INDUCTION OF P21 AND P27 IN LIVER AFTER CCL4 INJURY

描述：四氯化碳（CCl4）诱导肝损伤，包括 许多病理过程。在对损伤的反应中，肝脏具有独特的 再生能力。调节肝再生的信号必须包括 当肝脏质量恢复时抑制细胞分裂的因子。细胞周期蛋白 激酶抑制剂（CKIs）p21和p27是细胞周期蛋白依赖性的细胞周期蛋白的有效抑制剂， 激酶，并且它们的过表达可以抑制细胞周期进程。博士 泰纳的初步数据表明，p21和p27都是差异表达的。 在CCl4处理后在肝脏中调节。这两个因素的表达是 首先定位于在CCl4代谢后死亡的肝细胞。在 随后的时间点，p21和p27在门脉周围特异性表达， 肝细胞已经复制以恢复肝脏质量。泰纳医生假设 P21和P27在G1早期的局部表达可能代表了一种新的免疫反应， 检查点，防止受损细胞复制，两个CKI 在以后的时间点调节肝脏生长的程度。p21和p27都有 据报道，在调节细胞凋亡中发挥作用， 这些CKI的局部诱导也将影响细胞死亡的机制。 在人类癌症中检测到p21和p27表达降低， 这些关键的细胞周期检查点蛋白可能会导致增加 肝损伤后易发生肝肿瘤。这些 将通过检查野生型中的再生和细胞死亡来检验假设 和CKI敲除小鼠。p21基因对多种 细胞外信号及其在中央周围肝细胞中的表达被诱导 在CCl4给药后的短时间内。查明责任因素 用于诱导p21基因表达以响应CCl4，将导致进一步的 关于肝毒素引发的细胞信号级联的见解。

DESCRIPTION: Carbon tetrachloride (CCl4) induces liver injury, which involves many pathological processes. In response to injury, the liver has the unique ability to regenerate. Signals that regulate liver regeneration must include factors that inhibit cell division when liver mass is restored. The cyclin kinase inhibitors (CKIs) p21 and p27 are potent inhibitors of cyclin dependent kinases, and their overexpression can inhibit cell cycle progression. Dr. Tyner's preliminary data indicate that both p21 and p27 are differentially regulated in the liver following CCl4 treatment. Expression of both factors is first localized to hepatocytes that will die following metabolism of CCl4. At later time points, p21 and p27 are expressed specifically in periportal hepatocytes that have replicated to restore liver mass. Dr. Tyner hypothesizes that localized expression of p21 and p27 during early G1 may represent a checkpoint that prevents damaged cells from replicating and that the two CKIs regulate the extent of liver growth at later time points. Both p21 and p27 have been reported to play roles in regulating apoptosis, and it is possible that localized induction of these CKIs will also influence mechanisms of cell death. Decreased expression of p21 and p27 has been detected in human cancers and lack of these critical cell cycle checkpoint proteins may lead to increased susceptibility to development of liver tumors following liver injury. These hypotheses will be tested by examining regeneration and cell death in wildtype and CKI knockout mice. The p21 gene is responsive to a wide array of extracellular signals and its expression is induced in pericentral hepatocytes a short time following administration of CCl4. Identifying factors responsible for inducing p21 gene expression in response to CCl4, will lead to further insight about cellular signaling cascades initiated by hepatotoxins.