| Autor: |
Patyra K; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Turku Center for Disease Modeling, University of Turku, Turku, Finland., Jaeschke H; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland., Löf C; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Turku Center for Disease Modeling, University of Turku, Turku, Finland., Jännäri M; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland., Ruohonen ST; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Turku Center for Disease Modeling, University of Turku, Turku, Finland., Undeutsch H; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland., Khalil M; Department of Pathology and Laboratory Medicine, University of Calgary, Calgary,
Alberta, Canada., Kero A; Department of Pediatrics, Turku University Hospital, Finland., Poutanen M; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Turku Center for Disease Modeling, University of Turku, Turku, Finland., Toppari J; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Department of Pediatrics, Turku University Hospital, Finland., Chen M; Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA., Weinstein LS; Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA., Paschke R; Arnie Charbonneau Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada., Kero J; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Department of Pediatrics, Turku University Hospital, Finland. |
| Abstrakt: |
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 α subunit (Gα s ) in adult mice [tamoxifen-inducible G s protein α subunit deficient (iTGα s KO) mice] rapidly impairs thyrocyte function and leads to hypothyroidism. Consequently, iTGα s KO mice show reduced food intake and activity. However, body weight and the amount of white adipose tissue were decreased only in male iTGα 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 iTGα s KO mice at an older age. These tumors developed from nonrecombined thyrocytes still expressing Gα s in the presence of highly elevated serum TSH. In summary, we report that partial thyrocyte-specific Gα s deletion leads to hypothyroidism but also to tumor development in thyrocytes with remaining Gα 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., Löf, C., Jännäri, 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 Gα s deficiency leads to rapid-onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma-like lesions in mice. |
Plný text