Abstract
The High Mobility Group protein HMGA2 is a nuclear architectural factor that plays a critical role in a wide range of biological processes including regulation of gene expression, embryogenesis and neoplastic transformation. Several studies are trying to identify the mechanisms by which HMGA2 protein is involved in each of these activities, and only recently some new significant insights are emerging from the study of transgenic and knock-out mice. Overexpression of HMGA2 gene leads to the onset of prolactin and GH-hormone induced pituitary adenomas in mice, suggesting a critical role of this protein in pituitary tumorigenesis. This was also confirmed in the human pathology by the finding that HMGA2 amplification and/or overexpression is present in human prolactinomas. This review focuses on recent data that explain the mechanism by which HMGA2 induces the development of pituitary adenomas in mice. This mechanism entails the activation of the E2F1 protein by the HMGA2-mediated displacement of HDAC1 from pRB protein.
Highlights
Pituitary tumors constitute 10% of intracranial neoplasms, and are mostly benign with slow growth [1]
Prolactinomas account for the most common type of pituitary adenomas [1,2], while about one-third of pituitary adenomas are not associated with clinical hypersecretory syndromes, but with symptoms of an intracranial mass that leads to headaches, hypopituitarism or visual-field disturbances, which are classified as non-functioning pituitary adenomas (NFPAs)
Consistent with the onset of pituitary adenomas in highmobility group A2 (HMGA2)-transgenic mice, we have found the induction of HMGA2 expression in human prolactinomas in association with amplification and/or rearrangement of the gene [20], and, recently, we have shown that the majority of NFPAs express HMGA2, but, in these cases, it is not associated to over-representation of the HMGA2 region [21]
Summary
Pituitary tumors constitute 10% of intracranial neoplasms, and are mostly benign with slow growth [1]. By co-immunoprecipitating HMGA2 and pRB in pituitary adenomas developed by HMGA2 mice, we demonstrated the interaction between the two proteins occurring in the tumor. Luciferase and colony assays, we could establish that the overexpression of HMGA2 antagonizes the activity of pRB It blocks the pRB-dependent inhibition of both E2F1 target gene transcription and cell proliferation. By RT-PCR and ChIPs on tissues, expression of E2F-target genes, such as CDC1 and TK1, was shown to be enhanced, and E2F1 to be more acetylated in adenomas compared to normal glands (unpublished data) This suggests that E2F1 activity is a critical event in pituitary tumorigenesis of HMGA2 mice. Ent mechanisms are responsible for the pituitary alterations observed in the minority of these mice
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