A1 Refereed original research article in a scientific journal
Partial thyrocyte-specific Gαs deficiency leads to rapid-onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma-like lesions in mice
Authors: Konrad Patyra, Holger Jaeschke, Christoffer Löf, Meeri Jännäri, Suvi T. Ruohonen, Henriette Undeutsch, Moosa Khalil, Andreina Kero, Matti Poutanen, Jorma Toppari, Min Chen, Lee S. Weinstein, Ralf Paschke, Jukka Kero
Publisher: FEDERATION AMER SOC EXP BIOL
Publication year: 2018
Journal: FASEB Journal
Journal name in source: FASEB JOURNAL
Journal acronym: FASEB J
Volume: 32
Issue: 11
First page : 6239
Last page: 6251
Number of pages: 13
ISSN: 0892-6638
DOI: https://doi.org/10.1096/fj.201800211R
Abstract
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 (Gαs) in adult mice [tamoxifen-inducible G(s) protein subunit deficient (iTGαsKO) mice] rapidly impairs thyrocyte function and leads to hypothyroidism. Consequently, iTGαsKO mice show reduced food intake and activity. However, body weight and the amount of white adipose tissue were decreased only in male iTGαsKO mice. Unexpectedly, hyperplastic follicles and papillary thyroid cancer-like tumor lesions with increased proliferation and slightly increased phospho-ERK1/2 staining were found in iTGαsKO mice at an older age. These tumors developed from nonrecombined thyrocytes still expressing Gαs in the presence of highly elevated serum TSH. In summary, we report that partial thyrocyte-specific Gαs deletion leads to hypothyroidism but also to tumor development in thyrocytes with remaining Gαs 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 Gαs deficiency leads to rapid-onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma-like lesions in mice.
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 (Gαs) in adult mice [tamoxifen-inducible G(s) protein subunit deficient (iTGαsKO) mice] rapidly impairs thyrocyte function and leads to hypothyroidism. Consequently, iTGαsKO mice show reduced food intake and activity. However, body weight and the amount of white adipose tissue were decreased only in male iTGαsKO mice. Unexpectedly, hyperplastic follicles and papillary thyroid cancer-like tumor lesions with increased proliferation and slightly increased phospho-ERK1/2 staining were found in iTGαsKO mice at an older age. These tumors developed from nonrecombined thyrocytes still expressing Gαs in the presence of highly elevated serum TSH. In summary, we report that partial thyrocyte-specific Gαs deletion leads to hypothyroidism but also to tumor development in thyrocytes with remaining Gαs 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 Gαs deficiency leads to rapid-onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma-like lesions in mice.
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