Partial thyrocyte-specific G alpha(s) deficiency leads to rapid-onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma-like lesions in mice

Article

关键词: THYROTROPIN RECEPTOR;    CELL PROLIFERATION;    SOMATIC MUTATIONS;    ALPHA-SUBUNIT;    TSH RECEPTOR;    MOUSE MODEL;    L-THYROXINE;    SERUM TSH;    IN-VIVO;    HORMONE;   

DOI  :  10.1096/fj.201800211R

来源: SCIE

【 摘 要 】

Thyroid function is controlled by thyroid-stimulating hormone (TSH), which binds to its G protein-coupled receptor [thyroid-stimulating hormone receptor (TSHR)] on thyrocytes. TSHR can potentially couple to all G protein families, but it mainly activates the G(s)- and G(q/11)-mediated signaling cascades. To date, there is a knowledge gap concerning the role of the individual G protein cascades in thyroid pathophysiology. Here, we demonstrate that the thyrocyte-specific deletion of G(s) protein subunit (G(s)) in adult mice [tamoxifen-inducible G(s) protein subunit deficient (iTG(s)KO) mice] rapidly impairs thyrocyte function and leads to hypothyroidism. Consequently, iTG(s)KO mice show reduced food intake and activity. However, body weight and the amount of white adipose tissue were decreased only in male iTG(s)KO mice. Unexpectedly, hyperplastic follicles and papillary thyroid cancer-like tumor lesions with increased proliferation and slightly increased phospho-ERK1/2 staining were found in iTG(s)KO mice at an older age. These tumors developed from nonrecombined thyrocytes still expressing G(s) in the presence of highly elevated serum TSH. In summary, we report that partial thyrocyte-specific G(s) deletion leads to hypothyroidism but also to tumor development in thyrocytes with remaining G(s) expression. Thus, these mice are a novel model to elucidate the pathophysiological consequences of hypothyroidism and TSHR/G(s)/cAMP-mediated tumorigenesis.Patyra, K., Jaeschke, H., Lof, C., Jannari, M., Ruohonen, S. T., Undeutsch, H., Khalil, M., Kero, A., Poutanen, M., Toppari, J., Chen, M., Weinstein, L. S., Paschke, R., Kero, J. Partial thyrocyte-specific G(s) deficiency leads to rapid-onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma-like lesions in mice.

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