LEDGF regulation of alcohol and aldehyde dehydrogenases in lens epithelial cells: Stimulation of retinoic acid production and protection from ethanol toxicity

Nigar Fatma, Eri Kubo, Leo T. Chylack, Toshimichi Shinohara, Yoshio Akagi, Dhirendra P. Singh

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Retinoic acid (RA) is required for the normal growth and maintenance of many cell types, including lens epithelial cells (LECs). Alcohol (ADH) and aldehyde (ALDH) dehydrogenases are implicated in cellular detoxification and conversion of vitamin A to RA. Lens epithelium-derived growth factor (LEDGF) provides cellular protection against stress by transactivating stress-associated genes. Here we show evidence that LEDGF binds and transactivates heat shock (nGAAn) and stress response (A/TGGGGA/T) elements in the promoters of ADH1, ADH4, and retinaldehyde 2 (RALDH2) genes. Electrophoretic mobility and supershift assays disclosed specific binding of LEDGF to nGAAn and A/TGGGGA/T elements in these gene promoters. Transfection experiments in LECs with promoters linked to a chloramphenicol acetyltransferase (CAT) reporter gene along with LEDGF cDNA revealed higher CAT activity. RTPCR results confirmed that LECs overexpressing LEDGF contained increased levels of ADH1 ADH4, and RALDH2 mRNA. Notably, LECs displayed higher LEDGF mRNA and protein expression during ethanol stress. Cells overexpressing LEDGF typically exhibited elevated RA levels and survived well during ethanol stress. The present findings indicate that LEDGF is one of the transcriptional activators of these genes that facilitates cellular protection against ethanol stress and plays a role in RA production.

Original languageEnglish (US)
Pages (from-to)C508-C516
JournalAmerican Journal of Physiology - Cell Physiology
Volume287
Issue number2 56-2
DOIs
Publication statusPublished - Aug 1 2004

    Fingerprint

Keywords

  • Gene promoters
  • Lens epithelium-derived growth factor
  • Stress and heat shock elements
  • Transcription regulation

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Cite this