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

Martha A. Zeiger, Motoyasu Saji, Yuriy Gusev, William H. Westra, Yumi Takiyama, William C. Dooley, Leonard D. Kohn, Michael A. Levine

Research output: Contribution to journalArticle

Abstract

Thyroid cell growth and function are regulated by hormones and growth factors binding so 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 Gαs have been documented in subsets of thyroid neoplasms. To test the oncogenic potential of activated Gαs in transgenic mice, we used the cholera toxin A1 subunit that constitutively activates Gαs 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 Gαs-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.

Original languageEnglish (US)
Pages (from-to)3133-3140
Number of pages8
JournalEndocrinology
Volume138
Issue number8
DOIs
StatePublished - 1997

Fingerprint

Cholera Toxin
Hyperthyroidism
Transgenic Mice
Hyperplasia
Thyroid Gland
Transgenes
Thyroxine
Adenylyl Cyclases
Gq-G11 GTP-Binding Protein alpha Subunits
Thyrotropin Receptors
Gene Targeting
Thyroglobulin
G2 Phase
DNA
Cell Surface Receptors
Type C Phospholipases
Thyroid Neoplasms
Cell Division
Signal Transduction
Intercellular Signaling Peptides and Proteins

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Zeiger, M. A., Saji, M., Gusev, Y., Westra, W. H., Takiyama, Y., Dooley, W. C., ... Levine, M. A. (1997). Thyroid-specific expression of cholera toxin A1 subunit causes thyroid hyperplasia and hyperthyroidism in transgenic mice. Endocrinology, 138(8), 3133-3140. https://doi.org/10.1210/en.138.8.3133

Thyroid-specific expression of cholera toxin A1 subunit causes thyroid hyperplasia and hyperthyroidism in transgenic mice. / Zeiger, Martha A.; Saji, Motoyasu; Gusev, Yuriy; Westra, William H.; Takiyama, Yumi; Dooley, William C.; Kohn, Leonard D.; Levine, Michael A.

In: Endocrinology, Vol. 138, No. 8, 1997, p. 3133-3140.

Research output: Contribution to journalArticle

Zeiger, MA, Saji, M, Gusev, Y, Westra, WH, Takiyama, Y, Dooley, WC, Kohn, LD & Levine, MA 1997, 'Thyroid-specific expression of cholera toxin A1 subunit causes thyroid hyperplasia and hyperthyroidism in transgenic mice', Endocrinology, vol. 138, no. 8, pp. 3133-3140. https://doi.org/10.1210/en.138.8.3133
Zeiger, Martha A. ; Saji, Motoyasu ; Gusev, Yuriy ; Westra, William H. ; Takiyama, Yumi ; Dooley, William C. ; Kohn, Leonard D. ; Levine, Michael A. / Thyroid-specific expression of cholera toxin A1 subunit causes thyroid hyperplasia and hyperthyroidism in transgenic mice. In: Endocrinology. 1997 ; Vol. 138, No. 8. pp. 3133-3140.
@article{85d6d3a4f3154b3aa72fa826a3449339,
title = "Thyroid-specific expression of cholera toxin A1 subunit causes thyroid hyperplasia and hyperthyroidism in transgenic mice",
abstract = "Thyroid cell growth and function are regulated by hormones and growth factors binding so 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 Gαs have been documented in subsets of thyroid neoplasms. To test the oncogenic potential of activated Gαs in transgenic mice, we used the cholera toxin A1 subunit that constitutively activates Gαs 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 Gαs-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.",
author = "Zeiger, {Martha A.} and Motoyasu Saji and Yuriy Gusev and Westra, {William H.} and Yumi Takiyama and Dooley, {William C.} and Kohn, {Leonard D.} and Levine, {Michael A.}",
year = "1997",
doi = "10.1210/en.138.8.3133",
language = "English (US)",
volume = "138",
pages = "3133--3140",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "8",

}

TY - JOUR

T1 - Thyroid-specific expression of cholera toxin A1 subunit causes thyroid hyperplasia and hyperthyroidism in transgenic mice

AU - Zeiger, Martha A.

AU - Saji, Motoyasu

AU - Gusev, Yuriy

AU - Westra, William H.

AU - Takiyama, Yumi

AU - Dooley, William C.

AU - Kohn, Leonard D.

AU - Levine, Michael A.

PY - 1997

Y1 - 1997

N2 - Thyroid cell growth and function are regulated by hormones and growth factors binding so 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 Gαs have been documented in subsets of thyroid neoplasms. To test the oncogenic potential of activated Gαs in transgenic mice, we used the cholera toxin A1 subunit that constitutively activates Gαs 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 Gαs-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.

AB - Thyroid cell growth and function are regulated by hormones and growth factors binding so 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 Gαs have been documented in subsets of thyroid neoplasms. To test the oncogenic potential of activated Gαs in transgenic mice, we used the cholera toxin A1 subunit that constitutively activates Gαs 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 Gαs-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.

UR - http://www.scopus.com/inward/record.url?scp=0030741024&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030741024&partnerID=8YFLogxK

U2 - 10.1210/en.138.8.3133

DO - 10.1210/en.138.8.3133

M3 - Article

C2 - 9231760

AN - SCOPUS:0030741024

VL - 138

SP - 3133

EP - 3140

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 8

ER -