This Article Full Text Full Text (PDF) All Versions of this Article: 0008-5472.CAN-08-4133v1 69/5/1844    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by De Martino, I. Articles by Fusco, A. Search for Related Content PubMed PubMed Citation Articles by De Martino, I. Articles by Fusco, A.

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

¹ Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia di Napoli, ² Dipartimento di Scienze Neurologiche, Divisione di Neurochirurgia, and ³ Dipartimento di Endocrinologia, Universita' degli Studi di Napoli Federico II, ⁴ Istituto Nazionale dei Tumori, Fondazione Pascale, and ⁵ Naples Oncogenomic Center-CEINGE, Biotecnologie Avanzate-Napoli and SEMM-European School of Molecular Medicine-Naples Site, Naples, Italy; and ⁶ Institut National de la Sante et de la Recherche Medicale, Lyon, France

Requests for reprints: Monica Fedele, Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, via Pansini 5, 80131 Naples, Italy. Phone: 39-081-7463054; Fax: 39-081-7463749; E-mail: mfedele{at}unina.it or monica.fedele{at}cnr.it or Alfredo Fusco, Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, via Pansini 5, 80131 Naples, Italy. Phone: 39-081-7463602; Fax: 39-081-2296674; E-mail: afusco{at}napoli.com or alfusco{at}unina.it.

Key Words: HMGA • cyclin B2 • pituitary adenoma • transgenic mice

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. [Cancer Res 2009;69(5):1844–50]