Related Experiment Videos
Mutations of thyrotropin receptor isolated from thyroid autonomous functioning adenomas confer TSH-independent growth
A Porcellini1, G Ruggiano, S Pannain
1Istituto Nazionale dei Tumori, Fondazione G Pascale, Napoli & Dipartimento di Biologia e Patologia Molecolare e Cellulare L Califano, Facoltà di Medicina, Università Federico II, Italy.
Abstract:
TSH receptor mutants in the VI transmembrane segment, found in thyroid autonomously functioning adeonomas, have been expressed in differentiated thyroid cells. All mutant receptors constitutively stimulated adenylyl cyclase. The biological activity, measured as cAMP production relative to the wild type receptor, was specific for each mutant in transient and stable transfection assays. Cells expressing these mutants proliferated in the absence of TSH. The rate of growth in the absence of TSH paralleled basal cAMP production for each mutant receptor. Low TSH concentrations stimulated the growth of mutant receptor-expressing cells, and not of the cells expressing the wild type receptor. Also, the entry in the cell cycle and the plating efficiency were markedly stimulated by the expression of the mutant receptors. These data provide a molecular link between the occurrence of TSH receptor mutations and thyroid autonomously functioning adenomas.
Insights
Thyroid-stimulating hormone (TSH) receptor mutations in autonomously functioning adenomas constitutively activate signaling pathways, leading to uncontrolled cell proliferation. These mutations provide a molecular link to the development of these thyroid tumors.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Thyroid autonomously functioning adenomas are benign tumors characterized by excessive thyroid hormone production.
- The thyrotropin receptor (TSH receptor) plays a crucial role in regulating thyroid function.
- Mutations in the TSH receptor have been implicated in the pathogenesis of these adenomas.
Purpose of the Study:
- To investigate the functional consequences of TSH receptor mutations in the VI transmembrane segment.
- To determine the impact of these mutants on cellular signaling and proliferation in differentiated thyroid cells.
Main Methods:
- Expression of wild-type and mutant TSH receptors in differentiated thyroid cells.
- Assays for adenylyl cyclase activity and cyclic AMP (cAMP) production.
- Assessment of cell proliferation, cell cycle entry, and plating efficiency in the absence and presence of TSH.
Main Results:
- All expressed TSH receptor mutants constitutively stimulated adenylyl cyclase, indicating increased signaling.
- Biological activity varied specifically among different mutants.
- Cells expressing mutant receptors proliferated independently of TSH, with growth rates correlating to basal cAMP levels.
- Low TSH concentrations stimulated the growth of mutant-expressing cells but not wild-type cells.
- Mutant receptors enhanced cell cycle entry and plating efficiency.
Conclusions:
- TSH receptor mutations in the VI transmembrane segment lead to constitutive receptor activation and uncontrolled thyroid cell growth.
- These findings establish a direct molecular link between TSH receptor mutations and the development of thyroid autonomously functioning adenomas.
- The study highlights the role of aberrant TSH receptor signaling in thyroid tumorigenesis.