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J. Biol. Chem., Vol. 282, Issue 23, 17166-17178, June 8, 2007

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Intersectin-1s Regulates the Mitochondrial Apoptotic Pathway in Endothelial Cells^*

From the Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612

Intersectins (ITSNs) are multidomain adaptor proteins implicated in endocytosis, regulation of actin polymerization, and Ras/MAPK signaling. We have previously shown that ITSN-1s is required for caveolae fission and internalization in endothelial cells (ECs). In the present study, using small interfering RNA to knock down ITSN-1s protein expression, we demonstrate a novel role of ITSN-1s as a key antiapoptotic protein. Knockdown of ITSN-1s in ECs activated the mitochondrial pathway of apoptosis as determined by genomic DNA fragmentation, extensive mitochondrial fission, activation of the proapoptotic proteins BAK and BAX, and cytochrome c efflux from mitochondria. ITSN-1 knockdown acts as a proapoptotic signal that causes mitochondrial outer membrane permeabilization, dissipation of the mitochondrial membrane potential, and generation of reactive oxygen species. These effects were secondary to decreased activation of Erk1/2 and its direct activator MEK. Bcl-X_L overexpression prevented BAX activation and the apoptotic ECs death induced by suppression of ITSN-1s. Our findings demonstrate a novel role of ITSN-1s as a negative regulator of the mitochondrial pathway-dependent apoptosis secondary to activation of the Erk1/2 survival signaling pathway.

Received for publication, September 21, 2006 , and in revised form, April 3, 2007.

^* This work was supported by National Institutes of Health Grants PO1 HL60678 (to A. B. M.) and SDG0635175N (to S. A. P.). 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.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, University of Illinois College of Medicine, 835 S. Wolcott Ave., Chicago, IL 60612. Tel.: 312-996-1412; E-mail: sandap{at}uic.edu.

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