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J. Biol. Chem., Vol. 280, Issue 3, 1740-1745, January 21, 2005

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An Inhibitor of the F1 Subunit of ATP Synthase (IF1) Modulates the Activity of Angiostatin on the Endothelial Cell Surface^*

Nick R. Burwick, Miriam L. Wahl, Jun Fang, Zhaoxi Zhong, Tammy L. Moser¶, Bo Li, Roderick A. Capaldi||, Daniel J. Kenan, and Salvatore V. Pizzo**

From the Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, ^¶Departments of Medicine, Microbiology, and Immunology, University of North Carolina, Chapel Hill, North Carolina 27514, and ^||Department of Biology and Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403

Angiostatin binds to endothelial cell (EC) surface F₁-F₀ ATP synthase, leading to inhibition of EC migration and proliferation during tumor angiogenesis. This has led to a search for angiostatin mimetics specific for this enzyme. A naturally occurring protein that binds to the F1 subunit of ATP synthase and blocks ATP hydrolysis in mitochondria is inhibitor of F1 (IF1). The present study explores the effect of IF1 on cell surface ATP synthase. IF1 protein bound to purified F₁ ATP synthase and inhibited F₁-dependent ATP hydrolysis consistent with its reported activity in studies of mitochondria. Although exogenous IF1 did not inhibit ATP production on the surface of EC, it did conserve ATP on the cell surface, particularly at low extracellular pH. IF1 inhibited ATP hydrolysis but not ATP synthesis, in contrast to angiostatin, which inhibited both. In cell-based assays used to model angiogenesis in vitro, IF1 did not inhibit EC differentiation to form tubes and only slightly inhibited cell proliferation compared with angiostatin. From these data, we conclude that inhibition of ATP synthesis is necessary for an anti-angiogenic outcome in cell-based assays. We propose that IF1 is not an angiostatin mimetic, but it can serve a protective role for EC in the tumor microenvironment. This protection may be overridden in a concentration-dependent manner by angiostatin. In support of this hypothesis, we demonstrate that angiostatin blocks IF1 binding to ATP synthase and abolishes its ability to conserve ATP. These data suggest that there is a relationship between the binding sites of IF1 and angiostatin on ATP synthase and that IF1 could be employed to modulate angiogenesis.

Received for publication, May 27, 2004 , and in revised form, November 1, 2004.

^* This work was supported in part by a NIGMS, National Institutes of Health research grant (to N. R. B.), NCI, National Institutes of Health Grants CA-56690 (to M. L. W.), CA86344 (to S. V. 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.

These authors contributed equally to this study.

^** To whom correspondence should be addressed: Dept. of Pathology, Box 3712, Duke University Medical Center, Durham, NC 27710. Tel.: 919-684-3528; Fax: 919-684-8689; E-mail: Pizzo001{at}mc.duke.edu.

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