title: Proteasome inhibitor MG132 induces BAG3 expression through activation of heat shock factor 1.
abstract: BAG3 protein, a member of the BAG co-chaperones family, sustains cell survival in a variety of normal and neoplastic cell types, via its interaction with a variety of partners, such as the heat shock protein (HSP) 70, Bcl-2, Raf-1 and others. Expression of BAG3 is induced by some stressful stimuli, such as heat shock, heavy metal exposure. We have reported that proteasome inhibitors can also induce BAG3 expression at the transcriptional level and the induction of BAG3 compromises proteasome inhibitors-mediated apoptosis. However, the molecular mechanism of BAG3 upregulation has not been elucidated. In the current study, we provide evidence that heat shock transcription factor 1 (HSF1) is involved in BAG3 induction by proteasome inhibitor MG132. Using a series of varying lengths of 5'-flanking region of the BAG3 gene into luciferase reporter vectors, we found that MG132 stimulated the promoter activity via the -326/-233 and -825/-689 regions, which contains one putative heat shock-responsive element (HSE) for HSF1-binding, respectively. Site-directed deletion of the sites abrogated the enhanced reporter activity in response to MG132 treatment. Chromatin immunoprecipitation assay demonstrated that HSF1 directly bound to the MG132-responsive site on the BAG3 promoter. Activation of HSF1 occurred with MG132 along with BAG3 upregulation. Furthermore, knockdown HSF1 by small interfering RNA attenuated the BAG3 upregulation due to MG132.These results indicate that the proteasome inhibitor MG132 induces BAG3 expression through HSF1 activation.
authors.affiliation: Department of Endocrinology & Metabolism, The 1st Affiliated Hospital, China Medical University, Shenyang, China.
authors.forename: Zhen-Xian
authors.initials: ZX
authors.lastname: Du
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Meng
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Gao
authors.forename: Ren-Long
authors.initials: RL
authors.lastname: Zou
authors.forename: Bao-Qin
authors.initials: BQ
authors.lastname: Liu
authors.forename: Yifu
authors.initials: Y
authors.lastname: Guan
authors.forename: Hua-Qin
authors.initials: HQ
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D008969:Molecular Sequence Data; D061988:Proteasome Inhibitors; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D007976:Leupeptins; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D014157:Transcription Factors; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde