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: J C Curtin, K H Dragnev, D Sekula, A J Christie, E Dmitrovsky, M J Spinella
• Journal: Oncogene (Oncogene) Vol. 20 Issue 20 Pg. 2559-69 (May 03 2001) ISSN: 0950-9232 [Print] England
• PMID: 11420666 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Tumor Suppressor Protein p53
• fibroblast growth factor 14
• Tretinoin
• Fibroblast Growth Factors
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Carcinoma, Embryonal (drug therapy, genetics, pathology)
• Cell Differentiation (drug effects, physiology)
• Cisplatin (pharmacology)
• Drug Resistance, Neoplasm
• Fibroblast Growth Factors (genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, p53 (drug effects, genetics)
• Germinoma (drug therapy, genetics, pathology)
• Humans
• Male
• Testicular Neoplasms (drug therapy, genetics, pathology)
• Transcriptional Activation (drug effects)
• Tretinoin (pharmacology)
• Tumor Suppressor Protein p53 (biosynthesis, genetics, physiology)