Retinoic acid activates p53 in human embryonal carcinoma through retinoid receptor-dependent stimulation of p53 transactivation function

Oncogene. 2001 May 3;20(20):2559-69. doi: 10.1038/sj.onc.1204370.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

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