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The small heat shock protein αB-crystallin is a molecular chaperone that is induced by stress and protects cells by inhibiting protein aggregation and apoptosis. To identify novel transcriptional regulators of the αB-crystallin gene, we examined the αB-crystallin promoter for conserved transcription factor DNA-binding elements and identified a putative response element for the p53 tumor suppressor protein. Ectopic expression of wild-type p53 induced αB-crystallin mRNA and protein with delayed kinetics compared to p21. Additionally, the induction of αB-crystallin by genotoxic stress was inhibited by siRNAs targeting p53. Although the p53-dependent transactivation of an αB-crystallin promoter luciferase reporter required the putative p53RE, chromatin immunoprecipitation failed to detect p53 binding to the αB-crystallin promoter. These results suggested an indirect mechanism of transactivation involving p53 family members p63 or p73. ΔNp73 was dramatically induced by p53 in a TAp73-dependent manner, and silencing p73 suppressed the transcriptional activation of αB-crystallin by p53. Moreover, ectopic expression of ΔNp73α (but not other p73 isoforms) increased αB-crystallin mRNA levels in the absence of p53. Collectively, our results link the molecular chaperone αB-crystallin to the cellular genotoxic stress response via a novel mechanism of transcriptional regulation by p53 and p73.