B-Myc is preferentially expressed in hormonally-controlled tissues and inhibits cellular proliferation

Abstract

The myc family of genes plays an important role in several cellular processes including proliferation, apoptosis, di erentiation, and transformation. B-myc, a relatively new and largely unstudied member of the myc family, encodes a protein that is highly homologous to the N-terminal transcriptional regulatory domain of cMyc. Here, we show that high level B-myc expression is restricted to speci®c mouse tissues, primarily hormonally-controlled tissues, with the highest level of expression in the epididymis. We also report the identi®cation of the endogenous B-Myc protein from mouse tissues. Like other Myc family proteins, B-Myc is a short-lived nuclear protein which is phosphorylated on residues Ser-60 and Ser-68. Rapid proteolysis of B-Myc occurs via the ubiquitin-proteasome pathway. Finally, we found that overexpression of B-Myc signi®cantly slows the growth of Rat 1a ®broblasts and COS cells suggesting B-Myc functions as an inhibitor of cellular proliferation.

Loss of Bmyc results in increased apoptosis associated with upregulation of Myc expression in juvenile murine testis

“…It was originally identified in the rat and named after its high expression in the brain (Ingvarsson et al 1988). Subsequently, an even higher expression was reported in the mouse epididymis where its expression is regulated by androgens (Gregory et al 2000, Cornwall et al 2001. Lower levels of expression have been detected in several other hormonally controlled tissues, including the adrenal, pituitary, prostate, ovary, and uterus, and the protein has also been detected in the hypothalamus and testis (Gregory et al 2000).…”

“…Subsequently, an even higher expression was reported in the mouse epididymis where its expression is regulated by androgens (Gregory et al 2000, Cornwall et al 2001. Lower levels of expression have been detected in several other hormonally controlled tissues, including the adrenal, pituitary, prostate, ovary, and uterus, and the protein has also been detected in the hypothalamus and testis (Gregory et al 2000). In addition, Bmyc is the predominant Myc family gene expressed during mouse preimplantation development (Domashenko et al 1997).…”

“…Due to their high degree of homology, it has been suggested that transcriptional regulation may be partly mediated by competition for the same binding partners with MYC (Resar et al 1993). BMYC has also been shown to be phosphorylated in the TAD at sites conserved with MYC, which further implies interactions with the same partners (Gregory et al 2000). In addition to b-HLH-LZ-mediated binding, two regions responsible for other interactions, namely MYC boxes I and II (MBI and MBII), are well conserved amongs all MYC proteins (Henriksson & Luscher 1996).…”

“…However, it contains a transcriptional activation domain (TAD), localizes mainly in the nucleus, and has been shown in vitro to initiate transcription, to inhibit neoplastic transformation, and to inhibit transcriptional activation regulated by MYC (Resar et al 1993, Asker et al 1995. BMYC has also been shown to inhibit cellular proliferation (Gregory et al 2000).…”

Why are epididymal tumours so rare?

“…42 In adult mice, epididymal expression of c-Mos, A-raf, B-Raf, cRaf, L-Myc, N-Myc, B-Myc, C-Myc, c-Ret and Met have been identified. 43,44 Explanations for epididymal oncogene expression not being accompanied by typical oncogenic activity include: (i) the counter-balancing of antiproliferative gene expression (see above)-the expression of antiproliferative B-Myc protein exceeds that of pro-proliferative c-Myc; 45 (ii) the triggering, by high expression of some oncogenes (e.g., Ras family and C-Myc), of fail-safe mechanisms that induce senescence or apoptosis (see section on 'Intrinsic barriers to tumour formation'), instead of inducing proliferation; 46 (iii) the provision of protection against tumours by endogenous oncogenes. The expression of K-Ras, B-Raf and Myc, expressed in the adult human epididymis, 20 enhances the basal expression of the transcription factor Nrf2 (nuclear factor E2-related factor 2), which controls intracellular levels of ROS through an inducible antioxidant programme.…”