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Regular Article |
a Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114
b Laboratory of Integrative Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709
c Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina 28223
ABSTRACT
Recent studies with thymocytes have suggested a critical role for intracellular potassium in the regulation of apoptosis. In this study, we examined the pathways of K+ regulation during ovarian cell death. In initial studies, fluorographic analysis demonstrated a significant loss of K+ during apoptosis stimulated by doxorubicin in oocytes and trophic hormone deprivation in granulosa cells. In oocytes, suppression of potassium efflux by potassium-enriched medium prevented condensation, budding, and fragmentation, although it did not block DNA degradation, suggesting the existence of potassium-independent nucleases in oocytes. Culture of granulosa cells in potassium-enriched medium inhibited internucleosomal DNA cleavage, although high-molecular weight DNA cleavage was apparent, suggesting that the nuclease or nucleases responsible for generating 50-kilobase (kb) fragments in these cells is potassium independent. To address this directly, isolated granulosa cell nuclei were stimulated to autodigest their DNA, and internucleosomal, but not large-fragment, cleavage was completely blocked by 150 mM potassium. We next examined whether the proapoptotic caspases are targets for potassium regulation. In cell-free assays, processing of pro-interleukin-1ß and proteolysis of cellular actin by recombinant caspase-1 and caspase-3, respectively, were suppressed by the presence of 150 mM potassium. Other monovalent ions (NaCl, LiCl) exerted a similar effect in these cell-free assays. Thus, in oocytes and granulosa cells, potassium efflux appears to occur early in the cell death program and may regulate a number of apoptotic events including caspase activity and internucleosomal DNA cleavage. However, there also exist novel potassium-independent pathways in both ovarian germ cells and somatic cells that signal certain apoptotic events, such as large-fragment DNA cleavage.
First decision: 29 March 2000.
1 This study was supported by NIH grants R01-HD34226, R01-AG12279, and R01-ES08430 (J.L.T.), by Vincent Memorial Research Funds (J.L.T.), by NIEHS intramural funds (J.A.C.), and by internal research funds from the University of North Carolina at Charlotte (F.M.H.).
2 Correspondence: Francis M. Hughes, Jr., Department of Biology, UNCC, 9201 University City Blvd., Charlotte, NC 28223. FAX: 704 547 3128; mhughes{at}email.uncc.edu
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