Specificity and heregulin regulation of Ebp1 (ErbB3 binding protein 1) mediated repression of androgen receptor signalling

Zhang, Y; Hamburger, Anne W.

doi:10.1038/sj.bjc.6602257

Cited by 35 publications

(41 citation statements)

References 43 publications

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“…Further study is needed of the involvement of non-NRG, non-ERBB regulators of ERBB3, such as CDK5, [122][123][124] BRK, 125 SRC, 126 and MET. 120 The fascinating and widely expressed ERBB3 effector EBP1 has thus far been examined mainly in mammary and prostate cells; [154][155][156][157][158][159][160][161][162][163][164] may it be important also in other cancers where ERBB3 is clearly a player, such as lung and melanoma? It is hoped that full understanding of the regulation and functions of ERBB3 will facilitate its integration into cancer management.…”

Section: Discussionmentioning

confidence: 99%

“…157,[159][160][161][162] EBP1 contains an LXXLL motif mediating interactions with nuclear hormone receptors and binds androgen receptor, resulting in inhibition of activation of androgen-responsive gene promoters. 157,163,164 Transcriptional effects of EBP1 are dependent on phosphorylation at serine 363. 165 Thus, in both breast and prostate cancer cells, EBP1 is potentially a critical effector for ERBB3 signaling.…”

Section: Newly-identified Proteins Binding Erbb3 Phosphotyrosines-thementioning

confidence: 99%

“…Among the several known effects of the freed EBP1 is interaction with the androgen receptor as an inhibitor, so in androgen-dependent prostate cancer cells EBP1 suppressed proliferation and xenograft growth, in part by blocking androgen action. [162][163][164] Thus in such cells there is theoretical possibility of opposite effects of NRG activation of ERBB3: activation of the androgen receptor and its effects via AKT-dependent and -independent actions, and inhibition of it via EBP1. It is not surprising that variable effects have been seen experimentally with NRG applied to prostate cancer cells.…”

Section: Prostate Cancermentioning

confidence: 99%

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The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Newly-identified Proteins Binding Erbb3 Phosphotyrosines-thementioning

confidence: 99%

Section: Prostate Cancermentioning

confidence: 99%

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The ERBB3 receptor in cancer and cancer gene therapy

2008

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“…Our laboratory has demonstrated that Ebp1, a member of the PA2G4 family of proliferation-regulated proteins (12,13) that interacts with the ErbB3 receptor (14), is also an AR corepressor (15). Activity of both exogenous and endogenous AR-regulated promoters was inhibited by ectopic expression of ebp1 independent of prostate cell type (16). Ebp1 interacted with histone deacetylase (HDAC) 2 and also inhibited transcription of cell cycle regulators such as E2F1, cyclin D, and c-myc (17).…”

Section: Down-regulation Of the Androgen Receptor (Ar) Is Being Evalumentioning

confidence: 99%

The ErbB3-binding protein Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells

Zhang

Wang

Jelovac

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

101

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Down-regulation of the androgen receptor (AR) is being evaluatedas an effective therapy for the advanced stages of prostate cancer. We report that Ebp1, a protein identified by its interactions with the ErbB3 receptor, down-regulates expression of AR and ARregulated genes in the LNCaP prostate cancer cell line. Using microarray analysis, we identified six endogenous AR target genes, including the AR itself, that are down-regulated by ebp1 overexpression. Chromatin immunoprecipitation assays revealed that Ebp1 was recruited to the prostate-specific antigen gene promoter in response to the androgen antagonist bicalutamide, suggesting that Ebp1 directly affected the expression of AR-regulated genes in response to androgen antagonists. Ebp1 expression was reduced in cells that had become androgen-independent. Androgens failed to stimulate either the growth of ebp1 transfectants or transcription of AR-regulated reporter genes in these cells. The agonist activity of the antiandrogen cyproterone acetate was abolished in ebp1 transfectants. In severe combined immunodeficient mice, Ebp1 overexpression resulted in a reduced incidence of LNCaP tumors and slower tumor growth. These findings suggest that Ebp1 is a previously unrecognized therapeutic target for treatment of hormone refractory prostate cancer.ErbB receptors ͉ transcriptional corepressors ͉ androgen independence

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“…The regulated nuclear accumulation of Ebp1 suggested that Ebp1 might act as a transcription factor or transcriptional coregulator. Indeed, Ebp1 represses transcription of both E2F1 (Xia et al, 2001) and androgen receptor-regulated genes (Zhang et al, 2005a;Zhang and Hamburger, 2005). Ebp1 binds to the E2F-1 promoter in a complex with the E2F-1 transcription factor and retinoblastoma (Rb) (Zhang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor

Liu¹,

Oh²,

Okada³

et al. 2009

MBoC

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Human Bre1, an E3 ligase for H2B monoubiquitination, binds p53 and enhances activator-dependent transcription. Ebp1, an ErbB3 receptor-binding protein, inhibits cell proliferation and acts as a tumor suppressor. Here, we show that hBre1 acts as an E3 ubiquitin ligase for Ebp1 tumor suppressor and promotes its polyubiquitination and degradation. Ebp1 is polyubiquitinated in cancer cells, which is regulated by its phosphorylation. We identified hBre1 acting as an E3 ligase for Ebp1 and increasing its polyubiquitination. Depletion of hBre1 blocks Ebp1's polyubiquitination and elevates its protein level, preventing cancer proliferation. hBre1 binds Ebp1 and suppresses its repressive effect on E2F-1. Moreover, Ebp1 protein level is substantially diminished in human cancers. It is robustly phosphorylated and localized in the nucleus of primary gliomas, correlating with hBre1 subcellular residency. Thus, hBre1 inhibits Ebp1's tumor suppressive activity through mediating its polyubiquitination and degradation. INTRODUCTIONIn yeast, histone H2B K123 monoubiquitination is regulated by the E3 ligase Bre1 and E2-conjugating enzyme RAD6 (Robzyk et al., 2000;Hwang et al., 2003;Wood et al., 2003a). This process is a prerequisite for the subsequent histone H3-K4 and K79 methylation (Sun and Allis, 2002;Wood et al., 2003b), which marks actively transcribed genes (SantosRosa et al., 2002). Additionally, PAF complex is also required for H2B ubiquitination (Ng et al., 2003;Wood et al., 2003b). In humans, the homologue of yeast Bre1 (RNF20), designated as hBre1, acts as an E3 ligase for H2B and promotes its ubiquitination at K120, the equivalent of yeast H2B K123 (Kim et al., 2005;Zhu et al., 2005). Moreover, it has a coactivator function in activator-dependent transcription of several genes. Interestingly, hBre1 directly binds p53 and is recruited to the MDM2 promoter, regulating p53-responsive gene transcription in a p53-dependent manner. Overexpression and depletion of hBre1 increases and decreases global H2B ubiquitination, respectively. By contrast, ectopic hRAD6A and hRAD6B, human homologues of yRAD6, do not affect H2B ubiquitination or H3 methylation, suggesting that hRAD6 proteins are not cognate E2 enzymes for hBre1 (Kim et al., 2005). In addition to transcriptional coactivation of specific genes (Osley, 2004), Bre1 in Drosophila is required for Notch signaling and histone modification (Bray et al., 2005).Ebp1 was originally identified as an ErbB3 receptor-binding protein , and it is the human homologue of a previously identified cell cycle-regulated mouse protein p38-2G4 (Radomski and Jost, 1995). PA2G4 gene encodes two Ebp1 isoforms, p48 and p42, which differentially regulate PC12 cell survival and differentiation Liu et al., 2006). P48 is 54 amino acids longer than p42 at its N terminus. The longer form p48 localizes in both the cytoplasm and the nucleolus and suppresses apoptosis, whereas the shorter form p42 predominantly resides in the cytoplasm and promotes cell differentiation . Ebp1 binds the ribosome and double-st...

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Specificity and heregulin regulation of Ebp1 (ErbB3 binding protein 1) mediated repression of androgen receptor signalling

Cited by 35 publications

References 43 publications

The ERBB3 receptor in cancer and cancer gene therapy

The ERBB3 receptor in cancer and cancer gene therapy

The ErbB3-binding protein Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells

Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor

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