1. ¹Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ, USA
2. ²Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA
3. ³Department of Biological Sciences, Columbia University, New York, NY, USA
4. ⁴Department of Epidemiology and Public Health, Yale University, New Haven, CT, USA
5. ⁵Cold Spring Harbor Laboratories, Cold Spring Harbor, NY, USA
6. ⁶School of Natural Sciences, Institute for Advance Study, Princeton, NJ, USA

Correspondence: Dr AJ Levine, School of Natural Sciences, Institute for advanced study, Einstein Drive, Princeton, NJ 8540, USA. E-mail: alevine@ias.edu

⁷These two authors contributed equally to this work

Received 17 May 2005; Revised 7 July 2005; Accepted 7 July 2005; Published online 7 November 2005.

Abstract

The p53 protein is a transcription factor that integrates various cellular stress signals. The accumulation of the mutant huntingtin protein with an expanded polyglutamine tract plays a central role in the pathology of human Huntington's disease. We found that the huntingtin gene contains multiple putative p53-responsive elements and p53 binds to these elements both in vivo and in vitro. p53 activation in cultured human cells, either by a temperature-sensitive mutant p53 protein or by gamma-irradiation (-irradiation), increases huntingtin mRNA and protein expression. Similarly, murine huntingtin also contains multiple putative p53-responsive elements and its expression is induced by p53 activation in cultured cells. Moreover, -irradiation, which activates p53, increases huntingtin gene expression in the striatum and cortex of mouse brain, the major pathological sites for Huntington's disease, in p53+/+ but not the isogenic p53-/- mice. These results demonstrate that p53 protein can regulate huntingtin expression at transcriptional level, and suggest that a p53 stress response could be a modulator of the process of Huntington's disease.