Loss of tyrosine phosphorylation at Y406 abrogates the tumor suppressor functions of the thyroid hormone receptor β.

Abstract

We have recently identified that phosphorylation at tyrosine (Y)406 is critical for the tumor suppressor functions of the thyroid hormone receptor β1 (TRβ) in a breast cancer line. However, still unclear is whether the critical tumor suppressor role of phosphorylated Y406 of TRβ is limited to only breast cancer cells or could be extended to other cell types. In the present studies, we addressed this question by stably expressing TRβ, a mutated TRβ oncogene (PV), or a TRβ mutated at Y406 (TRβY406F) in rat PCCL3 thyroid follicular cells and evaluated their tumor characteristics in athymic mice with elevated thyroid stimulating hormone. PCCL3 cells stably expressing PV (PCCL3-PV), TRβY406F (PCCL3-TRβY406F), or vector only (PCCL3-Neo) developed tumors with sizes in the rank order of TRβY406F>PV = Neo, whereas PCCL3 cells expressing TRβ (PCCL3-TRβ) barely developed tumors. As evidenced by markedly elevated Ki67, cyclin D1, and p-Rb protein abundance, proliferative activity was high in PV and TRβY406F tumors, but low in TRβ tumors. These results indicate that TRβ acted as a tumor suppressor in PCCL3 cells, whereas TRβY406F and PV had lost tumor suppressor activity. Interestingly, TRβY406F tumors had very low necrotic areas with decreased TNFα-NFκB signaling to lower apoptotic activity. In contrast, PV tumors had prominent large necrotic areas, with no apparent changes in TNFα-NFκB signaling, indicating distinct oncogenic activities of mutant PV and TRβY406F. Thus, the present studies uncovered a novel mechanism by which TRβ could function as a tumor suppressor through modulation of the TNFα-NFκB signaling. © 2016 Wiley Periodicals, Inc.

• Authors: Jeong Won Park, Li Zhao, Mark C Willingham, Sheue-Yann Cheng
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 56 Issue 2 Pg. 489-498 (02 2017) ISSN: 1098-2744 [Electronic] United States
• PMID: 27254276 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: © 2016 Wiley Periodicals, Inc.

Chemical References

• Thyroid Hormone Receptors beta
• Tyrosine

Topics

• Animals
• Cell Line
• Cell Line, Tumor
• Cell Proliferation
• Female
• Genes, Tumor Suppressor
• Humans
• Mice
• Mice, Nude
• Phosphorylation
• Point Mutation
• Rats
• Thyroid Gland (metabolism, pathology)
• Thyroid Hormone Receptors beta (chemistry, genetics)
• Thyroid Neoplasms (genetics, pathology)
• Tyrosine (analysis, genetics)