Oncogenic mutations of thyroid hormone receptor β.
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.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Jeong Won
JW
Park
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Li
L
Zhao
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Mark
M
Willingham
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Sheue-Yann
SY
Cheng
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D064593:Heterografts; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D037042:Thyroid Hormone Receptors beta / Q000235:genetics* / Q000378:metabolism
D037042:Thyroid Hormone Receptors beta; D019869:Phosphatidylinositol 3-Kinases
oncogenes; protein-protein interactions; signaling transduction; thyroid hormone; thyroid hormone receptors