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Published 21 November 2005. doi:10.1083/jcb.200507076
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 4, 651-661
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Article

 Androgen-dependent apoptosis in male germ cells is regulated through the proto-oncoprotein Cbl

Nisrine El Chami1, Fouziha Ikhlef1, Krisztian Kaszas1, Sadok Yakoub1, Eric Tabone1, Benazir Siddeek1, Stéphanie Cunha1, Claude Beaudoin2, Laurent Morel2, Mohamed Benahmed1, and Daniel C. Régnier1

1 Faculté de Médecine Lyon-Sud, Institut National de la Santé et la Recherche Médicale, F-69921 Oullins Cedex, France
2 Physiologie Comparée et Endocrinologie Moléculaire, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 6547, 63177 Aubière Cedex, France

Correspondence to Daniel C. Régnier: regnier{at}grisn.univ-lyon1.fr

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 sublocalization 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 antiapoptotic 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.

N. El Chami, F. Ikhlef, and K. Kaszas contributed equally to this paper.

D.C. Régnier and M. Benahmed should be considered senior co-authors.

Abbreviations used in this paper: AR, androgen receptor; HC, hydrocortancyl; HX, hypophysectomy; IAP, inhibitor of apoptosis; IHC, immunohistochemistry; IP, immunoprecipitation; KO, knockout; PMC, peritubular myoid cell; pnd, postnatal day; PS, pachytene spermatocyte; SC, Sertoli cell; TGC, testicular germ cell; WB, Western blotting; WT, wild type.


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