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* Department of Biological Chemistry, D240 Medical Sciences I,
University of California, Irvine, CA 92697-1700;
Contributed by David E. Housman, March 14, 2000
Huntington's Disease (HD) is caused by an expansion of a
polyglutamine tract within the huntingtin (htt) protein. Pathogenesis in HD appears to include the cytoplasmic cleavage of htt and release of
an amino-terminal fragment capable of nuclear localization. We have
investigated potential consequences to nuclear function of a pathogenic
amino-terminal region of htt (httex1p) including aggregation,
protein-protein interactions, and transcription. httex1p was found to
coaggregate with p53 in inclusions generated in cell culture and to
interact with p53 in vitro and in cell culture. Expanded
httex1p represses transcription of the p53-regulated promoters,
p21WAF1/CIP1 and MDR-1.
httex1p was also found to interact in vitro with
CREB-binding protein (CBP) and mSin3a, and CBP to localize to neuronal
intranuclear inclusions in a transgenic mouse model of HD. These
results raise the possibility that expanded repeat htt causes aberrant
transcriptional regulation through its interaction with cellular
transcription factors which may result in neuronal dysfunction and cell
death in HD.
Medical Sciences
The Huntington's disease protein interacts with p53 and
CREB-binding protein and represses transcription
,
,,, and Department of Biology Center for Cancer Research,
Massachusetts Institute of Technology, Building E17-543, Cambridge, MA
02139; Medical and Molecular Genetics, GKT School of
Medicine, King's College, 8th Floor Guy's Tower, Guy's
Hospital, London SE1 9RT, United Kingdom; and
§ Max-Planck-Institut fur Molekulare Genetik, Ihnestraße
73, Berlin D-14195, Germany
¶
To whom reprint requests should be addressed at:
Department of Biological Chemistry, D240 Medical Sciences I, University
of California, Irvine, CA 92697-1700. E-mail: lmthomps{at}uci.edu.
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K. L. Sugars, R. Brown, L. J. Cook, J. Swartz, and D. C. Rubinsztein Decreased cAMP Response Element-mediated Transcription: AN EARLY EVENT IN EXON 1 AND FULL-LENGTH CELL MODELS OF HUNTINGTON'S DISEASE THAT CONTRIBUTES TO POLYGLUTAMINE PATHOGENESIS J. Biol. Chem., February 6, 2004; 279(6): 4988 - 4999. [Abstract] [Full Text] [PDF]
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