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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

A proposed molecular model to indicate a common activated signaling initiated from activation of PI3K by the C-terminal mutants of TRβ1Activation of PI3K-mTOR/ERK-MMPs led to cell proliferation and invasion. Activation of PI3K-STAT3-BIM led to decreased apoptosis to promote tumor growth. The broken lines show the changes found in the present studies. The up-arrows show the increases and down-arrows show the decreases.
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Figure 9: A proposed molecular model to indicate a common activated signaling initiated from activation of PI3K by the C-terminal mutants of TRβ1Activation of PI3K-mTOR/ERK-MMPs led to cell proliferation and invasion. Activation of PI3K-STAT3-BIM led to decreased apoptosis to promote tumor growth. The broken lines show the changes found in the present studies. The up-arrows show the increases and down-arrows show the decreases.

Mentions: Recent proteomic data have uncovered an interdependence of PI3K and STAT3 signaling [30]. We therefore further explored whether STAT3 signaling was affected in the tumors derived from TRβ1- and mutant-expressing cells. Interestingly, we found that consistent with the attenuated PI3K-AKT/ERK in tumors derived from MDA-TRβ1 cells, phosphorylated STAT3 at Y705 (p-STAT3Y705) was also decreased (Figure 8B-I-a, lanes 3 & 4). In contrast, activated p-STAT3Y705 in tumors derived from MDA-PV, MDA-Mkar, MDA-Mdbs, and MDA-AM cells (lanes 5-12) was found to be similar to that in control Neo tumors (lanes 1 & 2). No apparent changes were observed in the total STAT3 levels in all tumors (Figure 8B-I-b). The ratios of p-STAT3/total STAT3 were quantified from the band intensities to indicate that activation of p-STAT3 was higher in all tumors derived from mutants than from TRβ1-expressing cells (Figure 8B-II-a). One of the downstream effectors of STAT3 is BIM, a proapoptotic protein [31]. BIM was increased in tumors derived from MDA-TRβ1 cells (Figure 8B-I-c, lanes 3 & 4), but was markedly decreased in tumors derived from cells expressing mutants (lanes 5-12). The quantitative data shown in Figure 8B-II-b demonstrated that BIM was elevated 3.3-fold higher than that in the tumors from the four mutant-expressing cells. These changes were consistent with the increased apoptotic activity as shown by the findings that more cleaved caspase 3 was detected in the nuclear compartment of MDA-TRβ1 cells, but much less in tumors from cells expressing mutants (see Figure 6). Taken together, our results indicate that TRβ1 acts as a tumor suppressor via attenuation of PI3K-AKT/ERK/STAT3 signaling to reduce tumor growth by decreasing cell proliferation and increasing apoptosis, and by impeding tumor cell invasion. In contrast, the C-terminal mutants, PV, Mkar, Mdbs, and AM, have lost these activities, thereby functioning as oncogenes (see Figure 9).


Oncogenic mutations of thyroid hormone receptor β.

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

A proposed molecular model to indicate a common activated signaling initiated from activation of PI3K by the C-terminal mutants of TRβ1Activation of PI3K-mTOR/ERK-MMPs led to cell proliferation and invasion. Activation of PI3K-STAT3-BIM led to decreased apoptosis to promote tumor growth. The broken lines show the changes found in the present studies. The up-arrows show the increases and down-arrows show the decreases.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 9: A proposed molecular model to indicate a common activated signaling initiated from activation of PI3K by the C-terminal mutants of TRβ1Activation of PI3K-mTOR/ERK-MMPs led to cell proliferation and invasion. Activation of PI3K-STAT3-BIM led to decreased apoptosis to promote tumor growth. The broken lines show the changes found in the present studies. The up-arrows show the increases and down-arrows show the decreases.
Mentions: Recent proteomic data have uncovered an interdependence of PI3K and STAT3 signaling [30]. We therefore further explored whether STAT3 signaling was affected in the tumors derived from TRβ1- and mutant-expressing cells. Interestingly, we found that consistent with the attenuated PI3K-AKT/ERK in tumors derived from MDA-TRβ1 cells, phosphorylated STAT3 at Y705 (p-STAT3Y705) was also decreased (Figure 8B-I-a, lanes 3 & 4). In contrast, activated p-STAT3Y705 in tumors derived from MDA-PV, MDA-Mkar, MDA-Mdbs, and MDA-AM cells (lanes 5-12) was found to be similar to that in control Neo tumors (lanes 1 & 2). No apparent changes were observed in the total STAT3 levels in all tumors (Figure 8B-I-b). The ratios of p-STAT3/total STAT3 were quantified from the band intensities to indicate that activation of p-STAT3 was higher in all tumors derived from mutants than from TRβ1-expressing cells (Figure 8B-II-a). One of the downstream effectors of STAT3 is BIM, a proapoptotic protein [31]. BIM was increased in tumors derived from MDA-TRβ1 cells (Figure 8B-I-c, lanes 3 & 4), but was markedly decreased in tumors derived from cells expressing mutants (lanes 5-12). The quantitative data shown in Figure 8B-II-b demonstrated that BIM was elevated 3.3-fold higher than that in the tumors from the four mutant-expressing cells. These changes were consistent with the increased apoptotic activity as shown by the findings that more cleaved caspase 3 was detected in the nuclear compartment of MDA-TRβ1 cells, but much less in tumors from cells expressing mutants (see Figure 6). Taken together, our results indicate that TRβ1 acts as a tumor suppressor via attenuation of PI3K-AKT/ERK/STAT3 signaling to reduce tumor growth by decreasing cell proliferation and increasing apoptosis, and by impeding tumor cell invasion. In contrast, the C-terminal mutants, PV, Mkar, Mdbs, and AM, have lost these activities, thereby functioning as oncogenes (see Figure 9).

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