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Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone β receptor inhibits mitotic progression
Hao Ying, … , Mark C. Willingham, Sheue-yann Cheng
Hao Ying, … , Mark C. Willingham, Sheue-yann Cheng
Published November 1, 2006
Citation Information: J Clin Invest. 2006;116(11):2972-2984. https://doi.org/10.1172/JCI28598.
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Research Article Oncology

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

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Abstract

Overexpression of pituitary tumor–transforming 1 (PTTG1) is associated with thyroid cancer. We found elevated PTTG1 levels in the thyroid tumors of a mouse model of follicular thyroid carcinoma (TRβPV/PV mice). Here we examined the molecular mechanisms underlying elevated PTTG1 levels and the contribution of increased PTTG1 to thyroid carcinogenesis. We showed that PTTG1 was physically associated with thyroid hormone β receptor (TRβ) as well as its mutant, designated PV. Concomitant with thyroid hormone–induced (T3-induced) degradation of TRβ, PTTG1 proteins were degraded by the proteasomal machinery, but no such degradation occurred when PTTG1 was associated with PV. The degradation of PTTG1/TRβ was activated by the direct interaction of the liganded TRβ with steroid receptor coactivator 3 (SRC-3), which recruits proteasome activator PA28γ. PV, which does not bind T3, could not interact directly with SRC-3/PA28γ 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 TRβ. The loss of this regulatory function in PV led to an aberrant accumulation of PTTG1 disrupting mitotic progression that could contribute to thyroid carcinogenesis.

Authors

Hao Ying, Fumihiko Furuya, Li Zhao, Osamu Araki, Brian L. West, John A. Hanover, Mark C. Willingham, Sheue-yann Cheng

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Figure 1

Increased abundance of PTTG1 in metastatic thyroid carcinomas of TRβPV/PV mice.

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Increased abundance of PTTG1 in metastatic thyroid carcinomas of TRβPV/P...
Shown are thyroids from wild-type mice (A and B), thyroids from TRβPV/PV mice (C and D), and lung metastasis from TRβPV/PV mice (E and F) stained by H&E (A, C, and E) and immunostained by anti-PTTG1 antibody (B, D, and F) as described in Methods.

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