Decision Making by p53: Life versus Death.

Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York.
Molecular and Cellular Pharmacology 01/2010; 2(2):69-77. DOI: 10.4255/mcpharmacol.10.10
Source: PubMed

ABSTRACT Cellular response to DNA damage is multifacted in nature and involves a complex signaling network in which p53 functions as a "molecular node" for converging signals. p53 has been implicated in a variety of cellular processes primarily functioning as a transcription factor and also in a transcription-independent manner. It is rapidly activated following DNA damage with phosphorylation as one of the initial signals. Cellular context as well as the type and severity of DNA damage determine p53 activation code, and its activities are regulated predominantly through protein degradation, post-translational modification and interactions with various cellular co-factors. These events are crucial in decision making by p53 as it has the ability to receive, assess and integrate different signals and route them accordingly to induce cell death or promote cell survival. In this decision making process, its transcriptional role to activate a specific subset of target genes linked to inducing cell cycle arrest or apoptosis is critical that is further fine-tuned by its transcription-independent function. This article reviews the current state of knowledge about the role of p53 in determining the fate of cells that have incurred DNA damage.

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Available from: Lingyan Jiang, Dec 19, 2013
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    • "ROS-mediated DNA damage in mouse skin leads to enhanced expression of p53 and p21waf1 that causes cell cycle arrest at the G0/G1 and G2/M phases12 as reported by Abbas and Dutta in in vitro models69, to enhanced Bax/Bcl2 ratio and cytochrome c release, and to activated caspase 9 and 3 but not caspase 8, which result in apoptosis through the mitochondria-mediated pathway12. The p53 protein plays a key role in the DNA damage response pathway by transmitting a variety of stress signals associated with antiproliferative cellular responses that lead to apoptosis70, and the lack of enhancement in caspase 8 activity indicates that the extrinsic or death receptor pathway of apoptosis is not activated by CTN in mouse skin. Moreover, Kumar et al. clarified that topical treatment of bio-antioxidants such as butylated hydroxyanisole, quercetin and α-tocopherol abolishes CTN-induced oxidative stress, cell cycle arrest and apoptosis, confirming the direct involvement of ROS in CTN-induced toxicological manifestations in mouse skin12. "
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    ABSTRACT: Among the many mycotoxins, T-2 toxin, citrinin (CTN), patulin (PAT), aflatoxin B1 (AFB1) and ochratoxin A (OTA) are known to have the potential to induce dermal toxicity and/or tumorigenesis in rodent models. T-2 toxin, CTN, PAT and OTA induce apoptosis in mouse or rat skin. PAT, AFB1 and OTA have tumor initiating properties, and OTA is also a tumor promoter in mouse skin. This paper reviews the molecular mechanisms of dermal toxicity and tumorigenesis induced in rodent models by these mycotoxins especially from the viewpoint of oxidative stress-mediated pathways.
    Journal of Toxicologic Pathology 04/2014; 27(1):1-10. DOI:10.1293/tox.2013-0062 · 0.53 Impact Factor
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    • "The tumor suppressor p53 is a transcriptional activator that plays an essential role in DNA damage response by inducing cell cycle arrest, senescence and/or apoptosis [35], [36]. p53 triggers cell cycle arrest at G1 phase by transactivating cyclin-dependent kinase inhibitor 1A (CDKN1A)/p21 gene which causes cell cycle arrest and suppresses cell proliferation [37], [38], [39]. "
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    ABSTRACT: The human AP-endonuclease (APE1/Ref-1), an essential multifunctional protein involved in repair of oxidative DNA damage as well as in transcriptional regulation, is often overexpressed in tumor cells. APE1 was earlier shown to stimulate p53's DNA binding and its transactivation function in the expression of cyclin-dependent kinase inhibitor p21 (CDKN1A) gene. Here, we show APE1's stable binding to p53 cis elements which are required for p53-mediated activation of p21 in p53-expressing wild type HCT116 cells. However, surprisingly, we observed APE1-dependent repression of p21 in isogenic p53-null HCT116 cells. Ectopic expression of p53 in the p53-null cells abrogated this repression suggesting that APE1's negative regulatory role in p21 expression is dependent on the p53 status. We then identified APE1's another binding site in p21's proximal promoter region containing cis elements for AP4, a repressor of p21. Interestingly, APE1 and AP4 showed mutual dependence for p21 repression. Moreover, ectopic p53 in p53-null cells inhibited AP4's association with APE1, their binding to the promoter and p21 repression. These results together establish APE1's role as a co-activator or co-repressor of p21 gene, dependent on p53 status. It is thus likely that APE1 overexpression and inactivation of p53, often observed in tumor cells, promote tumor cell proliferation by constitutively downregulating p21 expression.
    PLoS ONE 07/2013; 8(7):e68467. DOI:10.1371/journal.pone.0068467 · 3.23 Impact Factor
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    • "Such a negative feedback loop between p53 and Mdm2 maintains p53 at a low level in unstressed cells. Upon induction of DNA damage, the inhibitory interaction between p53 and Mdm2 is disrupted by phosphorylation of both proteins, resulting in p53 accumulation [15]. To test whether the bimodal switch of p53 induction is a result of differences in Mdm2 activation, we performed immunoblotting to compare the dynamics of ensemble p53 and Mdm2 at 1 and 100 μmol/l etoposide, as under these two extreme concentrations, cells largely exhibited the same p53 dynamics of either pulsing or monotonic increase. "
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    ABSTRACT: The p53 pathway is differentially activated in response to distinct DNA damage, leading to alternative phenotypic outcomes in mammalian cells. Recent evidence suggests that p53 expression dynamics play an important role in the differential regulation of cell fate, but question remains how p53 dynamics and the subsequent cellular response are modulated by variable DNA damage. Here we identified a novel, bimodal switch of p53 dynamics modulated by DNA damage strength that is crucial for cell fate control. At low DNA damage, p53 underwent periodic pulsing and cells entered cell-cycle arrest. At high DNA damage, p53 underwent a strong monotonic increase and cells activated apoptosis. We found that the damage dose-dependent bimodal switch was due to differential Mdm2 up-regulation, which controlled the alternative cell fates mainly by modulating p53's induction level and pro-apoptotic activities. Our findings not only uncover a new mode of regulation for p53 dynamics and cell fate but also suggest that p53 oscillation may function as a suppressor, maintaining a low level of p53 induction and pro-apoptotic activities so as to render cell-cycle arrest that allows damage repair.
    BMC Biology 06/2013; 11(1):73. DOI:10.1186/1741-7007-11-73 · 7.98 Impact Factor
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