Dominant-negative Hsp90 reduces VEGF-stimulated nitric oxide release and migration in endothelial cells.

Dominant-negative Hsp90 reduces VEGF-stimulated nitric oxide release and migration in endothelial cells. Research Abstract Details 

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Dominant-negative Hsp90 reduces VEGF-stimulated nitric oxide release and migration in endothelial cells. Abstract Text:

Robert Q Miao,Jason Fontana,David Fulton,Michelle I Lin,Kenneth D Harrison,William C Sessa,Robert Q Miao,Jason Fontana,David Fulton,Michelle I Lin,Kenneth D Harrison,William C Sessa,

OBJECTIVE: Heat-shock protein 90 (Hsp90) coordinates the regulation of diverse signaling proteins. We try to develop a new tool to explore the regulatory functions of Hsp90 in endothelial cells (ECs) instead of the existing chemical approaches. METHODS AND RESULTS: We designed a dominant-negative Hsp90 construct by site-direct mutagenesis of residue Asp-88 to Asn (D88N-Hsp90) based on the structure of the ATP/ADP-binding site. Recombinant wild-type Hsp90 protein binds ATP-Sepharose beads in manner inhibited by ATP or 17-AAG, a specific inhibitor for Hsp90, however the binding activity of D88N-Hsp90 was markedly reduced and the inhibitory effects of ATP or 17-AAG were negligible. The dimerization between endogenous Hsp90alpha and exogenous HA-Hsp90beta was confirmed by immunoprecipitation, however the association between eNOS and D88N-Hsp90 was less than WT-Hsp90. Furthermore, adenoviral transduction of bovine aortic ECs with D88N-Hsp90 suppressed VEGF-induced phosphorylation of Akt, eNOS, and NO release and the inhibitory effect was blocked by okadaic acid. Moreover, D88N-Hsp90 abolished VEGF-stimulated Rac activation and suppressed VEGF-induced stress fiber formation. Transduction with D88N-Hsp90 decreased growth medium mediated migration of wild-type ECs, but not Akt1(-/-) ECs suggesting that Akt is key target of Hsp90. CONCLUSIONS: Our data demonstrate that dominant-negative Hsp90 modulates endothelial cell mobility mainly through PP2A-mediated dephosphorylation of Akt and Rac activation.

Dominant-negative Hsp90 reduces VEGF-stimulated nitric oxide release and migration in endothelial cells. Publishing Authors By Initials

RQ Miao,J Fontana,D Fulton,MI Lin,KD Harrison,WC Sessa,RQ Miao,J Fontana,D Fulton,MI Lin,KD Harrison,WC Sessa,

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Dominant-negative Hsp90 reduces VEGF-stimulated nitric oxide release and migration in endothelial cells. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Arteriosclerosis, thrombosis, and vascular biology

VOLUME: 28

Page Numbers: 105-11

Journal Abbreviation: Arterioscler. Thromb. Vasc. Bi

ISSN: 1524-4636

DAY: 1

MONTH: 11

YEAR: 2007

Dominant-negative Hsp90 reduces VEGF-stimulated nitric oxide release and migration in endothelial cells. Information

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LANGUAGE: eng

NlmUniqueID: 9505803

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AFFILIATION: Department of Pharmacology and Vascular Biology and Therapeutics Program, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: R01 HL 61371

ACRONYM: HL

MEDLINETA: Arterioscler Thromb Vasc Biol

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