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Physiological Reviews, Vol. 80, No. 2, April 2000, pp. 593-614
Copyright ©2000 by the American Physiological Society
Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, California
Hsu, Sheau Yu and
Aaron J. W. Hsueh.
Tissue-Specific Bcl-2 Protein Partners in Apoptosis: An
Ovarian Paradigm. Physiol. Rev. 80: 593-614, 2000.
Apoptosis is an essential
physiological process by which multicellular organisms eliminate
superfluous cells. An expanding family of Bcl-2 proteins plays a
pivotal role in the decision step of apoptosis, and the differential
expression of Bcl-2 members and their binding proteins allows the
regulation of apoptosis in a tissue-specific manner mediated by
diverse extra- and intracellular signals. The Bcl-2 proteins can be
divided into three subgroups: 1) antiapoptotic proteins with
multiple Bcl-2 homology (BH) domains and a transmembrane region,
2) proapoptotic proteins with the same structure but missing
the BH4 domain, and 3) proapoptotic ligands with only the
BH3 domain. In the mammalian ovary, a high rate of follicular cell
apoptosis continues during reproductive life. With the use of the yeast
two-hybrid system, the characterization of ovarian Bcl-2 genes
serves as a paradigm to understand apoptosis regulation in a
tissue-specific manner. We identified Mcl-1 as the main ovarian
antiapoptotic Bcl-2 protein, the novel Bok (Bcl-2-related ovarian
killer) as the proapoptotic protein, as well as BOD (Bcl-2-related ovarian death agonist) and BAD as the proapoptotic ligands. The activity of the proapoptotic ligand BAD is regulated by upstream follicle survival factors through its binding to constitutively expressed 14-3-3 or hormone-induced P11. In contrast, the
channel-forming Mcl-1 and Bok regulate cytochrome c
release and, together with the recently discovered Diva/Boo, control
downstream apoptosis-activating factor (Apaf)-1 homologs and
caspases. Elucidation of the role of Bcl-2 members and their
interacting proteins in the tissue-specific regulation of apoptosis
could facilitate an understanding of normal physiology and allow the
development of new therapeutic approaches for pathological states.
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