The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor.
The mammalian hairless (hr) gene plays a critical role in the maintenance of hair growth. Although the hr gene has been identified, the biochemical function of its encoded protein (Hr) has remained obscure. Here, we show that Hr functions as a transcriptional corepressor for thyroid hormone receptors (TRs). We find ... that two independent regions of Hr mediate TR binding and that interaction requires a cluster of hydrophobic residues similar to the binding motifs proposed for nuclear receptor corepressors (N-CoR and SMRT). Similarly, we show that Hr binds to the same region of TR as known corepressors. We show that Hr interacts with histone deacetylases (HDACs) and is localized to matrix-associated deacetylase (MAD) bodies, indicating that the mechanism of Hr-mediated repression is likely through associated HDAC activity. Thus, Hr is a component of the corepressor machinery, and despite its lack of sequence identity with previously described corepressors, its mode of action is remarkably conserved. On the basis of its thyroid hormone-inducible and tissue- and developmental-specific expression, Hr likely defines a new class of nuclear receptor corepressors that serve a more specialized role than ubiquitous corepressors. The discovery that Hr is a corepressor provides a molecular basis for specific hair loss syndromes in both humans and mice.
Mesh Terms:
Amino Acid Sequence, Blotting, Western, Cell Nucleus, Cells, Cultured, DNA-Binding Proteins, Fluorescent Antibody Technique, Fungal Proteins, Gene Expression, Genetic Vectors, Hair Diseases, Histone Deacetylases, Humans, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Nuclear Proteins, Nuclear Receptor Co-Repressor 1, Promoter Regions, Genetic, Proteins, Receptors, Thyroid Hormone, Recombinant Fusion Proteins, Repressor Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Transcription Factors, Two-Hybrid System Techniques
Amino Acid Sequence, Blotting, Western, Cell Nucleus, Cells, Cultured, DNA-Binding Proteins, Fluorescent Antibody Technique, Fungal Proteins, Gene Expression, Genetic Vectors, Hair Diseases, Histone Deacetylases, Humans, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Nuclear Proteins, Nuclear Receptor Co-Repressor 1, Promoter Regions, Genetic, Proteins, Receptors, Thyroid Hormone, Recombinant Fusion Proteins, Repressor Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Transcription Factors, Two-Hybrid System Techniques
Genes Dev.
Date: Oct. 15, 2001
PubMed ID: 11641275
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