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J. Biol. Chem., Vol. 278, Issue 22, 20037-20046, May 30, 2003

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Lens Epithelium-derived Growth Factor Relieves Transforming Growth Factor-1-induced Transcription Repression of Heat Shock Proteins in Human Lens Epithelial Cells^*

Preeti Sharma , Nigar Fatma , Eri Kubo ¶, Toshimichi Shinohara , Leo T. Chylack, Jr.  and Dhirendra P. Singh  ||

From the Center for Ophthalmic Research, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, the Department of Ophthalmology, University of Nebraska Medical Center, Omaha, Nebraska 68198, and the ^¶Department of Ophthalmology, Fukui Medical University, Fukui 9101193, Japan

Lens epithelium-cell derived growth factor (LEDGF) is a transcriptional activator. It protects the cells by binding to cis-stress response ((A/T)GGGG(T/A)), and heat shock (HSE; nGAAn) elements in the stress genes and activating their transcription. Transforming growth factor- (TGF-) has been implicated in the control of tissue homeostasis, terminal differentiation, and apoptosis. Here we provide evidence that TGF-1 down-regulates LEDGF expression and diminishes its affinity for DNA during TGF-1-induced phenotypic changes and apoptosis in human lens epithelial cells. Surprisingly, TGF-1 treatment for 48 h markedly decreased the LEDGF, Hsp27, and B-crystallin promoter activities with the decrease of abundance of LEDGF mRNA and protein. Deletion mutants of the LEDGF promoter showed that one TGF-1 inhibitory element (TIE) like sequence nnnTTGGnnn (–444 to –433) contributed to this negative regulation. Mutation of TIE (TTGG to TATT) abolished the down-regulation of the LEDGF promoter. Gel mobility and supershift assays showed that LEDGF in the nuclear extracts of TGF-1-treated human lens epithelial cells did not bind to stress-response elements and HSE. The TGF-1-induced down-regulation of LEDGF, Hsp27, and B-crystallin promoters activity was reversed by cotransfection with a plasmid expressing LEDGF. Because overexpression of LEDGF was able to relieve TGF-1 and/or stress-induced changes, it would be a candidate molecule to postpone age-related degenerating disorders.

Received for publication, November 25, 2002 , and in revised form, March 18, 2003.

^* This work was supported by National Institutes of Health Grants EY13394-01A1 and GA01051. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Ophthalmology, University of Nebraska Medical Center, Wittson Hall, Rm. 2008/9, Omaha, NE 68198-6395. Tel.: 402-559-8805; Fax: 402-559-8808; E-mail: dpsingh{at}unmc.edu.

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