Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA.
Cell Mol Life Sci. 2019 Jul;76(13):2525-2546. doi: 10.1007/s00018-019-03085-6. Epub 2019 Apr 3.
mTORC1 signaling is the prototypical pathway regulating protein synthesis and cell proliferation. mTORC1 is active in stem cells located at the base of intestinal crypts but silenced as transit-amplifying cells differentiate into enterocytes or secretory cells along the epithelium. After an insult or injury, self-limiting and controlled activation of mTORC1 is critical for the renewal and repair of intestinal epithelium. mTORC1 promotes epithelial cell renewal by driving cryptic stem cell division, and epithelial cell repair by supporting the dedifferentiation and proliferation of enterocytes or secretory cells. Under repeated insult or injury, mTORC1 becomes constitutively active, triggering an irreversible return to stemness, cell division, proliferation, and inflammation among dedifferentiated epithelial cells. Epithelium-derived cytokines promulgate inflammation within the lamina propria, which in turn releases inflammatory factors that act back on the epithelium where undamaged intestinal epithelial cells participate in the pervading state of inflammation and become susceptible to tumorigenesis.
mTORC1 信号通路是调节蛋白质合成和细胞增殖的典型途径。mTORC1 在位于肠隐窝底部的干细胞中活跃，但在过渡扩增细胞沿着上皮分化为肠细胞或分泌细胞时被沉默。在受到损伤或伤害后，mTORC1 的自我限制和受控激活对于肠道上皮的更新和修复至关重要。mTORC1 通过驱动隐窝干细胞分裂来促进肠上皮细胞更新，并通过支持肠细胞或分泌细胞的去分化和增殖来支持上皮细胞修复。在反复受到损伤或伤害后，mTORC1 持续激活，引发去分化上皮细胞不可逆地回到干细胞状态、分裂、增殖和炎症。上皮细胞衍生的细胞因子在固有层内引发炎症，反过来，炎症因子作用于上皮细胞，未受损的肠上皮细胞参与弥漫性炎症状态，并易发生肿瘤形成。
