53 is degraded via the proteasome by a predominately apoptotic response (Crighton et al., 2006). ubiquitin-dependent mechanism, and a number of Inkeeping with its function as a transcription factor, ubiquitin ligases that promote the ubiquitination and p53 is predominately a nuclear protein. However, a subsequentdegradationof p53 have been identified fraction of p53 can be found in the cytoplasm. Recent (Table 1). studies have demonstrated an unexpected transcription- By far the best studied of these is Mdm2 (sometimes ally independent function for this pool of p53 as a BH3- referred to as HDM2 in humans) – a RING finger only protein, inducing apoptosis by directly binding to protein that is essential to regulate p53 and allow the pro-apoptotic proteins Bax and Bak, as well as the survival during normal development(Jones et al., 1995; anti-apoptotic proteins like BclxL (Mihara et al., 2003; Montes de Oca Luna et al., 1995). Mdm2 functions as a Chipuk et al., 2004; Leu et al., 2004). Interestingly ubiquitin ligase, in which the RING domain is necessary PUMA, a transcriptional target of p53, can activate to promote the ubiquitination and degradation of its this cytoplasmic function of p53 (Chipuk et al., 2005), target proteins, including p53 (Fang et al., 2000). Mdm2 Table 1 E3s that target p53, including the class of E3 and other targets E3 Class Other targets Referencess Mdm2 RING Mdm2, MdmX, Histone H2A and H2B, hnRNP Iwakuma and Lozano (2003), Brady et al. (2005), Zhang and K, RB, b-arrestin, MTBP, E2F/DP1, p21(Waf1) Zhang (2005), Cheng and Cohen (2007), Salcedo et al. (2006), Numb, PSD-95, androgen receptor, PCAF, Yang et al. (2006a) E-cadherin, G-protein coupled receptor kinase 2, TSG101, Tip60, Insulin-like growth factor 1 receptor, glucocorticoid receptor Cop1 RING Cop1, acetyl-coenzyme A carboxylase (ACC) Dornan et al. (2004, 2006), Qi et al. (2006) Pirh2 RING HDAC1 Leng et al. (2003), Logan et al. (2006) ARF BP1/ HECT MCL1, Myc Adhikary et al. (2005), Chen et al. (2005b), Zhong et al. (2005) HectH9/ MULE E6AP HECT AIB1 Reviewed in Longworth and Laimins (2004), Mani et al. (2006) CHIP U-box A range of chaperone-bound proteins, HSP70 McDonough and Patterson (2003), Esser et al. (2005) Cullin 7 RING Andrews et al. (2006) WWP1 HECT KLF2, KLF5, Smad4 Zhang et al. (2004), Moren et al. (2005), Chen et al. (2005a), Laine and Ronai (2006) Topors RING Hairy (Drosophila) Rajendra et al. (2004), Secombe and Parkhurst(2004) Carps RING Caspase 8 and 10 McDonald and El-Deiry (2004), Yang et al.
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