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

Abstract

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.

The orphan nuclear receptor small heterodimer partner mediates male infertility induced by diethylstilbestrol in mice

“…Germ cell death has previously been associated with androgen withdrawal (26,27). Consistent with previous data (28,29), DES induced a decrease in testosterone concentrations in Nr0b2 +/+ males at as little as 0.75 μg ( Figure 4A).…”

Mutant B-RAF mediates resistance to anoikis via Bad and Bim

“…Studies in osteoclasts show that the RING-finger E3 ubiquitin ligase, c-Cbl, can be coimmunoprecipitated with Bim and that the overexpression of c-Cbl is associated with increased Bim ubiquitylation and decreased Bim protein levels (Akiyama et al, 2003). Another group was able to detect an increase in Bim EL protein in the testis of Cbl knockout mice but were unable to coimmunoprecipitate Bim EL and Cbl (El Chami et al, 2005), indicating that c-Cbl regulation of Bim EL may not be direct. In melanoma cells, we were unable to confirm a role for c-Cbl in the regulation of Bim EL since efficient knockdown of c-Cbl did not increase Bim EL protein levels (Supplementary Figure 5).…”

Negative Regulation of Haematopoiesis: Role of Inhibitory Adaptors

“…Despite close structural similarities, loss of c-Cbl and Cbl-b proteins evokes prominent phenotypic differences (Table 5). c-Cbl-null mice have an enlarged thymus, expanded hematopoietic progenitor pools with increased repopulating capacity, splenomegaly with extramedullary hematopoiesis, as well as changes in energy metabolism, and reduced fertility of male mice (Murphy et al, 1998;Naramura et al, 1998;Molero et al, 2004;El Chami et al, 2005, Rathinam et al, 2008. However, the most marked alteration in c-Cbl and Cbl-b-deficient animals is being associated with thymocyte and peripheral T-cell activation, respectively.…”