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Wip1 promotes RUNX2-dependent apoptosis in p53-negative tumors and protects normal tissues during treatment with anticancer agents.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2012 Jan 10; Vol. 109 (2), pp. E68-75. Date of Electronic Publication: 2011 Nov 07. - Publication Year :
- 2012
-
Abstract
- The inactivation of the p53 tumor suppressor pathway in many cancers often increases their resistance to anticancer therapy. Here we show that a previously proposed strategy directed to Wip1 inhibition could be ineffective in tumors lacking p53. On the contrary, Wip1 overexpression sensitized these tumors to chemotherapeutic agents. This effect was mediated through interaction between Wip1 and RUNX2 that resulted, in response to anticancer treatment, in RUNX2-dependent transcriptional induction of the proapoptotic Bax protein. The potentiating effects of Wip1 overexpression on chemotherapeutic agents were directed only to tumor cells lacking p53. The overexpression of Wip1 in normal tissues provided protection from cisplatin-induced apoptosis through decreased strength of upstream signaling to p53. Thus, Wip1 phosphatase promotes apoptosis in p53-negative tumors and protects normal tissues during treatment with anticancer agents.
- Subjects :
- Animals
Antineoplastic Agents metabolism
Antineoplastic Agents therapeutic use
Apoptosis drug effects
Apoptosis physiology
Blotting, Western
Cell Line
DNA Primers genetics
Drug Synergism
Female
Gene Expression Regulation, Neoplastic genetics
Humans
Immunohistochemistry
Immunoprecipitation
Mice
Neoplasms metabolism
Plasmids genetics
Protein Phosphatase 2C
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Tumor Suppressor Protein p53 metabolism
bcl-2-Associated X Protein metabolism
Antineoplastic Agents pharmacology
Core Binding Factor Alpha 1 Subunit metabolism
Gene Expression Regulation, Neoplastic physiology
Neoplasms drug therapy
Phosphoprotein Phosphatases metabolism
Tumor Suppressor Protein p53 deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 109
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 22065775
- Full Text :
- https://doi.org/10.1073/pnas.1107017108