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Bcl-2 Protects Endothelial Cells against -Radiation via a Raf-MEK-ERK-Survivin Signaling Pathway That Is Independent of Cytochrome c Release

Departments of ¹ Biologic and Materials Sciences and ² Otorhinolaryngology, University of Michigan and ³ Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan

Requests for reprints: Pawan Kumar, Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Room 5205, 1011 North University Avenue, Ann Arbor, MI 48109. Phone: 734-647-7599; Fax: 734-764-2469; E-mail: pksuri{at}umich.edu or Peter J. Polverini, University of Michigan School of Dentistry, Room 1234, 1011 North University Avenue, Ann Arbor, MI 48109. Phone: 734-743-3311; E-mail: neovas{at}umich.edu.

The Bcl-2 oncoprotein is a potent inhibitor of apoptosis and is overexpressed in a wide variety of malignancies. Until recently, it was generally accepted that Bcl-2 primarily mediates its antiapoptotic function by regulating cytochrome c release from mitochondria. However, more recent studies have shown that Bcl-2 is present on several intracellular membranes and mitochondria may not be the only site where Bcl-2 exercises its survival function. In this study, we investigated if Bcl-2 can protect endothelial cells against -radiation by a cytochrome c–independent signaling pathway. Human dermal microvascular endothelial cells (HDMEC), when exposed to -radiation, exhibited a time-dependent activation of caspase-3 that was associated with increased cytochrome c release from mitochondria. Bcl-2 expression in endothelial cells (HDMEC-Bcl-2) significantly inhibited irradiation-induced caspase-3 activation. However, Bcl-2–mediated inhibition of caspase-3 was significantly reversed by inhibition of the Raf-mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinase (ERK) kinase (MEK)-ERK pathway. Interestingly, caspase-3 activation in HDMEC-Bcl-2 cells was not associated with cytochrome c release. We also observed that endothelial cell Bcl-2 expression significantly increased the expression of survivin and murine double minute-2 (Mdm2) via the Raf-MEK-ERK pathway. Endothelial cells expressing Bcl-2 also inhibited -radiation–induced activation of p38 MAPK and p53 accumulation. Inhibition of p53 accumulation in HDMEC-Bcl-2 could be due to the enhanced expression of Mdm2 in these cells. Taken together, these results show three mechanisms by which Bcl-2 may mediate endothelial cell cytoprotection independently of cytochrome c release: (a) increased survivin expression, (b) inhibition of p53 accumulation, and (c) inhibition of p38 MAPK. [Cancer Res 2007;67(3):1193–202]

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