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Identification and characterisation of new isoforms of the proto-oncogene c-Cbl and its new roles in apoptosis and cell proliferation

Abstract : The proto-oncogene c-cbl is cytoplasmic protein expressed in heamatopoetic tissues and testis, implicated in cellular signalling either as a scaffolding protein and/or as a negative modulator of cellular signalling. Although it has been studied extensively, not much attention was granted to examine it's role in the testis, one of the principal organs of it's expression. We report here that c-Cbl expression in rat and mouse testis is limited to developing germ cells with strongest expression in pachytene spermatocytes and round spermatids and its expression is upregulated by testosterone that can be inhibited by the anti-androgen flutamide. Androgen-regulated apoptosis occurring at the end of meiosis I is markedly lower in the testis of c-Cbl KO mice, while KOc-Cbl Mouse Embryo Fibroblasts (MEFs) show an increased sensitivity to apoptosis provoked by oxidative stress. We also cloned three other isoforms of p120c-Cbl from pachytene spermatocytes, named p115c-Cbl, p90c-Cbl and p85c-Cbl after their expected size, harbouring either one (D1 – p115; D2 - p90) or two (D1 & D2 - p85) deletions. The expression of p120c-Cbl and p115c-Cbl can be detected in testis, lung, spleen, thymus and brain while p90c-Cbl and p85c-Cbl expression seems to be restricted to germ cells. The deletion D1 corresponds to exon 10 (amino acids 459-502), deletion D2 originates from alternative splicing, stretching over exons 11 to 15 (amino acids 514-768). Both deletions contain PR regions with a Grb2 binding site but only p85c-Cbl failed to bind to Grb2, showing that the presence of any of these two sites is sufficient for Grb2 – c-Cbl binding. p90c-Cbl transfected cells had shown increased proliferation compared to the other isoforms. The above results suggest that c-Cbl has a finely regulated role in the regulation of spermatogenesis and some of this regulation is realised through a balance between alternative isoforms.
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https://tel.archives-ouvertes.fr/tel-00162460
Contributor : Kaszas Krisztian <>
Submitted on : Friday, July 13, 2007 - 3:02:24 PM
Last modification on : Wednesday, November 20, 2019 - 2:34:26 AM
Long-term archiving on: : Thursday, April 8, 2010 - 11:11:20 PM

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Kaszas Krisztian. Identification and characterisation of new isoforms of the proto-oncogene c-Cbl and its new roles in apoptosis and cell proliferation. Biomolecules [q-bio.BM]. Université Claude Bernard - Lyon I, 2007. English. ⟨tel-00162460⟩

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