Oncotarget

Research Papers:

Oncogenic mutations of thyroid hormone receptor β

Jeong Won Park, Li Zhao, Mark Willingham and Sheue-yann Cheng _

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Oncotarget. 2015; 6:8115-8131. https://doi.org/10.18632/oncotarget.3466

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Abstract

Jeong Won Park1, Li Zhao1, Mark Willingham1 and Sheue-yann Cheng1

1 Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Correspondence to:

Sheue-yann Cheng, email:

Keywords: thyroid hormone receptors, oncogenes, protein-protein interactions, signaling transduction, thyroid hormone

Received: November 20, 2014 Accepted: January 20, 2015 Published: February 28, 2015

Abstract

The C-terminal frame-shift mutant of the thyroid hormone receptor TRβ1, PV, functions as an oncogene. An important question is whether the oncogenic activity of mutated TRβ1 is uniquely dependent on the PV mutated sequence. Using four C-terminal frame-shift mutants—PV, Mkar, Mdbs, and AM—we examined that region in the oncogenic actions of TRβ1 mutants. Remarkably, these C-terminal mutants induced similar growth of tumors in mouse xenograft models. Molecular analyses showed that they physically interacted with the p85α regulatory subunit of PI3K similarly in cells. In vitro GST-binding assay showed that they bound to the C-terminal Src-homology 2 (CSH2) of p85α with markedly higher avidity. The sustained association of mutants with p85α led to activation of the common PI3K-AKT-ERK/STAT3 signaling to promote cell proliferation and invasion and to inhibit apoptosis. Thus, these results argue against the oncogenic activity of PV being uniquely dependent on the PV mutated sequence. Rather, these four mutants could favor a C-terminal conformation that interacted with the CSH2 domain of p85α to initiate activation of PI3K to relay downstream signaling to promote tumorigenesis. Thus, we propose that the mutated C-terminal region of TRβ1 could function as an “onco-domain” and TRβ1 is a potential therapeutic target.


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