Thyroid-specific expression of cholera toxin A1 subunit causes thyroid hyperplasia and hyperthyroidism in transgenic mice

Endocrinology. 1997 Aug;138(8):3133-40. doi: 10.1210/endo.138.8.5347.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenylyl Cyclases / physiology
  • Aneuploidy
  • Animals
  • Cell Cycle
  • Cholera Toxin / chemistry
  • Cholera Toxin / genetics
  • Cholera Toxin / toxicity*
  • Cyclic AMP / analysis
  • Cyclic AMP / metabolism
  • Cyclic AMP / physiology
  • DNA / analysis
  • Disease Models, Animal
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • GTP-Binding Protein alpha Subunits, Gs / physiology
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / physiology
  • Hyperplasia / chemically induced
  • Hyperplasia / pathology
  • Hyperthyroidism / chemically induced*
  • Hyperthyroidism / pathology
  • Image Cytometry
  • Mice
  • Mice, Transgenic
  • Promoter Regions, Genetic / genetics
  • Rats
  • Signal Transduction / physiology
  • Thyroglobulin / genetics
  • Thyroid Diseases / chemically induced*
  • Thyroid Diseases / pathology
  • Thyroid Gland / drug effects
  • Thyroid Gland / pathology*
  • Thyroid Gland / physiology
  • Thyroxine / blood
  • Time Factors


  • DNA
  • Thyroglobulin
  • Cholera Toxin
  • Cyclic AMP
  • GTP-Binding Proteins
  • GTP-Binding Protein alpha Subunits, Gs
  • Adenylyl Cyclases
  • Thyroxine