Department of Medicine, Stanford University , Stanford, California.
Department of Pathology, University of Pittsburgh , Pittsburgh, Pennsylvania.
Am J Physiol Gastrointest Liver Physiol. 2018 Jan 1;314(1):G1-G13. doi: 10.1152/ajpgi.00240.2017. Epub 2017 Sep 21.
Previously, we showed that receptor for activated C kinase 1 (Rack1) regulates growth of colon cells in vitro, partly by suppressing Src kinase activity at key cell cycle checkpoints, in apoptotic and cell survival pathways and at cell-cell adhesions. Here, we generated mouse models of Rack1 deficiency to assess Rack1's function in intestinal epithelia in vivo. Intestinal Rack1 deficiency resulted in proliferation of crypt cells, diminished differentiation of crypt cells into enterocyte, goblet, and enteroendocrine cell lineages, and expansion of Paneth cell populations. Following radiation injury, the morphology of Rack1-deleted small bowel was strikingly abnormal with development of large polypoid structures that contained many partly formed villi, numerous back-to-back elongated and regenerating crypts, and high-grade dysplasia in surface epithelia. These abnormalities were not observed in Rack1-expressing areas of intestine or in control mice. Following irradiation, apoptosis of enterocytes was strikingly reduced in Rack1-deleted epithelia. These novel findings reveal key functions for Rack1 in regulating growth of intestinal epithelia: suppressing crypt cell proliferation and regeneration, promoting differentiation and apoptosis, and repressing development of neoplasia. NEW & NOTEWORTHY Our findings reveal novel functions for receptor for activated C kinase 1 (Rack1) in regulating growth of intestinal epithelia: suppressing crypt cell proliferation and regeneration, promoting differentiation and apoptosis, and repressing development of neoplasia.
先前，我们表明激活 C 激酶 1（Rack1）受体在体外调节结肠细胞的生长，部分是通过抑制关键细胞周期检查点、细胞凋亡和细胞存活途径以及细胞间黏附中的Src 激酶活性来实现的。在这里，我们生成了 Rack1 缺陷的小鼠模型，以评估 Rack1 在体内肠上皮中的功能。肠上皮细胞中的 Rack1 缺乏导致隐窝细胞增殖，隐窝细胞向肠上皮细胞、杯状细胞和肠内分泌细胞谱系的分化减少，以及 Paneth 细胞群体的扩张。辐射损伤后，Rack1 缺失的小肠形态异常明显，形成大的息肉样结构，其中包含许多部分形成的绒毛、许多背靠背的拉长和再生的隐窝以及表面上皮的高级别异型增生。在 Rack1 表达区域的肠组织或对照小鼠中未观察到这些异常。在 Rack1 缺失的上皮细胞中，细胞凋亡显著减少。这些新发现揭示了 Rack1 在调节肠上皮细胞生长中的关键作用：抑制隐窝细胞增殖和再生，促进分化和凋亡，并抑制肿瘤的发展。
