TUMOR-SUPPRESSOR P53 IS A NEGATIVE REGULATOR IN THYROID-HORMONE RECEPTOR SIGNALING PATHWAYS

Thyroid hormone nuclear receptors (TRs) are ligand-dependent transcrip tion factors which regulate growth, differentiation, and development, The molecular mechanisms by which TRs mediate these diverse effects ar e unclear, One emerging hypothesis suggests that TRs could mediate the se diverse effects via cooperation with different transcription factor s/receptors, Indeed, we have recently shown that the human TR subtype beta 1 (h-TR beta 1) interacts with the tumor suppressor p53, p53 is a transcription factor that plays a critical role in cell cycle regulat ion and tumor development, To assess the physiological relevance of th e interaction of h-TR beta 1 with p53, the present study addressed the question as to whether the functions of h-TR beta 1 could be modulate d by p53, We first compared the h-TR beta 1-mediated transcriptional a ctivity in two pairs of isogenic cell lines, RKO/RKO E6 and MCF-7/MCF- 7 E6, RKO and MCF-7 cells are colon and breast carcinoma cell lines, r espectively, that contain p53 but lack TR beta 1, The isogenic RKO E6 and MCF-7 E6 cells are stable clones expressing high levels of papillo mavirus type 16 E6 protein, In these cells, the level of p53 protein w as lower than the parental cells, The impairment of p53 functions in t hese EG-containing cells led to an activation of TR beta 1-mediated tr anscriptional activity, Furthermore, in a growth hormone-producing cel l line in which the expression of the growth hormone gene is positivel y regulated by TRs, overexpression of the wild-type p53 led to repress ion in the expression of the growth hormone gene, Thus, TRs could cros s-talk with p53 in its signaling pathways to regulate gene regulatory functions, The present findings further strengthen the hypothesis that mediation of the pleiotropic effects of T-3 requires the cooperation of TRs with a large network of transcription factors.