Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
School of Life Sciences, University of Nevada Las Vegas, Las Vegas, NV, 89154, USA.
Stem Cell Rev Rep. 2015 Dec;11(6):813-25. doi: 10.1007/s12015-015-9617-5.
The Drosophila adult midgut contains intestinal stem cells that support homeostasis and repair. We show here that the leucine zipper protein Bunched and the adaptor protein Madm are novel regulators of intestinal stem cells. MARCM mutant clonal analysis and cell type specific RNAi revealed that Bunched and Madm were required within intestinal stem cells for proliferation. Transgenic expression of a tagged Bunched showed a cytoplasmic localization in midgut precursors, and the addition of a nuclear localization signal to Bunched reduced its function to cooperate with Madm to increase intestinal stem cell proliferation. Furthermore, the elevated cell growth and 4EBP phosphorylation phenotypes induced by loss of Tuberous Sclerosis Complex or overexpression of Rheb were suppressed by the loss of Bunched or Madm. Therefore, while the mammalian homolog of Bunched, TSC-22, is able to regulate transcription and suppress cancer cell proliferation, our data suggest the model that Bunched and Madm functionally interact with the TOR pathway in the cytoplasm to regulate the growth and subsequent division of intestinal stem cells.
果蝇成体肠道含有支持体内平衡和修复的肠道干细胞。我们在这里表明，亮氨酸拉链蛋白 Bunch 和衔接蛋白 Madm 是肠道干细胞的新型调节因子。MARCM 突变克隆分析和细胞类型特异性 RNAi 显示，Bunch 和 Madm 在肠道干细胞内增殖是必需的。标记的 Bunch 转基因表达显示在肠道前体细胞中存在细胞质定位，并且将核定位信号添加到 Bunch 中降低了其与 Madm 合作增加肠道干细胞增殖的功能。此外，由结节性硬化复合物缺失或 Rheb 过表达引起的细胞生长和 4EBP 磷酸化表型被 Bunched 或 Madm 的缺失所抑制。因此，虽然 Bunch 的哺乳动物同源物 TSC-22 能够调节转录并抑制癌细胞增殖，但我们的数据表明，Bunch 和 Madm 在细胞质中与 TOR 途径相互作用，以调节肠道干细胞的生长和随后的分裂。
