title: Multiple developmental defects derived from impaired recruitment of ASC-2 to nuclear receptors in mice: implication for posterior lenticonus with cataract.
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.
authors.affiliation: Department of Life Science, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors.forename: Seung-Whan
authors.initials: SW
authors.lastname: Kim
authors.forename: Cheolho
authors.initials: C
authors.lastname: Cheong
authors.forename: Young-Chang
authors.initials: YC
authors.lastname: Sohn
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Goo
authors.forename: Wan Je
authors.initials: WJ
authors.lastname: Oh
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Park
authors.forename: So Young
authors.initials: SY
authors.lastname: Joe
authors.forename: Hyen-Sam
authors.initials: HS
authors.lastname: Kang
authors.forename: Duk-Kyung
authors.initials: DK
authors.lastname: Kim
authors.forename: Changwon
authors.initials: C
authors.lastname: Kee
authors.forename: Jae Woon
authors.initials: JW
authors.lastname: Lee
authors.forename: Han-Woong
authors.initials: HW
authors.lastname: Lee
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002478:Cells, Cultured; D000013:Congenital Abnormalities; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000473:pathology / Q000502:physiology; D005123:Eye / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005804:Genes, Lethal; D017930:Genes, Reporter; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007905:Lens Diseases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D056918:Nuclear Receptor Coactivators; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011247:Pregnancy; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C486559:NCOA6 protein, human; C405683:Ncoa6 protein, mouse; D056918:Nuclear Receptor Coactivators; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors