| Abrogation of Wip1 expression by RITA-activated p53 potentiates apoptosis induction via activation of ATM and inhibition of HdmX. | |
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MedLine Citation:
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PMID: 21546907 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Inactivation of the p53 tumour suppressor, either by mutation or by overexpression of its inhibitors Hdm2 and HdmX is the most frequent event in cancer. Reactivation of p53 by targeting Hdm2 and HdmX is therefore a promising strategy for therapy. However, Hdm2 inhibitors do not prevent inhibition of p53 by HdmX, which impedes p53-mediated apoptosis. Here, we show that p53 reactivation by the small molecule RITA leads to efficient HdmX degradation in tumour cell lines of different origin and in xenograft tumours in vivo. Notably, HdmX degradation occurs selectively in cancer cells, but not in non-transformed cells. We identified the inhibition of the wild-type p53-induced phosphatase 1 (Wip1) as the major mechanism important for full engagement of p53 activity accomplished by restoration of the ataxia telangiectasia mutated (ATM) kinase-signalling cascade, which leads to HdmX degradation. In contrast to previously reported transactivation of Wip1 by p53, we observed p53-dependent repression of Wip1 expression, which disrupts the negative feedback loop conferred by Wip1. Our study reveals that the depletion of both HdmX and Wip1 potentiates cell death due to sustained activation of p53. Thus, RITA is an example of a p53-reactivating drug that not only blocks Hdm2, but also inhibits two important negative regulators of p53 - HdmX and Wip1, leading to efficient elimination of tumour cells.Cell Death and Differentiation advance online publication, 6 May 2011; doi:10.1038/cdd.2011.45. |
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Authors:
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C Spinnler; E Hedström; H Li; J de Lange; F Nikulenkov; A F A S Teunisse; M Verlaan-de Vries; V Grinkevich; A G Jochemsen; G Selivanova |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-06 |
Journal Detail:
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Title: Cell death and differentiation Volume: - ISSN: 1476-5403 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-6 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9437445 Medline TA: Cell Death Differ Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Microbiology, Tumour and Cell Biology (MTC), Karolinska Institutet, Nobels väg 16, Stockholm, S-17177, Sweden. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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