Proteasome Inhibitor MG132 Induces BAG3 Expression Through Activation of Heat Shock Factor 1

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-I 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 I (HSFI) is involved in BAG3 induction by proteasome inhibitor MG132. Using a series of varying lengths of 5'-flanking region of the BAG 3 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 HSFI-binding, respectively. Site-directed deletion of the sites abrogated the enhanced reporter activity in response to MG132 treatment. Chromatin immunoprecipitation assay demonstrated that HSFI directly bound to the MG132-responsive site on the BAG3 promoter. Activation of HSFI occurred with MG132 along with BAG3 upregulation. Furthermore, knockdown HSFI by small interfering RNA attenuated the BAG3 upregulation due to MG132. These results indicate that the. proteasome inhibitor MG132 induces BAG3 expression through HSFI activation.