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

• Published in: The Journal of biological chemistry 2003-05, Vol.278 (22), p.20037-20046
• Main Authors: Sharma, P, Fatma, N, Kubo, E, Shinohara, T, Chylack, LT Jr, Singh, D P
• Format: Article
• Language: English
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M212016200

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- beta (TGF- beta ) has been implicated in the control of tissue homeostasis, terminal differentiation, and apoptosis. Here we provide evidence that TGF- beta 1 down- regulates LEDGF expression and diminishes its affinity for DNA during TGF- beta 1-induced phenotypic changes and apoptosis in human lens epithelial cells. Surprisingly, TGF- beta 1 treatment for 48 h markedly decreased the LEDGF, Hsp27, and alpha B-crystallin promoter activities with the decrease of abundance of LEDGF mRNA and protein. Deletion mutants of the LEDGF promoter showed that one TGF- beta 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- beta 1- treated human lens epithelial cells did not bind to stress-response elements and HSE. The TGF- beta 1-induced down-regulation of LEDGF, Hsp27, and alpha B- crystallin promoters activity was reversed by cotransfection with a plasmid expressing LEDGF. Because overexpression of LEDGF was able to relieve TGF- beta 1 and/or stress-induced changes, it would be a candidate molecule to postpone age-related degenerating disorders.