P53 Structure and Function

Topics: P53, Cancer, DNA Pages: 47 (15729 words) Published: December 11, 2012
Review Article

p53: Structure, Function and Therapeutic Applications
Ling Bai and Wei-Guo Zhu1
Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China [L. Bai, W.-G. Zhu]; Department of Biotechnology, Guilin Medical College, Guilin, China [L. Bai] Since the p53 tumor suppressor gene has been found to be mutated in more than 50% of human cancers, it has attracted the interest of numerous researchers. The capacity of p53 for multiple biological functions can be attributed to its ability to act as a sequence-specific transcription factor to regulate expression of over one hundred different targets, and thus to modulate various cellular processes including apoptosis, cell cycle arrest and DNA repair. The p53 protein with its unique C- and N-terminal structures is rigidly modulated by several important biological processes such as phosphorylation, acetylation and ubiquitination, through which it effectively regulates cell growth and cell death. p53 mutations can lead either to loss or change of p53 binding activity to its downstream targets and may thus induce aberrant cell proliferation, with consequent malignant cellular transformation. Based on p53’s critical role in carcinogenesis, scientists have developed multiple effective strategies for treating cancer by enhancing function of wild-type p53 or increasing p53 stability. This review will focus on (i) discussing of the relationship between p53 structure and function, (ii) p53 mutations, and (iii) recent strategies for improving the efficacy of cancer treatment by therapeutic manipulation of p53. Journal of Cancer Molecules 2(4): 141-153, 2006.

p53 posttranslational modifications p53 mutation therapeutic strategies

p53 protein was first identified in 1979 as a transformation-related protein [1] and a cellular protein which accumulates in the nuclei of cancer cells and binds tightly to the simian virus 40 (SV402) large T antigen [2,3]. The gene encoding p53 was initially found to have weak oncogenic activity as the p53 protein was observed to be overexpressed in mouse and human tumor cells [4]. However, almost 10 years later, researchers discovered that it was a missense mutant of p53 which had originally been considered as wild-type p53 (wt p53) in that previous study, and that the oncogenic properties of p53 actually reReceived 6/20/06; Revised 7/30/06; Accepted 7/31/06. 1 Correspondence: Dr. Wei-Guo Zhu, Department of Biochemistry and Molecular Biology, Beijing University Health Science Center, No. 38, Xueyuan Road, Beijing, 100083, China. Phone: 86-10-8280 2235. Fax: 86-10-8280 5079. Email: zhuweiguo@bjmu.edu.cn 2 Abbreviations: SV40, simian virus 40; wt p53, wild-type p53; mt p53, mutated p53; MDM2, murine double minute 2; DSBs, double strand breaks in DNA; ATM, ataxia-telangiectasia mutated protein; ATR, ATM and Rad3-related protein; Gadd45, growth arrest and DNAdamage-inducible protein 45; CDK, cyclin-dependent kinase; Bax, Bcl2-associated X protein; DR5, death receptor 5; PIG3, p53-inducible gene 3; Puma, p53-upregulated modulator of apoptosis; PIDD, p53-induced protein with death domain; PERP, p53 apoptosis effector related to PMP-22; Apaf-1, apoptotic protease-activating factor-1; p53AIP1, p53regulated apoptosis-inducing protein 1; Bid, BH3-interacting death agonist; 5-FU, 5-fluorouracil; IAPs, inhibitor of apoptosis proteins; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; ASPP, Apoptotic-Stimulating Protein of p53; HDAC1, histone deacetylase 1; PML, promyelocytic leukaemia protein; YY1, Yin Yang 1; PLD, phospholipase D; HATs, histone acetyltransferases; PCAF, p300/CBPassociated factor; SSDB, sequence-specific DNA binding; APC, adenomatosis polyposis coli protein; HPV, human papilloma virus; PRIMA, p53 reactivation and induction of massive apoptosis.

sulted from a p53 mutation [5,6], which was later called “gain of oncogenic function” [7]. By the early 1990s,...
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