PMID- 11212249 OWN - NLM STAT- MEDLINE DCOM- 20010222 LR - 20231213 IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 61 IP - 2 DP - 2001 Jan 15 TI - Increased retinoic acid responsiveness in lung carcinoma cells that are nonresponsive despite the presence of endogenous retinoic acid receptor (RAR) beta by expression of exogenous retinoid receptors retinoid X receptor alpha, RAR alpha, and RAR gamma. PG - 556-64 AB - Nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are thought to mediate most of the effects of retinoids on cell growth and differentiation. Despite expressing abundant levels of RAR beta mRNA, lung adenocarcinoma H1792 cells are resistant to the growth-inhibitory effects of all-trans-retinoic acid, suggesting that they have a defect in retinoid signaling. To determine whether transfection of exogenous receptors can restore retinoid responsiveness, we transiently transfected into H1792 cells coexpression vectors containing cDNAs of cell surface antigen CD7 and either RAR alpha, RAR beta, RAR gamma, or RXR alpha. The cells were then treated with retinoids and incubated with 5'-bromo-2'-deoxyuridine. Cells that express exogenous receptor were identified using antibodies against CD7, and cells that synthesized DNA were identified with anti-5'-bromo-2'-deoxyuridine antibodies using secondary antibodies with red and green fluorescence, respectively. RXR alpha and RAR alpha enhanced growth inhibition by all-trans-retinoic acid or 9-cis-retinoic acid, whereas RAR gamma was less effective, and RAR beta was ineffective. The effects of the transfected receptors were associated with antagonism of activator protein 1 (AP-1) activity. Studies with RXR alpha deletion and point mutants indicated that growth suppression is: (a) dependent on intact DNA-binding and ligand-binding regions but not on the NH2-terminal region, which contains a ligand-independent transactivation function; (b) dependent on RXR homodimer formation and transactivation of RXR response element; and (c) associated with AP-1 antagonism. These results demonstrate that transfected receptors can restore responsiveness to retinoids by antagonizing AP-1 in H1792 cells. FAU - Wan, H AU - Wan H AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M D Anderson Cancer Center, Houston 77030, USA. FAU - Hong, W K AU - Hong WK FAU - Lotan, R AU - Lotan R LA - eng GR - P30 CA16672/CA/NCI NIH HHS/United States GR - U19 CA68437/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (DNA, Recombinant) RN - 0 (DNA-Binding Proteins) RN - 0 (RARA protein, human) RN - 0 (Receptors, Retinoic Acid) RN - 0 (Retinoic Acid Receptor alpha) RN - 0 (Retinoid X Receptors) RN - 0 (Transcription Factor AP-1) RN - 0 (Transcription Factors) RN - 0 (retinoic acid receptor beta) RN - 5688UTC01R (Tretinoin) RN - G34N38R2N1 (Bromodeoxyuridine) SB - IM MH - Binding Sites/genetics MH - Bromodeoxyuridine/metabolism MH - Cell Division MH - DNA, Recombinant MH - DNA-Binding Proteins/chemistry/genetics/physiology MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Lung Neoplasms/genetics/pathology/*prevention & control MH - Mutation MH - Plasmids/genetics MH - Protein Structure, Tertiary MH - Receptors, Retinoic Acid/chemistry/*genetics/physiology MH - Response Elements MH - Retinoic Acid Receptor alpha MH - Retinoid X Receptors MH - Transcription Factor AP-1/physiology MH - Transcription Factors/chemistry/genetics/physiology MH - Transcription, Genetic MH - Transfection MH - Tretinoin/*pharmacology MH - Tumor Cells, Cultured/cytology/drug effects/metabolism MH - Retinoic Acid Receptor gamma EDAT- 2001/02/24 12:00 MHDA- 2001/03/03 10:01 CRDT- 2001/02/24 12:00 PHST- 2001/02/24 12:00 [pubmed] PHST- 2001/03/03 10:01 [medline] PHST- 2001/02/24 12:00 [entrez] PST - ppublish SO - Cancer Res. 2001 Jan 15;61(2):556-64.