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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Herbert, Brittney-shea Dannenberg, Andrew J. Balmus, Gabriel Okayama, Sachiyo Kopelovich, Levy Weiss, Robert S. Subbaramaiah, Kotha |
| Description | Author Affiliation: Okayama S ( From the Department of Medicine, Weill Cornell Medical College, New York, New York 10065.) |
| Abstract | The p53 tumor suppressor gene encodes a homotetrameric transcription factor which is activated in response to a variety of cellular stressors, including DNA damage and oncogene activation. p53 mutations occur in >50% of human cancers. Although p53 has been shown to regulate Wnt signaling, the underlying mechanisms are not well understood. Here we show that silencing p53 in colon cancer cells led to increased expression of Aha1, a co-chaperone of Hsp90. Heat shock factor-1 was important for mediating the changes in Aha1 levels. Increased Aha1 levels were associated with enhanced interactions with Hsp90, resulting in increased Hsp90 ATPase activity. Moreover, increased Hsp90 ATPase activity resulted in increased phosphorylation of Akt and glycogen synthase kinase-3ß (GSK3ß), leading to enhanced expression of Wnt target genes. Significantly, levels of Aha1, Hsp90 ATPase activity, Akt, and GSK3ß phosphorylation and expression of Wnt target genes were increased in the colons of p53-null as compared with p53 wild type mice. Using p53 heterozygous mutant epithelial cells from Li-Fraumeni syndrome patients, we show that a monoallelic mutation of p53 was sufficient to activate the Aha1/Hsp90 ATPase axis leading to stimulation of Wnt signaling and increased expression of Wnt target genes. Pharmacologic intervention with CP-31398, a p53 rescue agent, inhibited recruitment of Aha1 to Hsp90 and suppressed Wnt-mediated gene expression in colon cancer cells. Taken together, this study provides new insights into the mechanism by which p53 regulates Wnt signaling and raises the intriguing possibility that p53 status may affect the efficacy of anticancer therapies targeting Hsp90 ATPase. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 10 |
| Volume Number | 289 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2014-03-07 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Adenosine Triphosphatases Metabolism Colonic Neoplasms Gene Expression Regulation, Neoplastic HSP90 Heat-Shock Proteins Molecular Chaperones Genetics Tumor Suppressor Protein P53 Wnt Signaling Pathway Animals Disease Models, Animal Li-Fraumeni Syndrome Mice Mice, Transgenic Pyrimidines Pharmacology Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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