Different Mechanisms of Calcitonin, Calcitonin Gene-Related Peptide, and Somatostatin Regulation by Glucocorticoids in a Cell Culture of Human Medullary Thyroid Carcinoma

We have employed the TT cell line, a model for the human medullary thyroid carcinoma cell, lo study the regulation of peptide hormone production by glucocorticoids. Complementary DNA probes were used to measure the calcitonin (CT), CT gene-related peptide (CGRP), and somatostatin (SRIF) mRNA levels. Dose-response experiments in serum-free medium showed that dexamethasone (six-day treatment) lowered somatostatin (to 1% of basal) and CGRP mRNA (to 50% of basal) and stimulated CT mRNA (threefold to thirteenfold) with a half-maximal effective concentration of 10−8 M. Time course studies for cells continuously exposed to 10−6 M dexamethasone showed a rapid (within hours) lowering of SRIF mRNA, whereas the effects on CT and CGRP mRNA required six to eight days. These results demonstrate the presence of two mechanisms, transcriptional (somatostatin) and posttranscriptional (the RNA splice decision to make CT or CGRP mRNA). that can be hormonally regulated

Transcriptional Regulation of the Human Calcitonin Gene: A Progress Report

We have applied DNA transfer techniques lo study the transcriptional regulation of the calcitonin (CT) gene in a C-cell line (TT) derived from a human medullary thyroid carcinoma. TT cells were transfected with a fusion gene containing the CT gene promoter and 5\u27 -flanking DNA attached to the promoter-less growth hormone gene (reporter). We quantitated the reporter gene product to monitor transcriptional activation by the CT promoter and deletion mutants of the 5\u27 -flanking DNA. We found that the proximal CT promoter which includes the DNA sequence from +1 to -129 bp upstream from the CT transcription start site did not induce transcription in C-cells or in NIH 3T3 cells. The attachment of additional 5\u27-flanking DNA, extending up to -1460 bp enhanced transcription up to twelvefold in TT cells but had no effect on transcription in 3T3 cells. Deletion of a sequence located at -1290 to -820 bp on the CT 5\u27 -flanking DNA abolished the transcription of the reporter gene. Attachment of the DNA sequence located between -1333 to -731 to the fusion gene, containing the CT promoter (+1 to -129) and the reporter gene, restored transcription of the reporter gene in TT cells. We conclude that an enhancer of CT transcription, which is active in C-cells but not in 3T3 cells, is located between -1290 and -820 of the CT 5\u27-flanking DNA

Impact of Prospective Screening for Multiple Endocrine Neoplasia Type 2

Prospective annual screening for hereditary medullary thyroid carcinoma (MTC) in the J-kindred, currently a 117-member family with multiple endocrine neoplasia type 2A, began in 1969. During the initial screening, 12 patients were found to have MTC. Subsequent screening has detected C-cell abnormalities (C-cell hyperplasia or microscopic MTC) in 22 of 23 addilional family members thyroidectomized for abnormal calcium- or pentagastrin-provocative calcitonin (CT) test results. Seven of the initial 12 patients thyroidectomized in 1970 to 1971 and 19 of 23 individuals thyroidectomized since 1971 remain disease-free by all criteria; three patients thyroidectomized since 1971 have had clearly abnormal serum CT measurements on one or more provocative tests. The significance of these abnormal test results is unclear because normal values were obtained when the samples were measured in another CT radioimmunoassay. Urine catecholamine abnormalities have been detected in 19 family members since 1969, resulting in ten bilateral and eight unilateral adrenalectomies. Four of the patients with initial unilateral adrenalectomy required reoperation for a pheochromocytoma in the contralateral gland nine to 13 years later. Hyperparathyroidism has not been observed in any of the family members with early C-cell disease. We conclude that prospective screening for hereditary MTC predicts histologic C-cell abnormalities in affected individuals, and follow-up of these patients provides support for the conclusion that early thyroidectomy is curative in most patients

The EIF4EBP3 translational repressor is a marker of CDC73 tumor suppressor haploinsufficiency in a parathyroid cancer syndrome

Germline mutation of the tumor suppressor gene CDC73 confers susceptibility to the hyperparathyroidism-jaw tumor syndrome associated with a high risk of parathyroid malignancy. Inactivating CDC73 mutations have also been implicated in sporadic parathyroid cancer, but are rare in sporadic benign parathyroid tumors. The molecular pathways that distinguish malignant from benign parathyroid transformation remain elusive. We previously showed that a hypomorphic allele of hyrax (hyx), the Drosophila homolog of CDC73, rescues the loss-of-ventral-eye phenotype of lobe, encoding the fly homolog of Akt1s1/ PRAS40. We report now an interaction between hyx and Tor, a central regulator of cell growth and autophagy, and show that eukaryotic translation initiation factor 4E-binding protein (EIF4EBP), a translational repressor and effector of mammalian target of rapamycin (mTOR), is a conserved target of hyx/CDC73. Flies heterozygous for Tor and hyx, but not Mnn1, the homolog of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor associated with benign parathyroid tumors, are starvation resistant with reduced basal levels of Thor/4E-BP. Human peripheral blood cell levels of EIF4EBP3 were reduced in patients with CDC73, but not MEN1, heterozygosity. Chromatin immunoprecipitation demonstrated occupancy of EIF4EBP3 by endogenous parafibromin. These results show that EIF4EBP3 is a peripheral marker of CDC73 function distinct from MEN1-regulated pathways, and suggest a model whereby starvation resistance and/or translational de-repression contributes to parathyroid malignant transformation

Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma

The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association