Esposito Francesco, Pierantoni Giovanna Maria, Battista Sabrina, Melillo Rosa Marina, Scala Stefania, Chieffi Paolo, Fedele Monica, Fusco Alfredo
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.
J Biol Chem. 2009 Sep 18;284(38):25993-6004. doi: 10.1074/jbc.M109.034280. Epub 2009 Jul 26.
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.
一般认为，脂肪生成的调控可预防肥胖。然而，控制脂肪生成的机制尚未完全明确。我们之前已经证明，HMGA1蛋白在脂肪生成中起关键作用。事实上，通过反义技术抑制HMGA1蛋白合成可显著提高3T3-L1细胞的生长速率并损害脂肪细胞分化。此外，我们还表明，HMGA1强烈增强CCAAT/增强子结合蛋白β（C/EBPβ）转录因子激活瘦素启动子（一种脂肪细胞特异性启动子）的能力。在本研究中，我们证明HMGA1与视网膜母细胞瘤蛋白（RB）发生物理相互作用，而RB在脂肪细胞分化中也是必需的。此外，我们表明RB、C/EBPβ和HMGA1蛋白均协同控制Id1和瘦素基因转录，它们在脂肪细胞分化过程中分别下调和上调。我们还证明，HMGA1/RB相互作用通过将HDAC1从RB-E2F1复合物中置换出来，调节早期脂肪细胞分化过程中由E2F-1蛋白诱导的CDC25A和CDC6启动子活性。此外，通过使用未能进行脂肪细胞分化的Hmga1(-/-)胚胎干细胞，我们证明了HMGA1蛋白在脂肪细胞分化中的关键作用，因为它关键参与了RB-C/EBPβ复合物的形成。总之，这些数据证明了HMGA1与RB之间的相互作用在脂肪细胞分化中的关键作用。
