Enhancement of BRCA1 E3 Ubiquitin Ligase Activity through Direct Interaction with the BARD1 Protein

Xia, Yan; Pao, Gerald M.; Chen, Hong Wu; Verma, Inder M.; Hunter, Tony

doi:10.1074/jbc.m204591200

Cited by 191 publications

(192 citation statements)

References 71 publications

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“…This appeared to be due to BRCA1 stabilizing the FOXA1 protein, increasing the half-life of this protein. This stabilizing effect of BRCA1 has also been observed for another of the interacting partners of BRCA1, namely BARD1 (Xia et al, 2003). Indeed, decreasing the protein expression of BRCA1 also decreased the expression of FOXA1 protein.…”

Section: Discussionsupporting

confidence: 57%

“…Since the effect on protein stability is observed only with a BRCA1 protein having an intact C-terminal BRCT repeat domain, we suggest that the interaction occurs at or near the C-terminus of BRCA1. As a comparison, BARD1 and BRCA1 interact via their N-terminal RING domains, and this interaction and the effect on protein stability is unaffected by C-terminal mutations of BRCA1 (Xia et al, 2003). Indeed, a study has demonstrated that FOXA1 is decreased in BRCA1-mutated breast cancers (van't Veer et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1

et al. 2005

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We have previously shown that the breast cancer susceptibility gene, BRCA1, can transcriptionally activate the p27 Kip1 promoter. The BRCA1-responsive element was defined as a 35 bp region from position À545 to À511. We next determined that within this region is also a potential binding site for the transcription factor Forkhead box (FOX)A1. RNA and protein analysis as well as immunohistochemistry showed that expression of FOXA1 correlated with the expression of the estrogen receptor in a panel of breast cancer cell lines and tissues. In transient transfection reporter assays, FOXA1 could activate the p27 Kip1 promoter. Cotransfection of BRCA1 and FOXA1 resulted in a synergistic activation of the p27 Kip1 promoter. Mutation of the FOXA1 DNA-binding site in the p27 Kip1 promoter-luciferase construct significantly diminished the activity of FOXA1 alone or in combination with BRCA1. Cotransfection of FOXA1 and BRCA1 resulted in a greater amount of each protein compared to transfection of each expression vector alone. The half-life of FOXA1 was increased when coexpressed with BRCA1. Electrophoretic mobility shift assay analysis demonstrated that FOXA1 could bind to a wild-type oligonucleotide containing the FOXA1 binding site in the p27 Kip1 promoter, but this binding was lost upon mutation of this FOXA1 binding site. The protein-DNA binding complex could be supershifted with an antibody directed against FOXA1. The activity of the p27 Kip1 promoter as well as FOXA1 expression was reduced in cells treated with BRCA1 siRNA, thus silencing the expression of BRCA1 protein. In summary, we identified a FOXA1 binding site within the BRCA1-responsive element of the p27 Kip1 promoter and showed that FOXA1 activated the promoter alone and in conjunction with BRCA1. Furthermore, we identified high expression of FOXA1 in breast cancer cell lines and tissues, discovered a role for BRCA1 in the regulation of p27 Kip1 transcription and a possible interaction with BRCA1.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1

et al. 2005

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“…Proteins can be polyubiquitylated through the formation of both K48-and K63-linked poly-Ub chains. Although the heterodimeric E2 Ubc13/Uev1A has been shown to cooperate with certain RING finger E3s (21,44,45) to catalyze the formation of poly-Ub chains linked through K63, UbcH5 and several other E2s have been shown to participate in K48-linked poly-Ub chain formation. K63-linked poly-Ub chains have been implicated in the regulation of target protein activities such as kinase activation (21), which is distinct from the traditional degradative, K48-linked ubiquitylation.…”

Section: Trac-1 Cooperates With Both Ubch5c and Ubc13/uev1a To Catalymentioning

confidence: 99%

A Novel E3 Ubiquitin Ligase TRAC-1 Positively Regulates T Cell Activation

Zhao

Pardo

et al. 2005

The Journal of Immunology

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TRAC-1 (T cell RING (really interesting new gene) protein identified in activation screen) is a novel E3 ubiquitin ligase identified from a retroviral vector-based T cell surface activation marker screen. The C-terminal truncated TRAC-1 specifically inhibited anti-TCR-mediated CD69 up-regulation in Jurkat cells, a human T leukemic cell line. In this study, we show that TRAC-1 is a RING finger ubiquitin E3 ligase with highest expression in lymphoid tissues. Point mutations that disrupt the Zn2+-chelating ability of its amino-terminal RING finger domain abolished TRAC-1’s ligase activity and the dominant inhibitory effect of C-terminal truncated TRAC-1 on TCR stimulation. The results of in vitro biochemical studies indicate that TRAC-1 can stimulate the formation of both K48- and K63-linked polyubiquitin chains and therefore could potentially activate both degradative and regulatory ubiquitin-dependent pathways. Antisense oligonucleotides to TRAC-1 specifically reduced TRAC-1 mRNA levels in Jurkat and primary T cells and inhibited their activation in response to TCR cross-linking. Collectively, these results indicate that the E3 ubiquitin ligase TRAC-1 functions as a positive regulator of T cell activation.

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“…The deleted domain included the RING domain, which binds to the BARD1 protein and which has ubiquitin ligase activity (Hashizume et al, 2001;Wu-Baer et al, 2003;Xia et al, 2003). We tested whether the ubiquitin ligase function was the critical activity deleted from DN-BRCA1 by generating specific point mutations of critical cysteines.…”

Section: Mutation Of the Amino-terminal Ring Domain Caused Growth Supmentioning

confidence: 99%

Expression of an amino-terminal BRCA1 deletion mutant causes a dominant growth inhibition in MCF10A cells

et al. 2004

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Expression of deletion mutants of the breast and ovarian cancer-specific tumor suppressor protein, BRCA1, in the mammary epithelial cell line MCF10A revealed a powerful growth suppressive effect by a mutant that has the amino-terminal 302 amino acids deleted (DN-BRCA1). The growth suppression is associated with an increase in apoptosis and amplification in centrosome number. The growth inhibitory effect of DN-BRCA1 was not observed in cervical epithelial HeLa cells, suggesting that the phenotypes of BRCA1 mutant proteins differ depending on the cell line being tested. An internal domain, including BRCA1 residues 303-1292, caused the suppression of MCF10A cell growth, and the amino terminus of BRCA1 autoinhibited the growth suppression. Single point mutations that disrupted the amino-terminal RING domain of BRCA1 caused significant suppression of growth in MCF10A cells. These results suggest that the proper function of the RING domain, likely to be ubiquitin ligase function, is important in regulating the growth of the mammary epithelial cell line and in autoregulating the powerful internal growth-inhibiting domain of the BRCA1 tumor suppressor.

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Enhancement of BRCA1 E3 Ubiquitin Ligase Activity through Direct Interaction with the BARD1 Protein

Cited by 191 publications

References 71 publications

BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1

BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1

A Novel E3 Ubiquitin Ligase TRAC-1 Positively Regulates T Cell Activation

Expression of an amino-terminal BRCA1 deletion mutant causes a dominant growth inhibition in MCF10A cells

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