HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 8, 6682-6691, February 25, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/8/6682    most recent M412767200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Müller, P. Articles by Vojtesek, B. Search for Related Content PubMed PubMed Citation Articles by Müller, P. Articles by Vojtesek, B. Social Bookmarking                      What's this?

Hsp90 Is Essential for Restoring Cellular Functions of Temperature-sensitive p53 Mutant Protein but Not for Stabilization and Activation of Wild-type p53

IMPLICATIONS FOR CANCER THERAPY^*

Petr Müller, Pavla Ceskova, and Borek Vojtesek

From the Department of Experimental Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno 656 53, Czech Republic

Several signaling pathways that monitor the dynamic state of the cell converge on the tumor suppressor p53. The ability of p53 to process these signals and exert a dynamic downstream response in the form of cell cycle arrest and/or apoptosis is crucial for preventing tumor development. This p53 function is abrogated by p53 gene mutations leading to alteration of protein conformation. Hsp90 has been implicated in regulating both wild-type and mutant p53 conformations, and Hsp90 antagonists are effective for the therapy of some human tumors. Using cell lines that contain human tumor-derived temperature-sensitive p53 mutants we show that Hsp90 is required for both stabilization and reactivation of mutated p53 at the permissive temperature. A temperature decrease to 32 °C causes conversion to a protein conformation that is capable of inducing expression of MDM2, leading to reduction of reactivated p53 levels by negative feedback. Mutant reactivation is enhanced by simultaneous treatment with agents that stabilize the reactivated protein and is blocked by geldanamycin, a specific inhibitor of Hsp90 activity, indicating that Hsp90 antagonist therapy and therapies that act to reactivate mutant p53 will be incompatible. In contrast, Hsp90 is not required for maintaining wild-type p53 or for stabilizing wild-type p53 after treatment with chemotherapeutic agents, indicating that Hsp90 therapy might synergize with conventional therapies in patients with wild-type p53. Our data demonstrate the importance of the precise characterization of the interaction between p53 mutants and stress proteins, which may shed valuable information for fighting cancer via the p53 tumor suppressor pathway.

Received for publication, November 11, 2004 , and in revised form, December 21, 2004.

^* This work was supported by Grant NC7131-3 from the Ministry of Health of the Czech Republic and Grant 301/02/0831 from the Grant Agency of the Czech Republic. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 420-543-133-303; Fax: 420-541-211-169, e-mail: vojtesek{at}mou.cz.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Sasaki, L. Nie, and C. G. Maki MDM2 Binding Induces a Conformational Change in p53 That Is Opposed by Heat-shock Protein 90 and Precedes p53 Proteasomal Degradation J. Biol. Chem., May 11, 2007; 282(19): 14626 - 14634. [Abstract] [Full Text] [PDF]

				J. S. Butler and S. N. Loh Folding and misfolding mechanisms of the p53 DNA binding domain at physiological temperature Protein Sci., November 1, 2006; 15(11): 2457 - 2465. [Abstract] [Full Text] [PDF]

				S. Yin, X. Li, Y. Meng, R. L. Finley Jr., W. Sakr, H. Yang, N. Reddy, and S. Sheng Tumor-suppressive Maspin Regulates Cell Response to Oxidative Stress by Direct Interaction with Glutathione S-Transferase J. Biol. Chem., October 14, 2005; 280(41): 34985 - 34996. [Abstract] [Full Text] [PDF]