Identification of BARD1 as Mediator between Proapoptotic Stress and p53-Dependent Apoptosis

Irminger-Finger, Irmgard; Leung, Wai-Choi; Li, Jian; Dubois‐Dauphin, Michel; Harb, Jean; Féki, Anis; Jefford, Charles Edward; Soriano, Jesús V.; Jaconi, Marisa; Montesano, Roberto; Krause, Karl‐Heinz

doi:10.1016/s1097-2765(01)00406-3

Cited by 105 publications

(148 citation statements)

References 28 publications

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“…Moreover, BARD1 (L107A þ NES), which is not retained in the nucleus by BRCA1 (see Figure 6b), was not inhibited in its apoptotic function by BRCA1, indicating that the antiapoptotic action of BRCA1 is mediated through its ability to mask the BARD1 NES. BARD1 proapoptotic activity was far less pronounced in p53-mutant T47D cells, consistent with previous observations of p53-dependency in mouse cells (Irminger-Finger et al, 2001), but nonetheless was still reduced by NES mutations in T47D cells. The above findings, when considered together, suggest that BARD1 localization is regulated by nuclear export in vivo, and that nuclear export stimulates BARD1 apoptotic activity.…”

Section: A Link Between Bard1 Nuclear Export and Its Apoptotic Functionsupporting

confidence: 92%

“…The only BARD1 function independent of BRCA1 yet identified is a p53-dependent proapoptotic activity, observed after the induction of BARD1 by genotoxic stress (Irminger-Finger et al, 2001). Interestingly, BARD1-dependent apoptosis was partially decreased (Brzovic et al, 2001a), showing BARD1 (blue), BRCA1 (red), and their respective nuclear export signals (NESs; green).…”

Section: A Link Between Bard1 Nuclear Export and Its Apoptotic Functionmentioning

confidence: 99%

“…Cell images and distribution profiles show that BRCA1 blocks export of wild-type BARD1, but not BARD1 containing a repositioned NES. by BRCA1 in mouse embryo stem cells (Irminger-Finger et al, 2001), and it was suggested that BARD1 was responsible for mediating the p53-dependent apoptosis previously observed in BRCA1-targeted mice (Xu et al, 2001). We tested whether silencing BRCA1 by siRNA affected apoptosis in different cell lines, and observed a small but consistent twofold increase in apoptosis in HBL-100 cells (Figure 8a) and U2OS cells (not shown), but not in T47D cells, which express mutant p53 (data not shown).…”

Section: A Link Between Bard1 Nuclear Export and Its Apoptotic Functionmentioning

confidence: 99%

“…Moreover, there is some experimental evidence from antisense RNA studies that repression of BARD1 expression in murine mammary epithelial cells resulted in phenotypic changes reminiscent of premalignancy (Irminger-Finger et al, 1998). Recently, BARD1 was shown to induce apoptosis in mouse embryo fibroblasts via a pathway dependent on p53, but not requiring BRCA1 (Irminger-Finger et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Nuclear–cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1

Rodriguez

Schüchner

et al. 2003

Oncogene

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The breast cancer-associated protein, BARD1, colocalizes with BRCA1 in nuclear foci in the S phase and after DNA damage, and the two proteins form a stable heterodimer implicated in DNA repair, protein ubiquitination, and control of mRNA processing. BARD1 has a BRCA1-independent proapoptotic activity; however, little is known about its regulation. Here, we show that BARD1 localization and apoptotic activity are regulated by nuclear-cytoplasmic shuttling. We identified a functional CRM1-dependent nuclear export sequence (NES) near the N-terminal RING domain of BARD1. The NES forms part of the BRCA1 dimerization domain, and coexpression of BRCA1 resulted in masking of the NES and nuclear retention of BARD1. In transient expression assays, BARD1 apoptotic activity was stimulated by nuclear export, and both apoptotic function and nuclear export were markedly reduced by BRCA1. Similar findings were obtained for endogenous BARD1. Silencing BRCA1 expression by siRNA, or disrupting the endogenous BARD1/BRCA1 interaction by peptide competition caused a reduction in BARD1 nuclear localization and foci formation, and increased the level of cytoplasmic BARD1 correlating with increased apoptosis. Our findings suggest that BRCA1/BARD1 heterodimer formation is important for optimal nuclear targeting of BARD1 and its role in DNA repair and cell survival.

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Section: A Link Between Bard1 Nuclear Export and Its Apoptotic Functionsupporting

confidence: 92%

Section: A Link Between Bard1 Nuclear Export and Its Apoptotic Functionmentioning

confidence: 99%

Section: A Link Between Bard1 Nuclear Export and Its Apoptotic Functionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Nuclear–cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1

Rodriguez

Schüchner

et al. 2003

Oncogene

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“…3C). As expected these p53-dependent genes [29][30][31] were no longer induced upon IKAP/hELP1 depletion in p53 deficient HCT116 cells (Fig. 3C).…”

Section: Ikap/help1 Depletion Modulates Gene Expression In a Cell-typsupporting

confidence: 82%

Deregulated expression of pro-survival and pro-apoptotic p53-dependent genes upon Elongator deficiency in colon cancer cells

Cornez

Creppe

Gillard

et al. 2008

Biochemical Pharmacology

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b i o c h e m i c a l p h a r m a c o l o g y 7 5 ( 2 0 0 8 ) 2 1 2 2 -2 1 3Abbreviations: B2M, beta-2-microglobulin; BARD1, BRCA1-associated RING domain 1; BAX, BCL2-associated X protein; BTG2, B-cell translocation gene 2; CDK9, cyclin-dependent kinase 9; DMEM, Dulbecco's modified Eagle's medium; DUSP4, dual-specificity phosphatase 4; Elp, Elongator protein; EMEM, Eagle's modified essential medium; FACT, facilitates chromatin transcription; GFP, green fluorescent protein; HA, haemagglutinin; hELP1, human ELP1; IKAP, IKK-associated protein; IKK, inhibitor of kappa light chain gene enhancer in B cells kinase complex; NR2F2, nuclear receptor subfamily 2, group F, member 2; p21, cyclin-dependent kinase inhibitor 1A; PARP, poly (ADP-ribose) polymerase 1; PKIB, protein kinase, cAMP-dependent catalytic, inhibitor beta; RhoE/Rnd3, Rho family GTPase 3; SESN2, sestrin 2; SGK, serum-and glucocorticoid-induced protein kinase; shRNA, short hairpin RNA; TFIIF, general transcription factor IIF; TFIIH, general transcription factor IIH; TNFRSF10D, tumor necrosis factor receptor superfamily, member 10D.

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Aberrant expression of BARD1 in breast and ovarian cancers with poor prognosis

Vlastos

Pelte

et al. 2005

Intl Journal of Cancer

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Mutations in tumor-suppressor gene BARD1 have been found in inherited and spontaneous breast, ovarian and uterine cancers. BARD1 plays a critical role in DNA repair and ubiquitination as binding partner of BRCA1, with which it colocalizes to nuclear dots. Independently of BRCA1, BARD1 can induce p53-dependent apoptosis in response to genotoxic stress. Therefore, BARD1 or p53 might be defective in cancer cells spared from apoptosis. We investigated BARD1 and p53 expression in ovarian, breast and non-small-cell lung cancers. BARD1 expression was highly upregulated and cytoplasmic in most cancer cells, while weak nuclear staining was observed in the surrounding normal tissue. Maximal BARD1 expression was associated with the most malignant ovarian cancer, clear cell carcinoma. In breast cancer, BARD1 expression was correlated with poor differentiation and large tumor size, established factors of poor prognosis, as well as short disease-free survival. In contrast to breast and ovarian cancers, no correlation of BARD1 expression with either grade or stage could be determined for lung cancer. RT-PCR, performed on 10 ovarian cancers, revealed absence of the 5 0 portion of the BARD1 transcript in 7 tumors, and sequencing of the remaining 3 identified a missense mutation (A1291G) resulting in an amino acid change of glutamine 406 to arginine. These data suggest that genetic and epigenetic changes might lead to elevated cytoplasmic expression of BARD1 and that cytoplasmic BARD1 might be a poor prognostic factor for breast and ovarian cancers. ' 2005 Wiley-Liss, Inc.Key words: BARD1; BRCA1; breast cancer; lung cancer; ovarian cancer; p53Cancer has become the second leading cause of death in Western countries. A total of 1,368,030 new cancer cases and 563,700 deaths are expected in the United States in 2004. Although lung cancer is the leading cause of cancer death for men, breast and ovarian cancers account for approximately 32% and 4% of cases in women, respectively. 1 Ninety percent of malignant primary ovarian neoplasms are surface epithelial-stromal tumors, and malignant germ cell or sexcord stroma tumors are less common. Serous, mucinous, endometrioid and clear cell adenocarcinomas are more frequent than transitional cell tumors, mixed epithelial and undifferentiated carcinomas. 1a Of these subtypes, clear cell carcinoma is reported to have the worst prognosis. 2 Only a few prognostic factors, although controversial, have been identified in ovarian cancer so far, including cyclin D, p53, p21, and CA125. 3,4 The frequency of overexpression of mutant p53 is significantly higher in advanced-stage (III/IV) ovarian cancer compared to stage I cases (10-20%). This may indicate that p53 inactivation is a late event in ovarian carcinogenesis. [5][6][7] More factors have been reported to influence the prognosis for breast cancer, including size, histologic type and grade of the primary tumor, lymph node involvement, status of estrogen and progesterone receptors and other biomarkers such as HER-2, p53, bcl-2, Bfl-1, Ki-67 and VEG...

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Identification of BARD1 as Mediator between Proapoptotic Stress and p53-Dependent Apoptosis

Cited by 105 publications

References 28 publications

Nuclear–cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1

Nuclear–cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1

Deregulated expression of pro-survival and pro-apoptotic p53-dependent genes upon Elongator deficiency in colon cancer cells

Aberrant expression of BARD1 in breast and ovarian cancers with poor prognosis

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