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.
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.
Division of Endocrinology, Harbor-University of California at Los Angeles Medical Center, Los Angeles Biomedical Research Institute, Torrance, California 90509, USA.
Yanira
Y
Vera
Krista
K
Erkkilä
Christina
C
Wang
Concepcion
C
Nunez
Sauli
S
Kyttänen
Yanhe
Y
Lue
Leo
L
Dunkel
Ronald S
RS
Swerdloff
Amiya P
AP
Sinha Hikim
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects; D005854:Germ Cells / Q000187:drug effects / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000172:deficiency*; D006146:Guanidines / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D012671:Seminiferous Tubules / Q000187:drug effects; D015398:Signal Transduction; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000097:blood / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C489013:DIABLO protein, rat; D006146:Guanidines; D006727:Hormone Antagonists; D024101:Mitochondrial Proteins; D047428:Protein Kinase Inhibitors; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D045304:Cytochromes c; D052247:Nitric Oxide Synthase Type II; D011065:Poly(ADP-ribose) Polymerases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; C004479:pimagedine