HMGA proteins up-regulate CCNB2 gene in mouse and human pituitary adenomas.
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.
De Martino
Ivana
I
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, Italy.
Visone
Rosa
R
Wierinckx
Anne
A
Palmieri
Dario
D
Ferraro
Angelo
A
Cappabianca
Paolo
P
Chiappetta
Gennaro
G
Forzati
Floriana
F
Lombardi
Gaetano
G
Colao
Annamaria
A
Trouillas
Jacqueline
J
Fedele
Monica
M
Fusco
Alfredo
A
D000236:Adenoma / Q000235:genetics*; D000818:Animals; D019926:Cyclin B / Q000235:genetics*; D056765:Cyclin B2; D015972:Gene Expression Regulation, Neoplastic; D025741:HMGA1a Protein / Q000502:physiology*; D025743:HMGA2 Protein / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D010911:Pituitary Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051381:Rats; D015854:Up-Regulation
C503758:CCNB2 protein, human; C503759:Ccnb2 protein, mouse; D019926:Cyclin B; D056765:Cyclin B2; D025743:HMGA2 Protein; D025741:HMGA1a Protein