Regulation of the mdm2 oncogene by thyroid hormone receptor

The mdm2 gene is positively regulated by p53 through a p53-responsive DNA e lement in the first intron of the mdm2 gene. mdm2 binds p53, thereby abroga ting the ability of p53 to activate the mdm2 gene, and thus forming an auto regulatory loop of mdm2 gene regulation, Although the mdm2 gene is thought to act as an oncogene by blocking the activity of p53, recent studies indic ate that mdm2 can act independently of p53 and block the G(1) cell cycle ar rest mediated by members of the retinoblastoma gene family and can activate E2F1/DP1 and the cyclin A gene promoter. In addition, factors other than p 53 have recently been shown to regulate the mdm2 gene. In this article, we report that thyroid hormone (T3) receptors (T3Rs), but not the closely rela ted members of the nuclear thyroid hormone/retinoid receptor gene family (r etinoic acid receptor, vitamin D receptor, peroxisome proliferation activat ion receptor, or retinoid X receptor), regulate mdm2 through the same intro n sequences that are modulated by p53, Chicken ovalbumin upstream promoter transcription factor I, an orphan nuclear receptor which normally acts as a transcriptional repressor, also activates mdm2 through the same intron reg ion of the mdm2 gene. Two T3R-responsive DNA elements were identified and f urther mapped to sequences within each of the p53 binding sites of the mdm2 intron, A 10-amino-acid sequence in the N-terminal region of T3R alpha tha t is important for transactivation and interaction with TFIIB was also foun d to be important for activation of the mdm2 gene response element. T3 was found to stimulate the endogenous mdm2 gene in GH4C1 cells. These cells are known to express T3Rs, and T3 is known to stimulate replication of these c ells via an effect in the G(1) phase of the cell cycle. Our findings, which indicate that T3Rs can regulate the mdm2 gene independently of p53, provid e an explanation for certain known effects of T3 and T3Rs on cell prolifera tion. In addition, these findings provide further evidence for p53-independ ent regulation of mdm2 which could lead to the development of tumors from c ells that express low levels of p53 or that express p53 mutants defective i n binding to and activating the mdm2 gene.