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Cell Cycle, Cell Death, and Senescence

Apoptosis of Mortal Human Fibroblasts Transformed by the Bovine Papillomavirus E5 Oncoprotein¹

¹ Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY

Requests for reprints: Lisa M. Petti, Center for Immunology and Microbial Disease, MC-151, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208. Phone: (518) 262-6285; Fax: (518) 262-5748. E-mail: pettil{at}mail.amc.edu

Mortal human fibroblasts can be partially transformed by the bovine papillomavirus E5 oncoprotein through activation of the platelet-derived growth factor ß receptor. Here, we report that these cells undergo massive apoptosis 2 weeks after confluence. Although activation of caspase 3 was observed in the apoptotic cells, it was not required for apoptosis. The appearance of the mitochondrial proteins cytochrome c and apoptosis-inducing factor in cytosolic and nuclear compartments, respectively, provided a basis for mitochondrial dysfunction and a caspase-independent mechanism of apoptosis in these cells. Although an activating conformational change in Bax also was evident in the apoptotic cells, enforced overexpression of Bcl-2 was insufficient to prevent apoptosis. Finally, a small peptide present in the conditioned medium from dying transformed cells appeared responsible for inducing apoptosis through affecting a conformational change in Bax and eventual relocalization of apoptosis-inducing factor to the nucleus. Thus, an atypical apoptotic pathway is activated in mortal human fibroblasts in response to transformation induced by sustained receptor tyrosine kinase activation.

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				L. M. Petti, E. C. Ricciardi, H. J. Page, and K. A. Porter Transforming signals resulting from sustained activation of the PDGF{beta} receptor in mortal human fibroblasts J. Cell Sci., April 15, 2008; 121(8): 1172 - 1182. [Abstract] [Full Text] [PDF]