Tessari Michela A, Gostissa Monica, Altamura Sandro, Sgarra Riccardo, Rustighi Alessandra, Salvagno Clio, Caretti Giuseppina, Imbriano Carol, Mantovani Roberto, Del Sal Giannino, Giancotti Vincenzo, Manfioletti Guidalberto
Dipartimento di Biochimica, Biofisica e Chimica delle Macromolecole. Centre of Excellence in Biocristallography, University of Trieste, via L. Giorgieri 1, 34127 Trieste, Italy.
Mol Cell Biol. 2003 Dec;23(24):9104-16. doi: 10.1128/MCB.23.24.9104-9116.2003.
The HMGA2 protein belongs to the HMGA family of architectural transcription factors, which play an important role in chromatin organization. HMGA proteins are overexpressed in several experimental and human tumors and have been implicated in the process of neoplastic transformation. Hmga2 knockout results in the pygmy phenotype in mice and in a decreased growth rate of embryonic fibroblasts, thus indicating a role for HMGA2 in cell proliferation. Here we show that HMGA2 associates with the E1A-regulated transcriptional repressor p120(E4F), interfering with p120(E4F) binding to the cyclin A promoter. Ectopic expression of HMGA2 results in the activation of the cyclin A promoter and induction of the endogenous cyclin A gene. In addition, chromatin immunoprecipitation experiments show that HMGA2 associates with the cyclin A promoter only when the gene is transcriptionally activated. These data identify the cyclin A gene as a cellular target for HMGA2 and, for the first time, suggest a mechanism for HMGA2-dependent cell cycle regulation.
HMGA2蛋白属于构建转录因子的HMGA家族，该家族在染色质组织中发挥重要作用。HMGA蛋白在多种实验性肿瘤和人类肿瘤中过度表达，并与肿瘤转化过程有关。Hmga2基因敲除导致小鼠出现侏儒表型，胚胎成纤维细胞生长速率降低，从而表明HMGA2在细胞增殖中发挥作用。在此我们表明，HMGA2与E1A调节的转录抑制因子p120（E4F）相关联，干扰p120（E4F）与细胞周期蛋白A启动子的结合。HMGA2的异位表达导致细胞周期蛋白A启动子的激活以及内源性细胞周期蛋白A基因的诱导。此外，染色质免疫沉淀实验表明，仅当细胞周期蛋白A基因转录激活时，HMGA2才与该基因的启动子相关联。这些数据确定细胞周期蛋白A基因为HMGA2的一个细胞靶点，并首次提出了HMGA2依赖的细胞周期调控机制。
