Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas Journal Article

   

Authors:	Xue, W.; Zender, L.; Miething, C.; Dickins, R. A.; Hernando, E.; Krizhanovsky, V.; Cordon-Cardo, C.; Lowe, S. W.
Article Title:	Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Abstract:	Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth. ©2007 Nature Publishing Group.
Keywords:	controlled study; protein expression; mutation; nonhuman; liver neoplasms; chemotherapy; protein function; mouse; animals; mice; animal tissue; apoptosis; immune system; animal experiment; animal model; rna interference; cell differentiation; tumor regression; protein p53; liver carcinoma; rna; tumor suppressor gene; dna; immune response; regulatory mechanism; murinae; tumor suppressor protein p53; cell cycle arrest; innate immunity; upregulation; senescence; tumor growth; tumor; cell aging; immunity, natural; liver carcinogenesis
Journal Title:	Nature
Volume:	445
Issue:	7128
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2007-02-08
Start Page:	656
End Page:	660
Language:	English
DOI:	10.1038/nature05529
PUBMED:	17251933
PROVIDER:	scopus
PMCID:	PMC4601097
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-33846937033&partnerID=40&md5=6abdb86be410d9f54c5572463e68890a
Notes:	--- - "Cited By (since 1996): 460" - "Export Date: 17 November 2011" - "CODEN: NATUA" - "Source: Scopus"

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