The significant advances toward achieving our goals in the fiscal year of 2005 - 2006 are highlighted as follows:TRbetaPV mouse is a valuable model to understand the molecular basis of attention deficit-hyperactivity disorder (ADHD): This study has shown that neural deficits contribute to thyroid-related neurological disorders, hyperactivity, and altered responsiveness to methylphenidate.Activation of the PI3K or peroxisome proliferator-activated receptor gamma (PPARgamma) signaling by the TRbeta mutant, PV contributes to thyroid carcinogenesis: The signaling pathways mediated by PI3K and PPARgamma were found to contribute to thyroid carcinogenesis. That PI3K signaling pathway is activated in the primary lesions and lung metastases suggests that PI3K inhibitors could be used to prevent thyroid tumor progression. Furthermore, treatment of TRbetaPV/PV mice with PPARgamma agonists results in the delay of the progression of thyroid carcinogenesis and prevention of metastasis. Therefore, PPARgamma agonists could be tested for potential treatment of thyroid cancer.Aneuploidy caused by PV-induced aberrant accumulation of pituitary tumor transforming gene (PTTG) underlies thyroid carcinogenesis: Overexpression of the pituitary tumor-transforming gene (PTTG) is associated with many human cancers including thyroid cancer. The highly elevated PTTG protein levels in the thyroid tumors and lung metastases of TRbetaPV/PV mice promoted us to elucidate the molecular mechanisms underlying the increased abundance of PTTG proteins and to study the contribution of increased PTTG to thyroid carcinogenesis. We found that the elevated PTTG levels is due to the loss of ability of PV to recruit the steroid receptor coactivator-3/proteasome activator (PA28gamma) complex that facilitate timely degradation of PTTG. The loss of this regulatory function in TRbetaPV leads to an aberrant accumulation of PTTG, disrupting mitotic progression that could contribute to thyroid carcinogenesis. Identification of novel rapid nongenomic actions of thyroid hormone in the cardiovascular system: The binding of thyroid hormone to TR mediates important physiological effects. However, the transcriptional effects of TR mediated by the thyroid hormone response element of T3 target genes (TRE) cannot explain many actions of T3. We postulate that TR can initiate rapid, non-TRE-mediated effects in the cardiovascular system through cross-coupling to the PI3K/AKT pathway. These findings indicate that the activation of PI3K/AKT pathways can mediate some of the rapid, non-TRE effects of TR and suggest that the activation of AKT and eNOS contributes to some of the acute vasodilatory and neuroprotective effects of thyroid hormone. The identification of the rapid nongenomic actions of thyroid hormone in the cardiovascular system sheds new insight on the molecular actions of T3 in vivo and provides new options in the treatment of cardiovascular disease.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
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