PubMed · 7452171
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S A Robinson, P Edgar. 1980. Recurrent hyperparathyroidism.. https://pubmed.ncbi.nlm.nih.gov/7452171/
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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.
Myf-3 is the human homologue of the murine Myo-D1 gene involved in muscle-cell differentiation. Using Southern blot analysis, we examined methylation of Myf-3 in histologically normal colonic mucosae, adenomas and carcinomas from a large series of patients with primary colorectal cancer. Hypermethylation of this gene in comparison with normal mucosa was observed in 88% of adenomas and in 99% of carcinomas. The pattern of Myf-3 methylation was similar in different areas of the same tumour, suggesting that methylation imbalances occur before the bulk of clonal-cell expansion. Significantly increased levels of Myf-3 methylation were observed in tumours which were more invasive, located in the proximal colon or from older patients. Patients whose tumours had extensive methylation showed a trend for shortened survival, though this was probably related to their being more invasive. Extensive methylation was significantly more frequent in tumours with microsatellite instability. Further work is required to determine whether the hypermethylation of Myf-3 observed in colorectal cancers is a specific alteration with functional significance or whether it reflects non-specific methylation imbalances occurring early during tumorigenesis.
Loss of serine or threonine phosphorylation sites from exon 3 of beta-catenin has been identified in approximately half of colorectal tumors which lack adenomatous polyposis coli (APC) mutations, but the overall contribution of beta-catenin mutations to sporadic colorectal tumorigenesis is unclear. We therefore used PCR to amplify and sequence exon 3 of beta-catenin from 202 sporadic colorectal tumors. Exon 3 beta-catenin mutations were identified in 6 of 48 small (< 1 cm) adenomas, 2 of 82 large (> or =1 cm) adenomas, and 1 of 72 invasive carcinomas. Eight of the nine mutations, including all of those in the small adenomas and the invasive cancer, involved loss of serine or threonine phosphorylation sites. The percentage of beta-catenin mutations in small adenomas (12.5%) was significantly greater than that in large adenomas (2.4%) and invasive cancers (1.4%; P = 0.05 and P = 0.02, respectively). We conclude that mutation of beta-catenin can be an early, perhaps initiating, event in colorectal tumorigenesis. Small adenomas with beta-catenin mutations do not appear to be as likely to progress to larger adenomas and invasive carcinomas as other adenomas, however, with the result that beta-catenin mutations are only rarely seen in invasive cancers. This suggests that APC and beta-catenin mutations are not functionally equivalent, and that the APC gene may have other tumor suppressor functions besides the degradation of beta-catenin.