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Endocrinology Vol. 138, No. 8 3133-3140
Copyright © 1997 by The Endocrine Society

ARTICLES

Thyroid-Specific Expression of Cholera Toxin A1 Subunit Causes Thyroid Hyperplasia and Hyperthyroidism in Transgenic Mice1

Martha A. Zeiger2, Motoyasu Saji2, Yuriy Gusev, William H. Westra, Yumi Takiyama, William C. Dooley, Leonard D. Kohn and Michael A. Levine

Departments of Surgery (M.A.Z., M.S., Y.G., Y.T., W.C.D.), Pathology (W.H.W.), and Medicine (M.A.L.), Johns Hopkins Medical Institutions, Baltimore, Maryland 21205; National Institute of Diabetes, Digestive, and Kidney Diseases (L.D.K.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Martha A. Zeiger, M.D., F.A.C.S., 600 North Wolfe Street, Carnegie 681, Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-8611.

Thyroid cell growth and function are regulated by hormones and growth factors binding to cell surface receptors that are coupled via G proteins, Gs and Gq, to the adenylyl cyclase and phospholipase C signal transduction systems, respectively. Activating mutations of the TSH receptor and G{alpha}s have been documented in subsets of thyroid neoplasms. To test the oncogenic potential of activated G{alpha}s in transgenic mice, we used the cholera toxin A1 subunit that constitutively activates G{alpha}s and used the rat thyroglobulin gene promoter for targeting this transgene (TGCT) to thyroid follicular cells. Three (M1392, F1358, and F1286) of six founders identified were able to transmit the transgene to their offspring and thyroid glands from these mice contained elevated levels of cAMP. Concentrations of serum thyroxine were elevated as early as 2 months of age (M 1392 and F 1286). F1358 mice were euthyroid until 8 months of age, at which time they developed hyperthyroidism. All three TGCT lines developed thyroid hyperplasia independent of their thyroxine levels. DNA image analysis of thyroid follicular cells from both the hyper and euthyroid mice showed that DNA index and "S+G2/M" phase were increased compared with normal, changes similar to that seen in poor prognosis human carcinomas. These data suggest that the G{alpha}s-adenylyl cyclase-cAMP pathway has an important role in thyroid hyperplasia and the transgenic mouse models reported herein will allow further examination of the role of this pathway in thyroid oncogenesis.




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