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PMID: 14614132 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Regulation of survivin function by Hsp90.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 100 ·No. 24 ·2003-11-25 ·Pages 13791-6

Fortugno P, Beltrami E, Plescia J, Fontana J, Pradhan D, Marchisio PC, Sessa WC, Altieri DC

Abstract

Pathways controlling cell proliferation and cell survival require flexible adaptation to environmental stresses. These mechanisms are frequently exploited in cancer, allowing tumor cells to thrive in unfavorable milieus. Here, we show that Hsp90, a molecular chaperone that is central to the cellular stress response, associates with survivin, an apoptosis inhibitor and essential regulator of mitosis. This interaction involves the ATPase domain of Hsp90 and the survivin baculovirus inhibitor of apoptosis repeat. Global suppression of the Hsp90 chaperone function or targeted Abmediated disruption of the survivin-Hsp90 complex results in proteasomal degradation of survivin, mitochondrial-dependent apoptosis, and cell cycle arrest with mitotic defects. These data link the cellular stress response to an antiapoptotic and mitotic checkpoint maintained by survivin. Targeting the survivin-Hsp90 complex may provide a rational approach for cancer therapy.

MeSH Terms
Animals Apoptosis/physiology Binding Sites Cell Cycle/physiology Cell Line Cell Line, Tumor Cell Survival/physiology HSP90 Heat-Shock Proteins/antagonists & inhibitors,chemistry,physiology HeLa Cells Humans In Vitro Techniques Inhibitor of Apoptosis Proteins Macromolecular Substances Mice Microtubule-Associated Proteins/chemistry,genetics,physiology Mutagenesis, Site-Directed Neoplasm Proteins Protein Folding Recombinant Proteins/chemistry,genetics,metabolism Survivin
Chemicals
BIRC5 protein, human HSP90 Heat-Shock Proteins Inhibitor of Apoptosis Proteins Macromolecular Substances Microtubule-Associated Proteins Neoplasm Proteins Recombinant Proteins Survivin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Fortugno Paola
Department of Cancer Biology and Cancer Center, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Beltrami Elena
Plescia Janet
Fontana Jason
Pradhan Deepti
Marchisio Pier Carlo
Sessa William C
Altieri Dario C
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34 references, click to expand
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.2434345100
Published
2003-11-25
Epub
2003-00-12
Pages
13791-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC283500
Subset
IM
Grants
NCI NIH HHS · R01 CA078810 · United States
NCI NIH HHS · CA78810 · United States
NHLBI NIH HHS · R37 HL054131 · United States
NCI NIH HHS · CA90917 · United States
NHLBI NIH HHS · HL54131 · United States
NHLBI NIH HHS · R01 HL054131 · United States
NCI NIH HHS · R01 CA090917 · United States
External Links
PubMed source DOI: 10.1073/pnas.2434345100 PMC Full Text View journal details
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