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Article: Glucose-regulated protein 78 as a novel effector of BRCA1 for inhibiting stress-induced apoptosis

TitleGlucose-regulated protein 78 as a novel effector of BRCA1 for inhibiting stress-induced apoptosis
Authors
KeywordsApoptosis
BRCA1
Breast cancer
GRP78
Ovarian cancer
Unfolded protein response
Issue Date2008
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2008, v. 27 n. 53, p. 6782-6789 How to Cite?
AbstractThe tumor suppressor BRCA1 is mutated in a high percentage of familial breast and ovarian cancer, but our understanding of its mechanisms of action remains incomplete. We report here that glucose-regulated protein (GRP)-78, a critical regulator of the unfolded protein response (UPR), is a novel downstream target of BRCA1. We showed that overexpression of wild-type BRCA1 suppressed the expression of GRP78, whereas expression of mutant BRCA1 gene or targeted inhibition of endogenous BRCA1 using small-interfering RNA (siRNA) enhanced GRP78 expression. Knockdown of BRCA1 also led to induction of other components of UPR, such as GRP94 and CHOP. Consistent with a role of BRCA1 knockdown in mediating cell survival, forced expression of GRP78 stimulated cell proliferation and prevented apoptosis, including that induced by endoplasmic reticulum stress and chemotherapy, in ovarian OVCAR-3 and breast MCF-7 cancer cells. Overexpression of wild-type BRCA1 could increase the apoptosis of GRP78-overexpressing cells. Conversely, knockdown GRP78 by siRNA sensitized ovarian and breast cancer cells to apoptosis. This effect was reduced when the expression of BRCA1 was simultaneously knockdown by siRNA, indicating that BRCA1 also negatively regulates GRP78-mediated cell survival and resistance to apoptosis. © 2008 Macmillan Publishers Limited All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/59994
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants Council7484/04M
Funding Information:

The present work was supported by Hong Kong Research Grants Council Grant (7484/04M) (AST Wong).

References

 

DC FieldValueLanguage
dc.contributor.authorYeung, BHYen_HK
dc.contributor.authorKwan, BWYen_HK
dc.contributor.authorHe, QYen_HK
dc.contributor.authorLee, ASen_HK
dc.contributor.authorLiu, Jen_HK
dc.contributor.authorWong, ASTen_HK
dc.date.accessioned2010-05-31T04:01:38Z-
dc.date.available2010-05-31T04:01:38Z-
dc.date.issued2008en_HK
dc.identifier.citationOncogene, 2008, v. 27 n. 53, p. 6782-6789en_HK
dc.identifier.issn0950-9232en_HK
dc.identifier.urihttp://hdl.handle.net/10722/59994-
dc.description.abstractThe tumor suppressor BRCA1 is mutated in a high percentage of familial breast and ovarian cancer, but our understanding of its mechanisms of action remains incomplete. We report here that glucose-regulated protein (GRP)-78, a critical regulator of the unfolded protein response (UPR), is a novel downstream target of BRCA1. We showed that overexpression of wild-type BRCA1 suppressed the expression of GRP78, whereas expression of mutant BRCA1 gene or targeted inhibition of endogenous BRCA1 using small-interfering RNA (siRNA) enhanced GRP78 expression. Knockdown of BRCA1 also led to induction of other components of UPR, such as GRP94 and CHOP. Consistent with a role of BRCA1 knockdown in mediating cell survival, forced expression of GRP78 stimulated cell proliferation and prevented apoptosis, including that induced by endoplasmic reticulum stress and chemotherapy, in ovarian OVCAR-3 and breast MCF-7 cancer cells. Overexpression of wild-type BRCA1 could increase the apoptosis of GRP78-overexpressing cells. Conversely, knockdown GRP78 by siRNA sensitized ovarian and breast cancer cells to apoptosis. This effect was reduced when the expression of BRCA1 was simultaneously knockdown by siRNA, indicating that BRCA1 also negatively regulates GRP78-mediated cell survival and resistance to apoptosis. © 2008 Macmillan Publishers Limited All rights reserved.en_HK
dc.languageengen_HK
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/oncen_HK
dc.relation.ispartofOncogeneen_HK
dc.subjectApoptosisen_HK
dc.subjectBRCA1en_HK
dc.subjectBreast canceren_HK
dc.subjectGRP78en_HK
dc.subjectOvarian canceren_HK
dc.subjectUnfolded protein responseen_HK
dc.titleGlucose-regulated protein 78 as a novel effector of BRCA1 for inhibiting stress-induced apoptosisen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0950-9232&volume=27&spage=6782&epage=6789&date=2008&atitle=Glucose-regulated+protein+78+as+a+novel+effector+of+BRCA1+for+inhibiting+stress-induced+apoptosisen_HK
dc.identifier.emailWong, AST: awong1@hkucc.hku.hken_HK
dc.identifier.authorityWong, AST=rp00805en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/onc.2008.290en_HK
dc.identifier.pmid18776923-
dc.identifier.scopuseid_2-s2.0-56249087893en_HK
dc.identifier.hkuros147558en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-56249087893&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume27en_HK
dc.identifier.issue53en_HK
dc.identifier.spage6782en_HK
dc.identifier.epage6789en_HK
dc.identifier.eissn1476-5594-
dc.identifier.isiWOS:000260866200008-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridYeung, BHY=24402173100en_HK
dc.identifier.scopusauthoridKwan, BWY=36869595900en_HK
dc.identifier.scopusauthoridHe, QY=34770287900en_HK
dc.identifier.scopusauthoridLee, AS=7405629878en_HK
dc.identifier.scopusauthoridLiu, J=8943925800en_HK
dc.identifier.scopusauthoridWong, AST=23987963300en_HK
dc.identifier.citeulike3207078-

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