HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity.
HMGA2 gene amplification and overexpression in human prolactinomas and the development of pituitary adenomas in HMGA2 transgenic mice showed that HMGA2 plays a crucial role in pituitary tumorigenesis. We have explored the pRB/E2F1 pathway to investigate the mechanism by which HMGA2 acts. Here we show that HMGA2 interacts with pRB and induces E2F1 activity in mouse pituitary adenomas by displacing HDAC1 from the pRB/E2F1 complex-a process that results in E2F1 acetylation. We found that loss of E2F1 function (obtained by mating HMGA2 and E2F1(-/-) mice) suppressed pituitary tumorigenesis in HMGA2 mice. Thus, HMGA2-mediated E2F1 activation is a crucial event in the onset of these tumors in transgenic mice and probably also in human prolactinomas.
Fedele
Monica
M
Istituto di Endocrinologia ed Oncologia Sperimentale del CNR and Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, 80131 Naples, Italy.
Visone
Rosa
R
De Martino
Ivana
I
Troncone
Giancarlo
G
Palmieri
Dario
D
Battista
Sabrina
S
Ciarmiello
Andrea
A
Pallante
Pierlorenzo
P
Arra
Claudio
C
Melillo
Rosa Marina
RM
Helin
Kristian
K
Croce
Carlo Maria
CM
Fusco
Alfredo
A
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004247:DNA / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D025743:HMGA2 Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010911:Pituitary Neoplasms / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020218:Response Elements; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction
D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D025743:HMGA2 Protein; D006657:Histones; D016160:Retinoblastoma Protein; D004247:DNA; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases