The BAG-1 cochaperone is a negative regulator of p73-dependent transcription.
High-level expression of Bcl-2 associated athanogene (BAG-1) protects cancer cells from stress-induced cell death and growth inhibition. These protective effects of BAG-1 are dependent on interactions with the HSC70 and HSP70 chaperones. However, the key stress-response molecules that are regulated by a BAG-1/chaperone mechanism have not been identified. In this study, we investigated the effects of BAG-1 overexpression on the function of p53 family proteins, p53, p63 and p73. Overexpression of BAG-1 isoforms interfered with the transactivating activity of p73 and p63, but had modest and variable effects on p53-dependent transcription. p73 and BAG-1 interacted in intact cells and overexpression of BAG-1 decreased the expression of p73. siRNA-mediated ablation of endogenous BAG-1 increased the activity of a p73-responsive promoter and this was reversed by knock-down of p73. The ability of BAG-1 to modulate p73 activity and expression, and to interact with p73 were dependent on amino acid residues required for the interaction of BAG-1 with HSC70 and HSP70. These results show that BAG-1 inhibits the transactivating functions of p73 and provide new insight into the mechanisms that control the expression of p73. Inhibition of p73 function may be one mechanism that contributes to the pro-survival activity of BAG-1.
Wang
X-H
XH
Cancer Research UK Clinical Centre, Cancer Sciences Division, University of Southampton School of Medicine, Southampton, UK.
O'Connor
D
D
Brimmell
M
M
Packham
G
G
D016475:3T3 Cells; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D007668:Kidney / Q000196:embryology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D012516:Osteosarcoma / Q000235:genetics; D010957:Plasmids; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D014157:Transcription Factors; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins