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PMID: 11839795 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Interaction of Huntington disease protein with transcriptional activator Sp1.

Molecular and cellular biology ·Vol. 22 ·No. 5 ·2002-03-00 ·Pages 1277-87

Li SH, Cheng AL, Zhou H, Lam S, Rao M, Li H, Li XJ

Abstract

Polyglutamine expansion causes Huntington disease (HD) and at least seven other neurodegenerative diseases. In HD, N-terminal fragments of huntingtin with an expanded glutamine tract are able to aggregate and accumulate in the nucleus. Although intranuclear huntingtin affects the expression of numerous genes, the mechanism of this nuclear effect is unknown. Here we report that huntingtin interacts with Sp1, a transcription factor that binds to GC-rich elements in certain promoters and activates transcription of the corresponding genes. In vitro binding and immunoprecipitation assays show that polyglutamine expansion enhances the interaction of N-terminal huntingtin with Sp1. In HD transgenic mice (R6/2) that express N-terminal-mutant huntingtin, Sp1 binds to the soluble form of mutant huntingtin but not to aggregated huntingtin. Mutant huntingtin inhibits the binding of nuclear Sp1 to the promoter of nerve growth factor receptor and suppresses its transcriptional activity in cultured cells. Overexpression of Sp1 reduces the cellular toxicity and neuritic extension defects caused by intranuclear mutant huntingtin. These findings suggest that the soluble form of mutant huntingtin in the nucleus may cause cellular dysfunction by binding to Sp1 and thus reducing the expression of Sp1-regulated genes.

MeSH Terms
Animals Cell Compartmentation Humans Huntingtin Protein Huntington Disease/etiology,genetics,metabolism Mice Mice, Transgenic Mutation Nerve Tissue Proteins/genetics,metabolism Nuclear Proteins/genetics,metabolism Peptides/genetics Promoter Regions, Genetic Protein Binding Receptors, Nerve Growth Factor/genetics Recombinant Fusion Proteins/metabolism Sp1 Transcription Factor/metabolism Transcription, Genetic Trinucleotide Repeat Expansion
Chemicals
HTT protein, human Htt protein, mouse Huntingtin Protein Nerve Tissue Proteins Nuclear Proteins Peptides Receptors, Nerve Growth Factor Recombinant Fusion Proteins Sp1 Transcription Factor polyglutamine
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Li Shi-Hua
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Cheng Anna L
Zhou Hui
Lam Suzanne
Rao Manjula
Li He
Li Xiao-Jiang
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.22.5.1277-1287.2002
Published
2002-03-00
Pages
1277-87
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC134707
Subset
IM
Grants
NIA NIH HHS · R56 AG019206 · United States
NINDS NIH HHS · R01 NS041669 · United States
NIA NIH HHS · R01 AG019206 · United States
NIA NIH HHS · AG19206 · United States
NINDS NIH HHS · NS41669 · United States
External Links
PubMed source DOI: 10.1128/MCB.22.5.1277-1287.2002 PMC Full Text View journal details
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