HMGA Proteins Up-regulate CCNB2 Gene in Mouse and Human Pituitary Adenomas

Abstract

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.

Downregulation of miR-410 targeting the cyclin B1 gene plays a role in pituitary gonadotroph tumors

“…Indeed, we previously demonstrated that another member of cyclin B family, CCNB2, was increased in pituitary adenomas with respect to normal pituitary 14 and that its expression was mainly regulated by the HMGA1 and HMGA2 proteins whose overexpression represents an important event in pituitary adenomas as also demonstrated by the development of GH/ PRL adenomas in transgenic mice overexpressing these genes. 15 Moreover, cyclin B1 regulates the G2/M transition in the cell cycle, and its appropriate regulation is essential for mitosis initiation.…”

“…In fact, HMGA proteins are overexpressed in most of the human pituitary adenomas. 13,14 Moreover transgenic mice overexpressing these genes developed mixed PRL/GH pituitary adenomas 15 and increased E2F1 activity or expression can lead to pituitary tumorigenesis. 16,17 Furthermore, Leone et.…”

Fusion Oncogenes in Salivary Gland Tumors: Molecular and Clinical Consequences

“…Genomic rearrangements of the 3 0 -part of HMGA2 due to fusions with the 3'-parts of NFIB, WIF1 or FHIT (Fig. 1) result in activation of the expression of HMGA2 and its target genes, including the cell cycle regulators CCNA1 and CCNB2 [58,59]. The molecular mechanism leading to activation of HMGA2 is still partly unknown.…”

CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1

“…RNA extraction, cDNA preparation, semiquantitative, and qRT-PCR Total RNA isolation, RT-PCR, and qRT-PCR from human tissues or from cells were performed as described earlier (De Martino et al, 2009 …”