STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration
STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration
复制标题
DOI：
10.1074/jbc.m202807200
复制
发表时间：
2002-08-09
影响因子：
4.8
通讯作者：
Taub, R
中科院分区：
文献类型：
--
作者：
Li, W;Liang, XP;Taub, R
STAT 3在肝再生期间以白细胞介素6（IL-6）依赖性方式被快速诱导，并且IL-6是正常肝再生所需的。我们想知道STAT 3是否也是肝再生所必需的，但在胚胎阶段STAT 3基因的破坏会导致死亡。因此，使用白蛋白启动子驱动的Cre-loxP重组系统在成年小鼠肝脏中产生STAT 3缺失，以研究STAT 3在肝再生中的作用。在部分肝切除术后，在Alb（+）STAT 3（fl/fl）肝脏中几乎没有STAT 3 RNA或蛋白诱导。在Alb（+）STAT 3（fl/fl）肝脏中也不存在STAT 3 DNA结合活性。与对照肝脏不同，STAT 1在STAT 3条件突变肝脏切除术后被激活。Alb+ STAT 3（fl/fl）肝脏切除术后40小时的肝细胞DNA合成减少至对照组的约三分之一。Alb（+）STAT 3（fl/fl）肝脏在即刻早期基因活化方面存在异常，其与IL-6-/-肝脏中观察到的异常在很大程度上相关但不相同。G1期细胞周期蛋白D1和E在Alb（+）STAT 3（fl/fl）肝组织中的表达水平较低，提示G1期向S期的转变异常。因此，STAT 3在肝再生过程中占肝细胞DNA合成反应的一部分，这不能通过诱导STAT 1来补偿。在Alb（+）STAT 3（fl/fl）肝脏中MAPK途径的正常激活强化了IL-6对肝细胞增殖的至少部分作用不由STAT 3介导的事实。这项研究提供了第一个体内证据，表明STAT 3在生理生长条件下促进细胞周期进程和细胞增殖。
STAT3 is rapidly induced during liver regeneration in an interleukin 6 (IL-6)-dependent fashion, and IL-6 is required for normal liver regeneration. We wanted to know whether STAT3 was also required for liver regeneration but disruption of the STAT3 gene during embryonic stages causes lethality. Therefore, an albumin promoter-driven Cre-loxP recombination system was used to create a STAT3 deletion in the adult mouse liver to study the role of STAT3 in liver regeneration. After partial hepatectomy, there was virtually no STAT3 RNA or protein induction in Alb(+) STAT3(fl/fl) livers. STAT3 DNA binding activity was also absent in Alb(+) STAT3(fl/fl) livers. Unlike in control livers, STAT1 was activated in STAT3 conditional-mutant livers posthepatectomy. Hepatocyte DNA synthesis at 40 h posthepatectomy in Alb+ STAT3(fl/fl) livers was reduced to approximately one-third of the control. Alb(+) STAT3(fl/fl) livers had abnormalities in immediate-early gene activation that largely correlated with but were not identical to those seen in IL-6-/-livers. G(1) phase cyclins including cyclins D1 and E had lower expression levels in Alb(+) STAT3(fl/fl) livers, indicating an abnormal G, to S phase transition. Therefore, STAT3 accounts for part of the DNA synthetic response of the hepatocytes during liver regeneration, which cannot be compensated for by induction of STAT1. Normal activation of the MAPK pathway in Alb(+) STAT3(fl/fl) livers reinforces the fact that at least part of the effect of IL-6 on hepatocyte proliferation is not mediated by STAT3. This study provides the first in vivo evidence that STAT3 promotes cell cycle progression and cell proliferation under physiological growth conditions.