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

Abstract

BRE binds to the cytoplasmic domains of tumor necrosis factor receptor-1 and Fas, and in cell lines can attenuate death receptor-initiated apoptosis by inhibiting t-BIDinduced activation of the mitochondrial apoptotic pathway. Overexpression of BRE by transfection can also attenuate intrinsic apoptosis and promote growth of the transfected Lewis lung carcinoma line in mice. There is, however, a complete lack of in vivo data about the protein.Here, we report that by using our BRE-specific monoclonal antibody on the immunohistochemistry of 123 specimens of human hepatocellular carcinoma (HCC), significant differences in BRE expression levels between the paired tumoral and non-tumoral regions (Po2.2eÀ16) were found. Marked overexpression of BRE was detected in majority of the tumors, whereas most non-tumoral regions expressed the same low level of the protein as in normal livers. To investigate whether BRE overexpression could promote cell survival in vivo, liver-specific transgenic BRE mice were generated and found to be significantly resistant to Fas-mediated lethal hepatic apoptosis. The transgenic model also revealed post-transcriptional regulation of Bre level in the liver, which was not observed in HCC and non-HCC cell lines. Indeed, all cell lines analysed express high levels of BRE. In conclusion, BRE is antiapoptotic in vivo, and may promote tumorigenesis when overexpressed.

High BRE expression in pediatric MLL-rearranged AML is associated with favorable outcome

“…15,35 Recently, overexpression of BRE has been described in hepatocellular and esophageal carcinomas. 32,36 However, to date BRE has never been associated with hematological malignancies. This study shows that BRE has a role in pediatric AML and mainly in patients with t(9;11)(p22;q23).…”

A Unique Pharmacophore for Activation of the Nuclear Orphan Receptor Nur77 In vivo and In vitro

“…Furthermore, we found that Csn-B analogues promote Nur77 antitumor activity through a novel cross-talk between Nur77 and brain and reproductive organ-expressed protein (BRE). BRE, a death receptor-associated protein, specifically downregulates death receptor-mediated apoptosis by inhibiting activation of the mitochondrial apoptotic pathway (26,27). The Csn-B analogues prepared in this study repress the transcriptional activity of BRE through recruitment of corepressor N-CoR.…”

“…To identify novel apoptotic genes specifically responsible for Nur77 regulation, we performed a Gene Chip analysis and found that a novel downstream gene, BRE (brain and reproductive organ-expressed protein), was dramatically repressed by Csn-B. 3 Although BRE is a known antiapoptotic protein that functions by inhibiting the mitochondrial apoptotic pathway (26,27), a regulatory mechanism involving BRE and Nur77 is unknown. Reverse transcription-PCR (RT-PCR) analysis confirmed that endogenous BRE mRNA levels were indeed reduced by three compounds, 10a, 10f, or 10i (Fig.…”

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

“…Livers over-expressing BRE transgene are under heightened state of stressresponse, as revealed by comparative proteomics BRE is normally expressed at very low levels in the liver (Chan, et al, 2008). It binds to TNF-R1 and Fas, and modulates the actions of these cytokines Chan et al, 2010).…”

“…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. The expression of the BRE gene has been investigated in various biological models including adrenal glands (Miao et al, 2001), testis (Miao et al, 2005) and hepatocellular carcinoma cells (Chan et al, 2008), but the function of BRE has still not been clarified -the protein structure of BRE do not have identifiable functional domain. It has been suggested the BRE contained 2 ubiquitinconjugating enzyme family-like regions (Hu et al, 2011).…”