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First published online 26 March 2003
doi: 10.1242/jcs.00390

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Oxidant-induced cell death in retinal pigment epithelium cells mediated through the release of apoptosis-inducing factor

¹ National Eye Institute, Building 10 – Room 10N119, 9000 Rockville Pike, Bethesda, Maryland 20892-1857, USA
² Department of Ophthalmology, University of Miami, Miami, Florida

^* Author for correspondence (e-mail: kcsaky{at}helix.nih.gov)

Accepted 27 January 2003

In the present study, the pathways involved in oxidant-induced cell death of a primary cell of the retina, ARPE-19, were investigated and compared with a leukemic cell, U937 cells. Both ARPE-19 and U937 cells exhibited similar viability when exposed to menadione. At lethal doses, both cell lines demonstrated extensive membrane blebbing. However, although U937 cells exhibited caspase-3, -9 PARP cleavage and 200 bp laddering, no such cleavage or laddering was noted in ARPE-19 cells. Furthermore, addition of exogenous cytochrome c and ATP to a cell-free system again resulted in cleavage of caspase-3 and -9 in extracts of U937 but not ARPE cells. Further studies in ARPE-19 cells undergoing menadione-induced cell death demonstrated mitochondrial membrane depolarization, release of cytochrome c, nuclear translocation of apoptosis-inducing factor and subsequent 50 kilo-base pair laddering, and nuclear shrinkage. All of these findings were abrogated by the pretreatment of ARPE-19 cells with hepatocyte growth factor/scatter factor. These findings demonstrate the complex nature of cell death in primary cells of the retina and highlight the role of caspase-independent signals, growth factors and intracellular survival factors in programmed cell death pathways.

Key words: Apoptosis, RPE cells, Apoptosis-inducing factor, Caspase, Cell-free

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