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Molecular and Cellular Biology, December 2002, p. 8409-8414, Vol. 22, No. 24
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.24.8409-8414.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Multiple Developmental Defects Derived from Impaired Recruitment of ASC-2 to Nuclear Receptors in Mice: Implication for Posterior Lenticonus with Cataract

Seung-Whan Kim,1 Cheolho Cheong,2,3 Young-Chang Sohn,1 Young-Hwa Goo,1 Wan Je Oh,3 Jung Hwan Park,3 So Young Joe,3,4 Hyen-Sam Kang,2 Duk-Kyung Kim,3,4,5 Changwon Kee,3,4,6 Jae Woon Lee,1* and Han-Woong Lee3,4,7*

Department of Life Science, Pohang University of Science and Technology, Pohang 790-784,1 School of Biological Sciences and Department of Microbiology, Seoul National University, Seoul 151-742,2 Samsung Biomedical Research Institute,3 Molecular Therapy Research Center, Samsung Medical Center, Seoul 135-710,5 Department of Medicine,6 Department of Ophthalmology,7 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea4

Received 19 April 2002/ Returned for modification 2 August 2002/ Accepted 17 September 2002

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.

* Corresponding author. Mailing address for Han-Woong Lee: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea. Phone: 82 31 299 6135. Fax: 82 31 299 6435. E-mail: hwl{at}skku.ac.kr. Mailing address: Jae Woon Lee, Department of Life Science, Pohang University of Science and Technology, Pohang 790-784, Korea. Phone: 82 54 279 2129. Fax: 82 54 279 8374. E-mail: jaewoon{at}postech.ac.kr.

Molecular and Cellular Biology, December 2002, p. 8409-8414, Vol. 22, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.24.8409-8414.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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