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Induction of the small heat shock protein αB-crystallin by genotoxic stress is mediated by p53 and p73

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Abstract

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.

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Acknowledgments

We are indebted to Dr. Sam Lee (Harvard Medical School) for providing the EJ-p53 cells and Dr. Xinbin Chen (University of California-Davis) for providing p73 plasmids and advice. These studies were supported by NIH grants R01CA097198 (VLC), R21CA125181 (VLC), T32CA09560 (JRE), and by the Breast Cancer Research Foundation (VLC).

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  1. Cell Death Regulation Lab, Departments of Medicine and Cell and Molecular Biology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Lurie 4-113, 303 East Superior Street, Chicago, IL, 60611, USA

    Joseph R. Evans, Joshua D. Bosman, Fruma Yehiely & Vincent L. Cryns

  2. Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

    Lauren Brown-Endres

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  1. Joseph R. Evans
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  2. Joshua D. Bosman
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  5. Vincent L. Cryns
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Correspondence to Vincent L. Cryns.

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Evans, J.R., Bosman, J.D., Brown-Endres, L. et al. Induction of the small heat shock protein αB-crystallin by genotoxic stress is mediated by p53 and p73. Breast Cancer Res Treat 122, 159–168 (2010). https://doi.org/10.1007/s10549-009-0542-7

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