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Review
. 2010 Aug;1804(8):1684-9.
doi: 10.1016/j.bbapap.2010.05.002. Epub 2010 May 13.

SIRT1 and p53, Effect on Cancer, Senescence and Beyond

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Free PMC article
Review

SIRT1 and p53, Effect on Cancer, Senescence and Beyond

Jingjie Yi et al. Biochim Biophys Acta. .
Free PMC article

Abstract

NAD(+)-dependent Class III histone deacetylase SIRT1 is a multiple function protein critically involved in stress responses, cellular metabolism and aging through deacetylating a variety of substrates including p53, forkhead-box transcription factors, PGC-1alpha, NF-kappaB, Ku70 and histones. The first discovered non-histone target of SIRT1, p53, is suggested to play a central role in SIRT1-mediated functions in tumorigenesis and senescence. SIRT1 was originally considered to be a potential tumor promoter since it negatively regulates the tumor suppressor p53 and other tumor suppressors. There is new evidence that SIRT1 acts as a tumor suppressor based on its role in negatively regulating beta-catenin and survivin. This review provides an overview of current knowledge of SIRT1-p53 signaling and controversies regarding the functions of SIRT1 in tumorigenesis.

Figures

Figure 1
Figure 1
SIRT1 promotes p53 transcription-independent apoptosis. In mouse embryonic stem cells, intracellular ROS activates cytoplasm SIRT1 protein. SIRT1 binds to and deacetylates p53 at K379 (human K382) and blocks p53 nuclear translocation. Deacetylated p53 translocates onto the mitochondrial outer-membrane and releases proapototic BCL protein BAX by interacting with anti-apoptotic BCL proteins including BCL2, BCLxl. Activated BAX leads to the release of Cytochrome c from mitochondrial to cytoplasm. p53 transcription-independent apoptosis initiated.
Figure 2
Figure 2
SIRT1 promotes tumorigenesis. Upon genotoxic stress, p53 is acetylated at K382, which enhanced DNA binding and transactivation activity. HIC1, miR34a, and DBC1 suppress SIRT1 activity. Multilayered inhibition of SIRT1 allows the activation status of p53 for p21, PUMA and BAX genes expression which induced cell cycle arrest, apoptosis, and senescence. Resveratrol and AROS, Along with other SIRT1 activators, enhance SIRT1 deacetylation on p53 and suppress p53 transcription-dependent cell cycle arrest and apoptosis by genotoxic stress.

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