BRE: a modulator of TNF‐α action

Abstract

A stress-responsive gene highly expressed in brain and reproductive organs (BRE) is down-regulated after UV irradiation, DNA damaging agents, or retinoic acid treatment. The human BRE gene encodes a mRNA of 1.9 kb, which gives rise to a protein of 383 amino acids with a molecular size of 44 kilodaltons. BRE is not homologous to any known gene and its function has not been defined. Here we report that BRE was identified multiple times in a yeast two-hybrid screen of a murine cerebellar cDNA library, using the juxtamembrane domain of the p55 tumor necrosis factor alpha (TNF) receptor. The interaction between the p55 receptor and BRE was verified by an in vitro biochemical assay by using recombinant fusion proteins and by co-immunoprecipitation of transfected mammalian cells. In the yeast two-hybrid assay, BRE specifically interacted with p55 TNF receptor but not with other TNF family members such as the Fas receptor, the p75 TNF receptor, and p75 neurotrophin receptor. Overexpression of BRE inhibited TNF-induced NFkappaB activation, indicating that the interaction of BRE protein with the cytoplasmic region of p55 TNF receptor may modulate signal transduction by TNF-alpha.

BRE is an antiapoptotic protein in vivo and overexpressed in human hepatocellular carcinoma

“…Cells receive external signals through surface death receptors, such as the widely expressed tumor necrosis factor receptor-1 and Fas (Nagata, 1997;Aggarwal, 2003), or internal stress signals such as DNA damage (Dive et al, 1992), to undergo the extrinsic or intrinsic pathway of apoptosis, respectively (Strasser et al, 1995). In a yeast two-hybrid experiment designed to isolate novel intracellular binding proteins of tumor necrosis factor receptor-1, brain and reproductive organ-expressed protein (BRE) was identified as one such protein that binds to the juxtamembrane domain of the death receptor (Gu et al, 1998). BRE was first discovered as a ultraviolet-responsive gene, whose transcription could also be downregulated by a DNA-damaging chemical, 4-nitroquinoline-1-oxide, and a differentiation-inducing agent, retinoic acid (Li et al, 1995).…”

Comparative Proteomics: An Approach to Elucidating the Function of a Novel Gene Called BRE

“…Furthermore, we have also determined p53 expression was down-regulated; whereas TNF-R1 expression was up-regulated in SHEEC cells ( Figure 10). It has been reported that BRE can interact with the intracellular juxtamembrane domain TNF-R1 and inhibit the TNFinduced activation of NF-B (Gu et al, 1998). Therefore, we propose that BRE plays an antiapoptotic role in SHEEC cells.…”

“…Recent finding also showed that TRAF6 was involved in the RANK-TRAF6-NF-B pathways during osteoclastogenesis (Inoue et al, 2007). Overexpression of BRE in human 293 embryonic kidney cells has been reported to inhibit NF-B activation in response to TNF (Gu et al, 1998). This finding suggests that BRE indirectly cross-talk with TRAF6 and NF- , where it may play a central role in regulating cell proliferation, differentiation and survival.…”

“…The BRE gene encodes a 1.7-1.9 kb mRNA which give rise to a protein with 383 amino acid residues and a molecular weight of 44 kDa. Using the yeast two-hybrid assay, it was reported that BRE interacts with the juxtamembrane (JM) region of p55-TNFR, but has no affinity for the p75-TNFR, Fas or p75-NGFR of the TNFR family (Gu et al, 1998). Meanwhile, over-expression of BRE in the human 293 embryonic kidney cells that was treated with TNF-could inhibit the activation of the transcriptional factor NF-B (Gu et al, 1998).…”

“…Using the yeast two-hybrid assay, it was reported that BRE interacts with the juxtamembrane (JM) region of p55-TNFR, but has no affinity for the p75-TNFR, Fas or p75-NGFR of the TNFR family (Gu et al, 1998). Meanwhile, over-expression of BRE in the human 293 embryonic kidney cells that was treated with TNF-could inhibit the activation of the transcriptional factor NF-B (Gu et al, 1998). Since NF-B is known to induce the survival pathway associated with TNF receptor, it is likely that BRE can modulate the cell death process.…”