Involvement of p38 mitogen-activated protein kinase and inducible nitric oxide synthase in apoptotic signaling of murine and human male germ cells after hormone deprivation.
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Vera Y, Erkkila K, Wang C, Nunez C, Kyttanen S, Lue Y, Dunkel L, Swerdloff RS, Sinha Hikim AP
Involvement of p38 mitogen-activated protein kinase and inducible nitric oxide synthase in apoptotic signaling of murine and human male germ cells after hormone deprivation.
Mol Endocrinol. 2006 Jul;20(7):1597-609. doi: 10.1210/me.2005-0395. Epub 2006 Feb 9.
- PubMed ID
- 16469770 [ View in PubMed]
- Abstract
This study investigates the role of p38 MAPK, inducible nitric oxide synthase (iNOS), and the intrinsic pathway signaling in male germ cell death in rats after hormonal deprivation by a potent GnRH antagonist treatment. Germ cell apoptosis, involving exclusively middle (VII-VIII) stages, was activated by d 5 after GnRH antagonist treatment. Initiation of germ cell apoptosis was preceded by p38 MAPK activation and induction of iNOS. p38 MAPK activation and iNOS induction were further accompanied by a marked perturbation of the BAX/BCL-2 rheostat, cytochrome c, and DIABLO release from mitochondria, caspase activation, and poly(ADP-ribose) polymerase cleavage. Concomitant administration of aminoguanidine, a selective iNOS inhibitor, significantly prevented hormone deprivation-induced germ cell apoptosis. Inhibitors of iNOS or p38 MAPK were also effective in preventing human male germ cell apoptosis induced by hormone-free culture conditions. Together, these results establish a new signal transduction pathway involving p38 MAPK and iNOS that, through activation of the intrinsic pathway signaling, promotes male germ cell death in response to a lack of hormonal stimulation across species.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Pimagedine Nitric oxide synthase, inducible Protein Humans YesInhibitorDownregulatorDetails