title: Retinoic acid activates p53 in human embryonal carcinoma through retinoid receptor-dependent stimulation of p53 transactivation function.
abstract: Although retinoids are known to regulate gene transcription by activating retinoid receptors, the targets of retinoid receptors are largely unknown. This study indicates effective all-trans retinoic acid (RA)-induced differentiation of human embryonal carcinoma cells engages p53. Unexpectedly, RA has been found to activate the transactivation function of p53 in the human embryonal carcinoma cell line, NT2/D1, in a retinoid receptor-dependent manner. A derived RA-resistant line, NT2/D1-R1, is deficient in this activity and is co-resistant to cisplatin. This indicates that RA and cisplatin responses may share a common pathway involving p53 in embryonal carcinomas. RA has no effect on p53 steady-state protein levels in either line. RA enhances endogenous p53 transactivation activity in NT2/D1 but not NT2/D1-R1 cells. In addition, RA induces transactivation activity of a gal4-p53 fusion protein, suggesting that RA activates p53 independent of increasing p53 levels or sequence-specific DNA binding. This activity is absent in retinoic acid receptor gamma (RARgamma)-deficient NT2/D1-R1 cells but can be restored upon co-transfection with specific RARs. Transient transfection of a dominant-negative p53 construct in NT2/D1 cells blocks the RA-mediated transcriptional decline of a differentiation-sensitive reporter plasmid and enhances survival of NT2/D1 cells following cisplatin treatment. Taken together, these findings indicate that RA activates the intrinsic activation function of p53 by a novel mechanism independent of effects on p53 stability or DNA binding and that this activation may be a general mechanism that contributes to RA-mediated G1 arrest.
authors: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire, NH 03755, USA.
authors: J C
authors: JC
authors: Curtin
authors: K H
authors: KH
authors: Dragnev
authors: D
authors: D
authors: Sekula
authors: A J
authors: AJ
authors: Christie
authors: E
authors: E
authors: Dmitrovsky
authors: M J
authors: MJ
authors: Spinella
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D018236:Carcinoma, Embryonal / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005346:Fibroblast Growth Factors / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016158:Genes, p53 / Q000187:drug effects / Q000235:genetics; D018237:Germinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015533:Transcriptional Activation / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; C112971:fibroblast growth factor 14; D014212:Tretinoin; D005346:Fibroblast Growth Factors; D002945:Cisplatin