Journal of Clinical Endocrinology & Metabolism, Vol 81, 1134-1140, Copyright © 1996 by Endocrine Society

ARTICLES

Screening of candidate oncogenes in human thyrotroph tumors: absence of activating mutations of the G alpha q, G alpha 11, G alpha s, or thyrotropin-releasing hormone receptor genes

Q Dong, F Brucker-Davis, BD Weintraub, RC Smallridge, FE Carr, J Battey, AM Spiegel and A Shenker
Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

Activating mutations encoding substitutions at positions Arg201 and Gln227 of the alpha-subunit of the stimulatory G protein. G10 have been found in about 40% of pituitary somatotroph tumors. Although the etiology of thyrotroph adenomas is unknown, their autonomous behavior and blunted response to stimulatory hypothalamic hormone superficially resemble those of somatotroph tumors. We hypothesized that a subset of thyrotroph tumors might be caused by dominant somatic mutations that lead to inappropriate activation of the Gq/phospholipase C beta/Ca2+/protein kinase C. pathway normally triggered by occupancy of the TRH receptor (TRHR). We, therefore, screened samples from nine thyrotroph tumors for the presence of activating mutations of the alpha q, alpha 11, and TRHR genes. Fragments of alpha q and alpha 11 complementary DNA encompassing residues (Arg183 and Gln209) that correspond to Arg201 and Gln227 of alpha q were amplified and sequenced. Temperature gradient gel electrophoresis was used to screen for heterozygous mutations in the TRHR coding sequence as well as for known alpha s mutations. No mutations were detected. We conclude that mutations in these regions of the alpha q, alpha 11, alpha s, and TRHR genes occur infrequently, if at all, in human thyrotroph tumors. Alternative mechanisms underlying thyrotroph tumorigenesis, including changes in the expression levels of G protein alpha-subunits or TRHR, dysregulation of downstream components, inappropriate activation of other stimulatory pathways, or loss of inhibitory inputs, remain to be explored.

This article has been cited by other articles:

				S. A. Boikos and C. A. Stratakis Molecular genetics of the cAMP-dependent protein kinase pathway and of sporadic pituitary tumorigenesis Hum. Mol. Genet., April 15, 2007; 16(R1): R80 - R87. [Abstract] [Full Text] [PDF]

				N. Wettschureck and S. Offermanns Mammalian G Proteins and Their Cell Type Specific Functions Physiol Rev, October 1, 2005; 85(4): 1159 - 1204. [Abstract] [Full Text] [PDF]

				A. Lania, G. Mantovani, and A. Spada Genetics of Pituitary Tumors: Focus on G-Protein Mutations Experimental Biology and Medicine, October 1, 2003; 228(9): 1004 - 1017. [Abstract] [Full Text] [PDF]

				V. A. Adarichev, R. Vaiskunaite, J. Niu, I. V. Balyasnikova, and T. A. Voyno-Yasenetskaya G{alpha}13-mediated transformation and apoptosis are permissively dependent on basal ERK activity Am J Physiol Cell Physiol, October 1, 2003; 285(4): C922 - C934. [Abstract] [Full Text] [PDF]

				S. Ando, N. J. Sarlis, E. H. Oldfield, and P. M. Yen Somatic Mutation of TR{beta} Can Cause a Defect in Negative Regulation of TSH in a TSH-Secreting Pituitary Tumor J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5572 - 5576. [Abstract] [Full Text] [PDF]

				L. S. Weinstein, S. Yu, D. R. Warner, and J. Liu Endocrine Manifestations of Stimulatory G Protein {alpha}-Subunit Mutations and the Role of Genomic Imprinting Endocr. Rev., October 1, 2001; 22(5): 675 - 705. [Abstract] [Full Text] [PDF]

				S. Ando, N. J. Sarlis, J. Krishnan, X. Feng, S. Refetoff, M. Q. Zhang, E. H. Oldfield, and P. M. Yen Aberrant Alternative Splicing of Thyroid Hormone Receptor in a TSH-Secreting Pituitary Tumor Is A Mechanism for Hormone Resistance Mol. Endocrinol., September 1, 2001; 15(9): 1529 - 1538. [Abstract] [Full Text] [PDF]

				F. Brucker-Davis, E. H. Oldfield, M. C. Skarulis, J. L. Doppman, and B. D. Weintraub Thyrotropin-Secreting Pituitary Tumors: Diagnostic Criteria, Thyroid Hormone Sensitivity, and Treatment Outcome in 25 Patients Followed at the National Institutes of Health J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 476 - 486. [Abstract] [Full Text]

				S. L. Asa and S. Ezzat The Cytogenesis and Pathogenesis of Pituitary Adenomas Endocr. Rev., December 1, 1998; 19(6): 798 - 827. [Abstract] [Full Text]

				M. D. Ringel, M. Saji, W. F. Schwindinger, D. Segev, M. A. Zeiger, and M. A. Levine Absence of Activating Mutations of the Genes Encoding the {alpha}-Subunits of G11 and Gq in Thyroid Neoplasia J. Clin. Endocrinol. Metab., February 1, 1998; 83(2): 554 - 559. [Abstract] [Full Text]

				N. M. Oyesiku, C.-O. Evans, M. R. Brown, L. S. Blevins, G. T. Tindall, and J. S. Parks Pituitary Adenomas: Screening for G{alpha}q Mutations J. Clin. Endocrinol. Metab., December 1, 1997; 82(12): 4184 - 4188. [Abstract] [Full Text] [PDF]

				I. Shimon and S. Melmed Pituitary Tumor Pathogenesis J. Clin. Endocrinol. Metab., June 1, 1997; 82(6): 1675 - 1681. [Full Text] [PDF]

				Q. Dong, L. V. Debelenko, S. C. Chandrasekharappa, M. R. Emmert-Buck, Z. Zhuang, S. C. Guru, P. Manickam, M. Skarulis, I. A. Lubensky, L. A. Liotta, et al. Loss of Heterozygosity at 11q13: Analysis of Pituitary Tumors, Lung Carcinoids, Lipomas, and Other Uncommon Tumors in Subjects with Familial Multiple Endocrine Neoplasia Type 1 J. Clin. Endocrinol. Metab., May 1, 1997; 82(5): 1416 - 1420. [Abstract] [Full Text] [PDF]