Abstract
ASC-2, a recently isolated transcriptional coactivator molecule, stimulates transactivation by multiple transcription factors, including nuclear receptors. We generated a potent dominant negative fragment of ASC-2, encompassing the N-terminal LXXLL motif that binds a broad range of nuclear receptors. This fragment, termed DN1, specifically inhibited endogenous ASC-2 from binding these receptors in vivo, whereas DN1/m, in which the LXXLL motif was mutated to LXXAA to abolish the receptor interactions, was inert. Interestingly, DN1 transgenic mice but not DN1/m transgenic mice exhibited severe microphthalmia and posterior lenticonus with cataract as well as a variety of pathophysiological phenotypes in many other organs. Our results provide a novel insight into the molecular and histopathological mechanism of posterior lenticonus with cataract and attest to the importance of ASC-2 as a pivotal transcriptional coactivator of nuclear receptors in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Animals
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Cells, Cultured
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Congenital Abnormalities*
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Disease Models, Animal
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Embryo, Mammalian / anatomy & histology
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Embryo, Mammalian / pathology
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Embryo, Mammalian / physiology
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Eye / pathology
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Female
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Genes, Lethal
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Genes, Reporter
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Humans
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Intracellular Signaling Peptides and Proteins*
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Lens Diseases / genetics
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Lens Diseases / metabolism*
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Mice
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Mice, Transgenic
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Nuclear Receptor Coactivators
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Peptide Fragments / genetics
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Peptide Fragments / metabolism*
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Phenotype
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Pregnancy
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Receptors, Retinoic Acid / metabolism
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Signal Transduction / physiology
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Intracellular Signaling Peptides and Proteins
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NCOA6 protein, human
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Ncoa6 protein, mouse
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Nuclear Receptor Coactivators
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Peptide Fragments
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Receptors, Cytoplasmic and Nuclear
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Receptors, Retinoic Acid
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Transcription Factors