A nuclear factor, ASC-2, as a cancer-amplified transcriptional coactivator essential for ligand-dependent transactivation by nuclear receptors in vivo : (Implication for Posterior Lenticonus with Cataract and Dilated Cardiomyopathy)

다국어 초록 (Multilingual Abstract)

ASC-2, a recently isolated transcriptional coactivator molecule, stimulates transactivation by multiple transcription factors, including nuclear receptors. We have 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 and dilated cardiomyopathy 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 dilated cardiomyopathy, suggesting the importance of ASC-2 as a bona fide coactivator of nuclear receptors in vivo.