PubMed · 6897598
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C R Pickardt. 1982-10-10. [The thyroid].. https://pubmed.ncbi.nlm.nih.gov/6897598/
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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.
We have screened 57 cases of primary, nonfunctional, pituitary adenomas for loss of heterozygosity of markers on chromosome 9p. Using a panel of 11 microsatellite markers, we found hemizygous deletion with at least one of the markers in 18 tumors (31.5%). The frequency of loss was similar in both noninvasive (8 of 26; 31%) and invasive tumors (10 of 31; 32%), suggesting that loss on this chromosome might be an early event in pituitary tumorigenesis. Two discrete areas of loss were punctuated by a region of retention of heterozygosity between the markers D9S171 and IFNA, indicative of homozygous deletion. However, multiplex PCR analysis (MTS1 and MTS2) and the presence of a 3' untranslated region polymorphism in MTS1 suggested that neither of these tumor suppressor genes was homozygously deleted. In 6 of the 18 tumors showing LOH, sufficient DNA was also available for Southern blot analysis and, in all cases, showed retention of MTS1. Cell mixing experiments of tumor cell DNA homozygously deleted for MTS1 with DNA in which neither copy of the gene was deleted only gave rise to a signal at contamination levels greater than 30% and could discriminate homozygous and hemizygous loss. These studies support the recent findings that mechanisms other than hemi- and homozygous deletion are most likely responsible for the loss of MTS1 gene product in pituitary tumors (M. Woloschak et al., Cancer Res., 56: 2493-2486, 1996.). These data show that losses on either side of 9p21-22, both or either of which may be deleted, are involved in pituitary tumorigenesis and provide evidence for distinct suppressor gene loci, in addition to MTS1, on chromosome 9p.
OBJECTIVE: To evaluate results of a combined dexamethasone suppression/thyrotropin-releasing hormone (TRH) stimulation test in horses suspected clinically to have a pars intermedia pituitary adenoma (PIPA). DESIGN: Case-control study. ANIMALS: 7 healthy adult horses and 5 horses suspected to have a PIPA. PROCEDURE: A baseline blood sample was collected, and dexamethasone (40 micrograms/kg [18 micrograms/lb] of body weight, IV) was administered; a second blood sample was collected 3 hours later, and TRH (1.1 mg, IV) was administered; serial blood samples were collected 15, 30, 45, 60, and 90 minutes and 21 hours after TRH administration (24 hours after dexamethasone injection). Cortisol concentration was determined for all blood samples. RESULTS: Baseline cortisol concentration was significantly lower in horses suspected to have a PIPA than in healthy horses. Cortisol concentration was suppressed by dexamethasone in both groups; however, after TRH administration, cortisol concentration returned to baseline values in horses suspected to have a PIPA, but not in healthy horses. Concentration was still less than the baseline value 24 hours after dexamethasone administration in healthy horses. CLINICAL IMPLICATIONS: The combined dexamethasone suppression/TRH stimulation test may be a useful diagnostic test in horses suspected to have a PIPA. For clinical application, collection of a blood sample 30 minutes after TRH administration is recommended.