Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular mechanisms responsible for aberrant calcium signaling in parathyroid disease are poorly understood. The loss of appropriate calcium-responsive modulation of PTH secretion observed in parathyroid disease is commonly attributed to decreased expression of the calcium-sensing receptor (CaSR), a G protein-coupled receptor. However, CaSR expression is highly variable in parathyroid adenomas, and the lack of correlation between CaSR abundance and calcium-responsive PTH kinetics indicates that mechanisms independent of CaSR expression may contribute to aberrant calcium sensing in parathyroid disease. To gain a better understanding of parathyroid tumors and the molecular determinants that drive parathyroid adenoma development, we performed gene expression profiling on a panel of 64 normal and neoplastic parathyroid tissues. The microarray data revealed high-level expression of genes known to be involved in parathyroid biology (PTH, VDR, CGA, CaSR, and GCM2). Moreover, our screen identified regulator of G protein signaling 5 (RGS5) as a candidate inhibitor of CaSR signaling. We confirmed RGS5 to be highly expressed in parathyroid adenomas relative to matched-pair normal glands. Transient expression of RGS5 in cells stably expressing CaSR resulted in dose-dependent abrogation of calcium-stimulated inositol trisphosphate production and ERK1/2 phosphorylation. Furthermore, we found that RGS5-nullizygous mice display reduced plasma PTH levels, an outcome consistent with attenuated opposition to CaSR activity. Collectively, these data suggest that RGS5 can act as a physiological regulator of calcium sensing by CaSR in the parathyroid gland. The abnormally elevated expression of RGS5 observed in parathyroid adenomas could thus represent a novel mechanism of CaSR desensitization in patients with primary hyperparathyroidism.
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PMID:Regulator of G protein signaling 5 is highly expressed in parathyroid tumors and inhibits signaling by the calcium-sensing receptor. 2139 47

Sporadic primary hyperparathyroidism (PHPT), one of the most common endocrine disorders, is characterized by hypercalcemia and elevated PTH levels. The majority of cases are caused by a benign parathyroid adenoma, but somatic or de novo germ-line mutations that lead to adenoma formation have only been identified in few glands. GCMB is a parathyroid-specific transcription factor, which causes hypoparathyroidism when inactivated on both parental alleles or when a dominant-negative, heterozygous mutation is present. It is overexpressed in some parathyroid adenomas, and we therefore tested the hypothesis that GCMB mutations can be a cause of parathyroid adenomas. Nucleotide sequence analysis was performed on all coding exons and exon-intron borders of GCMB in 30 sporadic parathyroid adenomas and we identified several known polymorphisms that were either heterozygous or homozygous. In addition, one of the 30 investigated glands revealed a novel heterozygous missense mutation, c.1144G>A, which introduced methionine at position 382 for valine (V382M), a conserved amino acid residue. Western blot analysis using mutant GCMB (GCMB-V382M) from lysates of transiently transfected DF-1 fibroblasts, luciferase assays using extracts from these cells, and electrophoretic mobility assays failed to reveal differences between wild-type and mutant GCMB in expression level, transactivational capacity, and DNA-binding ability. Furthermore, pulse-chase experiments demonstrated no difference in half-life of wild-type and mutant protein. We conclude that mutations in the transcription factor GCMB do not seem to play a major role in the pathogenesis of PHPT.
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PMID:Mutational analysis of GCMB, a parathyroid-specific transcription factor, in parathyroid adenoma of primary hyperparathyroidism. 2164 77