EVIDENCE FOR IMPAIRED RETINOIC ACID RECEPTOR-THYROID HORMONE-RECEPTORAF-2 COFACTOR ACTIVITY IN HUMAN LUNG-CANCER

Retinoic acid (RA) is required for normal airway epithelial cell growt h and differentiation both in vivo and in vitro. One of the earliest e vents following the exposure of bronchial epithelial cells to RA is th e strong induction of RA receptor beta (RAR beta) mRNA. Previous work established that many lung cancer cell lines and primary tumors displa y abnormal RAR beta mRNA expression, most often absence or weak expres sion of the RAR beta 2 isoform, even after RA treatment. Restoration o f RAR beta 2 into RAR beta-negative lung cancer cell lines has been re ported to inhibit tumorigenicity. Since RAR beta 2 inactivation may co ntribute to lung cancer, we have investigated the molecular mechanism of defective RAR beta 2 expression. Nuclear run-on assays and transien t transfections with RAR beta 2 promoter constructs indicate the prese nce of trans-acting transcriptional defects in most lung cancer cell l ines, which map to the RA response element (RARE). These defects canno t be complemented by RAR-retinoid X receptor cotransfection and can be separated into two types: (i) one affecting transcription from direct repeat RAREs, but not palindromic RAREs, and (ii) another affecting t ranscription from both types of RARE. Studies using chimeras between R AR alpha, TR alpha, and other transcription factors suggest the existe nce of novel RAR-thyroid hormone receptor AP-2-specific cofactors, whi ch are necessary for high levers of transcription. Furthermore, these factors may be frequently inactivated in human lung cancer.