Document Detail


The small heat shock protein HspB2 is a novel anti-apoptotic protein that inhibits apical caspase activation in the extrinsic apoptotic pathway.
MedLine Citation:
PMID:  20087649     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Members of the conserved small heat shock protein (sHSP) family, such as αB-crystallin and Hsp27, are constitutively expressed in diverse malignancies and have been linked to several hallmark features of cancer including apoptosis resistance. In contrast, the sHSP HspB2/MKBP, which shares an intergenic promoter with αB-crystallin, was discovered as a chaperone of the myotonic dystrophy protein kinase and has not been previously implicated in apoptosis regulation. Here we describe a new function for HspB2 as a novel inhibitor of apical caspase activation in the extrinsic apoptotic pathway. Specifically, we demonstrate that HspB2 is expressed in a subset of human breast cancer cell lines and that ectopic expression of HspB2 in breast cancer cells confers resistance to apoptosis induced by both TRAIL and TNF-α. We also show that HspB2 inhibits the extrinsic apoptotic pathway by suppressing apical caspases-8 and 10 activation, thereby blocking downstream apoptotic events, such as Bid cleavage and caspase-3 activation. Consistent with these in vitro effects, HspB2 attenuates the anti-tumor activity of TRAIL in an orthotopic xenograft model of breast cancer. Collectively, our results reveal a novel function of HspB2 as an anti-apoptotic protein that negatively regulates apical caspase activation in the extrinsic apoptotic pathway.
Authors:
Shayna E Oshita; Feng Chen; Toni Kwan; Fruma Yehiely; Vincent L Cryns
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-01-20
Journal Detail:
Title:  Breast cancer research and treatment     Volume:  124     ISSN:  1573-7217     ISO Abbreviation:  Breast Cancer Res. Treat.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-10-18     Completed Date:  2011-02-09     Revised Date:  2014-09-24    
Medline Journal Info:
Nlm Unique ID:  8111104     Medline TA:  Breast Cancer Res Treat     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  307-15     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis* / drug effects
Apoptosis Regulatory Proteins / genetics,  metabolism*
BH3 Interacting Domain Death Agonist Protein / metabolism
Breast Neoplasms / drug therapy,  enzymology*,  genetics,  pathology
Caspase 3 / metabolism*
Caspase 8 / metabolism*
Cell Line, Tumor
Drug Resistance, Neoplasm
Enzyme Activation
Female
HSP27 Heat-Shock Proteins / genetics,  metabolism*
Humans
Injections, Intraperitoneal
Mice
Mice, Nude
TNF-Related Apoptosis-Inducing Ligand / administration & dosage
Time Factors
Transfection
Tumor Burden
Tumor Necrosis Factor-alpha / metabolism
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
R01 CA097198/CA/NCI NIH HHS; R01CA097198/CA/NCI NIH HHS; T32 DK007169/DK/NIDDK NIH HHS; T32DK007169/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/BH3 Interacting Domain Death Agonist Protein; 0/BID protein, human; 0/HSP27 Heat-Shock Proteins; 0/HSPB2 protein, human; 0/TNF-Related Apoptosis-Inducing Ligand; 0/Tumor Necrosis Factor-alpha; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/CASP8 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 8
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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