Lens epithelium-derived growth factor relieves transforming growth factor-β1-induced transcription repression of heat shock proteins in human lens epithelial cells

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

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30 Scopus citations

Abstract

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-β (TGF-β) has been implicated in the control of tissue homeostasis, terminal differentiation, and apoptosis. Here we provide evidence that TGF-β1 down-regulates LEDGF expression and diminishes its affinity for DNA during TGF-β1-induced phenotypic changes and apoptosis in human lens epithelial cells. Surprisingly, TGF-β1 treatment for 48 h markedly decreased the LEDGF, Hsp27, and αB-crystallin promoter activities with the decrease of abundance of LEDGF mRNA and protein. Deletion mutants of the LEDGF promoter showed that one TGF-β1 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-β1-treated human lens epithelial cells did not bind to stress-response elements and HSE. The TGF-β1-induced down-regulation of LEDGF, Hsp27, and αB-crystallin promoters activity was reversed by cotransfection with a plasmid expressing LEDGF. Because overexpression of LEDGF was able to relieve TGF-β1 and/or stress-induced changes, it would be a candidate molecule to postpone age-related degenerating disorders.

Original languageEnglish (US)
Pages (from-to)20037-20046
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number22
DOIs
StatePublished - May 30 2003

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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