Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone β receptor inhibits mitotic progression

Overexpression of pituitary tumor-transforming 1 (PTTG1) is associated with thyroid cancer. We found elevated PTTG 1 levels in the thyroid tumors of a mouse model of follicular thyroid carcinoma (TR beta(PV/PV) mice). Here we examined the molecular mechanisms underlying elevated PTTG1 levels and the contribution of increased PTTG1 to thyroid carcinogenesis. We showed that PTTG I was physically associated with thyroid hormone 0 receptor (TR beta) as well as its mutant, designated PV. Concomitant with thyroid hormone-induced (T3-induced) degradation of TR beta, PTTG1 proteins were degraded by the proteasomal machinery, but no such degradation occurred when PTTG1 was associated with PV. The degradation of PTTG1/TRP was activated by the direct interaction of the liganded TR beta with steroid receptor coactivator 3 (SRC-3), which recruits proteasome activator PA28 gamma. PV, which does not bind T3, could not interact directly with SRC-3/PA28 gamma to activate proteasome degradation, resulting in elevated PTTG1 levels. The accumulated PTTG1 impeded mitotic progression in cells expressing PV. Our results unveil what we believe to be a novel mechanism by which PTTG1, an oncogene, is regulated by the liganded TR beta. The loss of this regulatory function in PV led to an aberrant accumulation of PTTG1 disrupting mitotic progression that could contribute to thyroid carcinogenesis.