We known that the biological activity of T3 is mediated through the interaction of T3 with thyroid hormone receptors (TRs). It is unclear whether the two TR isoforms, TRalpha and TRbeta, have differential biological functions. These two isoforms are derived from the TRalpha and TRbeta genes, which are located on chromosome 17 and 3, respectively. Four domains, A/B, C (DNA binding domain), D and E (hormone binding domain), can be assigned to each TR. For the first time we found that the two isoforms bind to the thyroid hormone response elements with different affinities and have differential transactivational activity which is mediated by the interplay of their domains. We believe that this isoform-specific transcriptional activity could serve as an important regulatory mechanism to achieve diversity and specificity of pleiotropic T3 effect. We further discovered that one of the mechanisms to regulate the differential expression of the two TR isoforms is via the tissue-dependent selective stability of TRbeta1 protein. This isoform-specific stabilization is conferred by phosphorylation which plays a novel role in regulating the TR levels. In the past year, we also identifed glutamine 252 of TRbeta1 as an important amino acid in transmitting the hormonal signal from the T3 binding domain to the DNA binding domain to affect the gene regulating activity of TRbeta1. These findings have advanced our understanding on the molecular basis of T3-dependent transcriptional activation.
The manifestation of resistance to thyroid hormone syndrome (RTH) is due to the mutations on the TRbeta gene, resulting in interference of the functions of wild type TRs in a dominant negative fashion. In the past year, we demonstrated clearly the formation of the wild type TR/mutant heterodimers which correlates well with the potency of dominant negative effect in cells (Zhu, X-G. et al., Endocrinology). Our findings have provided an additional mechanism by which TR mutants could act to affect RTH patients. In collaboration with Dr. K.-H. Lin of Chang Guang Medical College, Taiwan, we discovered that mutation on TRalpha gene does occur naturally which has the same functional characteristics as the TRbeta1 mutants (Lin, K.-H. et al., Endocrinology). This novel finding that mutation could occur in the TRalpha gene opens a new area of research to further understand the molecular basis of RTH.
We have shown that the transcriptional activity TRbeta1 is modulated by the
tumor suppressor p53 (Yap, N. et al., Proc Natl Acad Sci USA).
Because the region of TRbeta1 to which p53 binds is the DNA binding domain,
which is highly homologous among the steroid hormone/retinoic acid/thyroid
hormone receptor superfamily, we have ascertained whether other members of
superfamily also interacts with p53. Indeed, we found that the transcriptional
activity of glucocorticoid receptor and estrogen receptor is modulated by
p53. This exciting discovery opens the possiblity for p53 to cross-talk with
a large network of receptor superfamily to modulatre cellular functions.
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