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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 tumor growth rates derived from injection of MDA-TRβ1, MDA-PV, MDA-Mkar, MDA-Mdbs, MDA-AM, and Neo control cellsA. Equal numbers of cells were inoculated onto the right flank of mice 6-week-old female athymic NCr-nu/nu mice. Tumor sizes were measured weekly and the rates of tumor growth were compared. *p < 0.05. B. Representative pictures of tumors bearing mice (B-a) and dissected tumors (“i and ii” represent duplicates, B-b). C. Tumors were dissected at the endpoint and the weight was determined. The data are expressed as mean ± SE (n = 6) and the p-values are shown.
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Figure 3: Comparison of tumor growth rates derived from injection of MDA-TRβ1, MDA-PV, MDA-Mkar, MDA-Mdbs, MDA-AM, and Neo control cellsA. Equal numbers of cells were inoculated onto the right flank of mice 6-week-old female athymic NCr-nu/nu mice. Tumor sizes were measured weekly and the rates of tumor growth were compared. *p < 0.05. B. Representative pictures of tumors bearing mice (B-a) and dissected tumors (“i and ii” represent duplicates, B-b). C. Tumors were dissected at the endpoint and the weight was determined. The data are expressed as mean ± SE (n = 6) and the p-values are shown.

Mentions: We have recently shown that TRβ1 acts as a tumor suppressor to inhibit the induction of MDA tumor growth in mouse xenograft models. To test whether C-terminal mutants of TRβ1 had lost the tumor suppressor functions in vivo, we inoculated MDA-PV, MDA-Mkar, MDA-Mdbs, and MDA-AM cells into athymic mice. Figure 3A shows that the tumor growth rate derived from MDA-TRβ1 (open squares) was clearly markedly slower than that of the control Neo cells (solid squares). The tumor growth rates of cells stably expressing PV, Mkar, Mdbs, or AM were indistinguishable from each other and that of the control Neo cells. Importantly, their rates were faster than that of cells stably expressing TRβ1. Moreover, the tumor size derived from MDA-TRβ1 cells was clearly smaller than that from the control Neo cells and from MDA- PV, MDA-Mkar, MDA-Mdbs, and MDA-AM cells, as shown by the representative examples (Figure 3B-a and 3B-b). Figure 3C shows a quantitative comparison of the tumor sizes developed from injecting Neo, MDA-TRβ1, MDA-PV, MDA-Mkar, MDA-Mdbs, or MDA-AM cells. The tumor size from cells expressing TRβ1 was about 30-50% smaller than that from the Neo control cells (bar 2 vs. bar 1), PV (bar 3), Mkar (bar 4), Mdbs (bar 5), or AM (bar 6). Consistent with the cell-based findings shown above, these in vivo results indicate that mutations of the C-terminal helix 11 and 12 led to the loss of tumor suppressor functions of TRβ1.


Oncogenic mutations of thyroid hormone receptor β.

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

Comparison of tumor growth rates derived from injection of MDA-TRβ1, MDA-PV, MDA-Mkar, MDA-Mdbs, MDA-AM, and Neo control cellsA. Equal numbers of cells were inoculated onto the right flank of mice 6-week-old female athymic NCr-nu/nu mice. Tumor sizes were measured weekly and the rates of tumor growth were compared. *p < 0.05. B. Representative pictures of tumors bearing mice (B-a) and dissected tumors (“i and ii” represent duplicates, B-b). C. Tumors were dissected at the endpoint and the weight was determined. The data are expressed as mean ± SE (n = 6) and the p-values are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Comparison of tumor growth rates derived from injection of MDA-TRβ1, MDA-PV, MDA-Mkar, MDA-Mdbs, MDA-AM, and Neo control cellsA. Equal numbers of cells were inoculated onto the right flank of mice 6-week-old female athymic NCr-nu/nu mice. Tumor sizes were measured weekly and the rates of tumor growth were compared. *p < 0.05. B. Representative pictures of tumors bearing mice (B-a) and dissected tumors (“i and ii” represent duplicates, B-b). C. Tumors were dissected at the endpoint and the weight was determined. The data are expressed as mean ± SE (n = 6) and the p-values are shown.
Mentions: We have recently shown that TRβ1 acts as a tumor suppressor to inhibit the induction of MDA tumor growth in mouse xenograft models. To test whether C-terminal mutants of TRβ1 had lost the tumor suppressor functions in vivo, we inoculated MDA-PV, MDA-Mkar, MDA-Mdbs, and MDA-AM cells into athymic mice. Figure 3A shows that the tumor growth rate derived from MDA-TRβ1 (open squares) was clearly markedly slower than that of the control Neo cells (solid squares). The tumor growth rates of cells stably expressing PV, Mkar, Mdbs, or AM were indistinguishable from each other and that of the control Neo cells. Importantly, their rates were faster than that of cells stably expressing TRβ1. Moreover, the tumor size derived from MDA-TRβ1 cells was clearly smaller than that from the control Neo cells and from MDA- PV, MDA-Mkar, MDA-Mdbs, and MDA-AM cells, as shown by the representative examples (Figure 3B-a and 3B-b). Figure 3C shows a quantitative comparison of the tumor sizes developed from injecting Neo, MDA-TRβ1, MDA-PV, MDA-Mkar, MDA-Mdbs, or MDA-AM cells. The tumor size from cells expressing TRβ1 was about 30-50% smaller than that from the Neo control cells (bar 2 vs. bar 1), PV (bar 3), Mkar (bar 4), Mdbs (bar 5), or AM (bar 6). Consistent with the cell-based findings shown above, these in vivo results indicate that mutations of the C-terminal helix 11 and 12 led to the loss of tumor suppressor functions of TRβ1.

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