Thyroid hormone receptor is a negative regulator in p53-mediated signaling pathways

Thyroid hormone nuclear receptors (TRs) are ligand-dependent transcription factors which regulate growth, differentiation, and development. The molecular mechanism by which TRs mediated these effects remains unclear. A prevailing hypothesis is that TRs exert their biological effects by cooperating with other transcription factors. We have recently shown that the human TR subtype beta 1 (hTR beta 1) interacts with the tumor suppressor p53, which plays a critical role in cell-cycle regulation and tumorigenesis. This interaction of hTR beta 1 with p53 leads to an impairment of TR function. The present study examined whether hTR beta 1 could modulate the function of p53, Mapping of the domains of p53 responsible for the interaction with hTR beta 1 indicated that the regions involved resided in the DNA-binding domain and carboxy terminus of p53, In agreement with this finding, hTR beta 1 increased the binding of p53 to p53 DNA-binding elements. This increase in DNA binding, however, resulted in repression of p53-dependent transcription activation in transfected cells. Furthermore, hTR beta 1 led to an inhibition of the p53-mediated induction of bax and gadd45 expression. In contrast, the p53-induced expression of p21 was not affected by hTR beta 1, suggesting that the expression of p53-regulated genes is differentially modulated by hTR beta 1. Because the expressions of bax, gadd45, and p21 are directly regulated by p53, these results indicate that hTR beta 1 can modulate p53-regulated gene expression and support the hypothesis that there is cross-talk between these two regulatory pathways. The cross-talk between these two transcription factors could play an important role in the biology of normal and cancer cells.