Medical School, Ningbo University, Ningbo, 315211, China.
Mol Cell Biochem. 2013 Feb;374(1-2):173-80. doi: 10.1007/s11010-012-1517-2. Epub 2012 Nov 16.
Active mutations of Notch1 play pivotal roles during leukemogenesis, but the downstream targets and molecular mechanisms of activated Notch1 signaling have not yet been fully clarified. In this study, we detected the overexpression of the high mobility group A1 (HMGA1) and activation of Notch1 signaling in mouse thymic lymphomas. A direct regulation of Notch1 on HMGA1 transcription was demonstrated and two Notch1/RBPJ cobinding sites of T/CTCCCACA were found in HMGA1 promoter regions. It was the first time demonstrated that HMGA1 was the downstream target of Notch1 signaling. Moreover, knockdown of HMGA1 resulted in significantly impaired cell growth and decreased expressions of cyclin D and cyclin E in human T leukemia cells. The formation of complexes was also observed between HMGA1 and retinoblastoma (RB) protein indicating a mechanism of cell cycle regulation. These findings suggest that activated HMGA1 regulates cell proliferation through the Notch1 signaling pathway, which represents an important molecular pathway leading to leukemogenesis.
Notch1 的活性突变在白血病发生过程中发挥着关键作用，但激活的 Notch1 信号通路的下游靶标和分子机制尚未完全阐明。在这项研究中，我们检测到高迁移率族蛋白 A1（HMGA1）在小鼠胸腺淋巴瘤中的过度表达和 Notch1 信号的激活。证明了 Notch1 对 HMGA1 转录的直接调控，并在 HMGA1 启动子区域发现了两个 Notch1/RBPJ 结合位点 T/CTCCCACA。这是首次证明 HMGA1 是 Notch1 信号通路的下游靶标。此外，在人类 T 白血病细胞中敲低 HMGA1 会导致细胞生长明显受损，细胞周期蛋白 D 和 E 的表达降低。还观察到 HMGA1 与视网膜母细胞瘤（RB）蛋白之间形成复合物，表明存在细胞周期调控机制。这些发现表明，激活的 HMGA1 通过 Notch1 信号通路调节细胞增殖，这代表了导致白血病发生的重要分子途径。
