Androgen-dependent apoptosis in male germ cells is regulated through the proto-oncoprotein Cbl.
The proto-oncoprotein Cbl is known to control several signaling processes. It is highly expressed in the testis, and because spermatogenesis is androgen dependent, we investigated the androgen dependency expression of Cbl through its testicular sub-localization and its expression levels in rats that were exposed to the antiandrogen flutamide or were hypophysectomized. We report the androgen dependency of Cbl as it localizes in pachytene spermatocytes during androgen-dependent stages, is down-regulated upon flutamide exposure, and is up-regulated with testosterone in hypophysectomized rats. Coculture experiments showed the key control exerted by the Sertoli cell on Cbl activity. As flutamide induces germ cell apoptosis, we investigate members of the Bcl-2 family upon flutamide exposure. We show that the proapoptotic Bcl-2 family member Bim mirrored Cbl expression through a posttranscriptional process. We also show that in Cbl knockout mouse testes, the imbalance between the high expression of Bim and Smac/Diablo and anti-apoptotic factors such as cellular inhibitor of apoptosis 2 favors a survival process, which makes these mice unresponsive to androgen withdrawal and could explain their hypofertility.
El Chami
Nisrine
N
Faculté de Médecine Lyon-Sud, Institut National de la Santé et la Recherche Médicale, F-69921 Oullins Cedex, France.
Ikhlef
Fouziha
F
Kaszas
Krisztian
K
Yakoub
Sadok
S
Tabone
Eric
E
Siddeek
Benazir
B
Cunha
Stéphanie
S
Beaudoin
Claude
C
Morel
Laurent
L
Benahmed
Mohamed
M
Régnier
Daniel C
DC
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000378:metabolism; D018920:Coculture Techniques; D005485:Flutamide / Q000494:pharmacology; D005786:Gene Expression Regulation; D005854:Germ Cells / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012708:Sertoli Cells / Q000378:metabolism; D013090:Spermatocytes / Q000378:metabolism; D013737:Testis / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation
D000726:Androgen Antagonists; D000728:Androgens; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C000606778:Bcl2l11 protein, rat; D002352:Carrier Proteins; C489013:DIABLO protein, rat; C499605:Diablo protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D013739:Testosterone; D005485:Flutamide; D050721:Proto-Oncogene Proteins c-cbl