PubMed · 6337458
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M F Brennan. 1983. Primary hyperparathyroidism.. https://pubmed.ncbi.nlm.nih.gov/6337458/
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The high mobility group As (HMGAs) belong to a family of nonhistone nuclear proteins that orchestrate the assembly of nucleoprotein complexes. Through a complex network of protein-DNA and protein-protein interaction, they play important roles in gene transcription, recombination, and chromatin structure. This protein family is involved, through different mechanisms, in both benign and malignant neoplasias. We have recently reported that transgenic mice carrying the Hmga1 or Hmga2 genes under transcriptional control of the cytomegalovirus promoter develop pituitary adenomas secreting prolactin and growth hormone. We have shown that the mechanism of the HMGA2-induced pituitary adenoma is based on the increased E2F1 activity. The expression profile of mouse normal pituitary glands and adenomas induced in HMGA transgenic mice revealed an increased expression of the ccnb2 gene, coding for the cyclin B2 protein, in the neoplastic tissues compared with the normal pituitary gland. Here, we show, by electrophoretic mobility shift assay and chromatin immunoprecipitation, a direct binding of HMGA proteins to the promoter of ccnb2 gene, whereas luciferase assays showed that HMGAs are able to up-regulate ccnb2 promoter activity. Finally, we report an increased CCNB2 expression in human pituitary adenomas of different histotypes that is directly correlated with HMGA1 and HMGA2 expression. Because cyclin B2 is involved in the regulation of the cell cycle, these results taken together indicate that HMGA-induced cyclin B2 overexpression gives an important contribution to experimental and human pituitary tumorigenesis.
The mechanisms of corticotropin-releasing hormone (CRH) induced excitation of ACTH-secreting adenoma cells were investigated using the perforated whole-cell clamp technique and intracellular Ca2+ concentration ([Ca2+]i) measurement. CRH depolarized ACTH-secreting adenoma cells by activating a nonselective cation current that showed slight inward rectification. This channel did not seem to be a member of the Ca(2+)-activated cation currents because it was activated even when the [Ca2+]i was chelated below 50 nM. The activation of the current was induced by protein kinase A-mediated pathways. By [Ca2+]i measurement, CRH increased [Ca2+]i of these cells dependently on voltage-gated Ca2+ current. This CRH-induced [Ca2+]i increase was abolished in Na(+)-free extracellular solution, but was not abolished by the addition of 5 microM tetrodotoxin to the extracellular solution. CRH-induced ACTH secretion from the cultured adenoma cells was also abolished in Na(+)-free extracellular solution, but not in tetrodotoxin-containing extracellular solution. These data indicate that a Na+ current (maybe the nonselective cation current) other than voltage-gated Na+ current plays an important role in CRH-induced [Ca2+]i increase and ACTH secretion. CRH also activated a nonselective cation current in nonadenoma human corticotrophs, suggesting that the activation of a nonselective cation current is a physiological mechanism of CRH-induced excitation in human corticotrophs.
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