Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198-5805, USA.
Mol Cell Biol. 2010 Sep;30(17):4149-58. doi: 10.1128/MCB.00224-10. Epub 2010 Jun 21.
Pre-B-cell expansion is driven by signals from the interleukin-7 receptor and the pre-B-cell receptor and is dependent on cyclin D3 and c-Myc. We have shown previously that interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to suppress pre-B-cell proliferation. However, the molecular mechanisms through which Ikaros and Aiolos exert their growth inhibitory effect remain to be determined. Here, we provide evidence that Aiolos and Ikaros bind to the c-Myc promoter in vivo and directly suppress c-Myc expression in pre-B cells. We further show that downregulation of c-Myc is critical for the growth-inhibitory effect of Ikaros and Aiolos. Ikaros and Aiolos also induce expression of p27 and downregulate cyclin D3 in pre-B cells, and the growth-inhibitory effect of Ikaros and Aiolos is compromised in the absence of p27. A time course analysis further reveals that downregulation of c-Myc by Ikaros and Aiolos precedes p27 induction and cyclin D3 downregulation. Moreover, downregulation of c-Myc by Ikaros and Aiolos is necessary for the induction of p27 and downregulation of cyclin D3. Collectively, our studies identify a pre-B-cell receptor signaling induced inhibitory network, orchestrated by Ikaros and Aiolos, which functions to terminate pre-B-cell expansion.
前 B 细胞的扩增是由白细胞介素 7 受体和前 B 细胞受体的信号驱动的，并且依赖于细胞周期蛋白 D3 和 c-Myc。我们之前已经表明，干扰素调节因子 4 和 8 诱导 Ikaros 和 Aiolos 的表达，以抑制前 B 细胞的增殖。然而，Ikaros 和 Aiolos 发挥其生长抑制作用的分子机制仍有待确定。在这里，我们提供的证据表明，Aiolos 和 Ikaros 在体内与 c-Myc 启动子结合，并直接抑制前 B 细胞中的 c-Myc 表达。我们进一步表明，下调 c-Myc 对于 Ikaros 和 Aiolos 的生长抑制作用至关重要。Ikaros 和 Aiolos 还在前 B 细胞中诱导 p27 的表达并下调细胞周期蛋白 D3 的表达，而在缺乏 p27 的情况下，Ikaros 和 Aiolos 的生长抑制作用受到损害。时间过程分析进一步表明，Ikaros 和 Aiolos 下调 c-Myc 先于 p27 诱导和细胞周期蛋白 D3 下调。此外，Ikaros 和 Aiolos 下调 c-Myc 对于 p27 诱导和细胞周期蛋白 D3 下调是必需的。总之，我们的研究确定了一个由 Ikaros 和 Aiolos 协调的前 B 细胞受体信号诱导的抑制网络，该网络的功能是终止前 B 细胞的扩增。
