Interaction between HMGA1 and retinoblastoma protein is required for adipocyte differentiation.
It is generally accepted that the regulation of adipogenesis prevents obesity. However, the mechanisms controlling adipogenesis have not been completely defined. We have previously demonstrated that HMGA1 proteins play a critical role in adipogenesis. In fact, suppression of HMGA1 protein synthesis by antisense technology dramatically increased growth rate and impaired adipocyte differentiation in 3T3-L1 cells. Furthermore, we showed that HMGA1 strongly potentiates the capacity of the CCAAT/enhancer-binding protein beta (C/EBPbeta) transcriptional factor to transactivate the leptin promoter, an adipocytic-specific promoter. In this study we demonstrate that HMGA1 physically interacts with retinoblastoma protein (RB), which is also required in adipocyte differentiation. Moreover, we show that RB, C/EBPbeta, and HMGA1 proteins all cooperate in controlling both Id1 and leptin gene transcriptions, which are down- and up-regulated during adipocyte differentiation, respectively. We also demonstrate that HMGA1/RB interaction regulates CDC25A and CDC6 promoter activities, which are induced by E2F-1 protein during early adipocyte differentiation, by displacing HDAC1 from the RB-E2F1 complex. Furthermore, by using Hmga1(-/-) embryonic stem cells, which failed to undergo adipocyte differentiation, we show the crucial role of HMGA1 proteins in adipocyte differentiation due to its pivotal involvement in the formation of the RB-C/EBPbeta complex. Altogether these data demonstrate a key role of the interaction between HMGA1 and RB in adipocyte differentiation.
Esposito
Francesco
F
Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli Federico II, Via S. Pansini 5, 80131 Naples, Italy.
Pierantoni
Giovanna Maria
GM
Battista
Sabrina
S
Melillo
Rosa Marina
RM
Scala
Stefania
S
Chieffi
Paolo
P
Fedele
Monica
M
Fusco
Alfredo
A
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology*; D050687:E2F1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D024003:HMGA Proteins / Q000235:genetics / Q000378:metabolism*; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology; D020687:cdc25 Phosphatases / Q000096:biosynthesis / Q000235:genetics
D022782:CCAAT-Enhancer-Binding Protein-beta; C502132:CDC6 protein, mouse; D018797:Cell Cycle Proteins; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D024003:HMGA Proteins; D020738:Leptin; D009687:Nuclear Proteins; D016160:Retinoblastoma Protein; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases