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Oncogenic mutations of thyroid hormone receptor β.

Park JW, Zhao L, Willingham M, Cheng SY - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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

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.

No MeSH data available.


Related in: MedlinePlus

Comparison of histological characteristics in tumors derived from Neo cells, MDA-TRβ1 and MDA-C-terminal mutants (PV, Mkar, Mdbs, and AM)Neo (panels a, b, & c), MDA-TRβ1 (panels d, e, & f), MDA-PV (panels g, h, & i), MDA-Mkar (panels j, k, & l), MDA-Mdbs (panels m, n, & o),and MDA-AM (panels p, q, & r) cells. The magnification was 40X in panels d, e, and f (insets) to indicate large nuclei (arrow) in tumors derived from MDA-TRβ1.
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Figure 4: Comparison of histological characteristics in tumors derived from Neo cells, MDA-TRβ1 and MDA-C-terminal mutants (PV, Mkar, Mdbs, and AM)Neo (panels a, b, & c), MDA-TRβ1 (panels d, e, & f), MDA-PV (panels g, h, & i), MDA-Mkar (panels j, k, & l), MDA-Mdbs (panels m, n, & o),and MDA-AM (panels p, q, & r) cells. The magnification was 40X in panels d, e, and f (insets) to indicate large nuclei (arrow) in tumors derived from MDA-TRβ1.

Mentions: We next compared the morphological features of the xenograft tumors derived from cells expressing TRβ1 or its mutants. Figure 4 shows the morphological features from three representative tumors derived from each cell line. The cells exhibit similar morphology in tumors derived from Neo control cells (panels a, b, & c), MDA-PV (panels g, h, & i), MDA-Mkar (panels j, k, & l), MDA-Mdbs (panels m, n, & o), and MDA-AM cells (panels p, q, & r). The histology in these fast-growing tumors shows small highly proliferative cells with pleomorphic nuclei and prominent nucleoli, numerous mitotic figures, and no significant evidence of necrosis or apoptosis. However, the smaller tumors derived from MDA-TRβ1show scattered cells with large distinct-looking nuclei (marked by arrows in panel d, e, & f, Figure 4; shown clearly in the insets). These unusual-looking large nuclei may reflect consequences of cell cycle arrest, perhaps due to cell fusion and/or failed mitoses, and occasional foci of necrosis and interstitial hemorrhage, all consistent with slow irregular growth and poor cell survival.


Oncogenic mutations of thyroid hormone receptor β.

Park JW, Zhao L, Willingham M, Cheng SY - Oncotarget (2015)

Comparison of histological characteristics in tumors derived from Neo cells, MDA-TRβ1 and MDA-C-terminal mutants (PV, Mkar, Mdbs, and AM)Neo (panels a, b, & c), MDA-TRβ1 (panels d, e, & f), MDA-PV (panels g, h, & i), MDA-Mkar (panels j, k, & l), MDA-Mdbs (panels m, n, & o),and MDA-AM (panels p, q, & r) cells. The magnification was 40X in panels d, e, and f (insets) to indicate large nuclei (arrow) in tumors derived from MDA-TRβ1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480739&req=5

Figure 4: Comparison of histological characteristics in tumors derived from Neo cells, MDA-TRβ1 and MDA-C-terminal mutants (PV, Mkar, Mdbs, and AM)Neo (panels a, b, & c), MDA-TRβ1 (panels d, e, & f), MDA-PV (panels g, h, & i), MDA-Mkar (panels j, k, & l), MDA-Mdbs (panels m, n, & o),and MDA-AM (panels p, q, & r) cells. The magnification was 40X in panels d, e, and f (insets) to indicate large nuclei (arrow) in tumors derived from MDA-TRβ1.
Mentions: We next compared the morphological features of the xenograft tumors derived from cells expressing TRβ1 or its mutants. Figure 4 shows the morphological features from three representative tumors derived from each cell line. The cells exhibit similar morphology in tumors derived from Neo control cells (panels a, b, & c), MDA-PV (panels g, h, & i), MDA-Mkar (panels j, k, & l), MDA-Mdbs (panels m, n, & o), and MDA-AM cells (panels p, q, & r). The histology in these fast-growing tumors shows small highly proliferative cells with pleomorphic nuclei and prominent nucleoli, numerous mitotic figures, and no significant evidence of necrosis or apoptosis. However, the smaller tumors derived from MDA-TRβ1show scattered cells with large distinct-looking nuclei (marked by arrows in panel d, e, & f, Figure 4; shown clearly in the insets). These unusual-looking large nuclei may reflect consequences of cell cycle arrest, perhaps due to cell fusion and/or failed mitoses, and occasional foci of necrosis and interstitial hemorrhage, all consistent with slow irregular growth and poor cell survival.

Bottom Line: 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.

View Article: PubMed Central - PubMed

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

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.

No MeSH data available.


Related in: MedlinePlus