Oncogenic mutations of thyroid hormone receptor β

The C-terminal frame-shift mutant of the thyroid hormone receptor TR beta 1, PV, functions as an oncogene. An important question is whether the oncogenic activity of mutated TR beta 1 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 TR beta 1 mutants. Remarkably, these C-terminal mutants induced similar growth of tumors in mouse xenograft models. Molecular analyses showed that they physically interacted with the p85 alpha 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 p85a with markedly higher avidity. The sustained association of mutants with p85a led to activation of the common PI3-KAKT-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 p85 alpha to initiate activation of PI3K to relay downstream signaling to promote tumorigenesis. Thus, we propose that the mutated C-terminal region of TR beta 1 could function as an onco-domain and TR beta 1 is a potential therapeutic target.