新功能、新界面、新体验,扫描即可下载生物谷APP!
首页 » Hepatology:发现Cdc42在肝脏再生过程中调控的新机制

Hepatology:发现Cdc42在肝脏再生过程中调控的新机制

来源:上海生命科学研究院 2009-01-20 09:12

近期,国际著名期刊《肝脏病学》(Hepatology.  2009  Jan;49(1):240-9)发表了上海生科院生化与细胞所陈正军组关于Cdc42影响肝脏再生过程的最新研究成果。

Cdc42蛋白是Rho  GTP酶家族中的一员,它是细胞内一种十分重要的蛋白质,担负着调节细胞骨架结构、细胞生长、细胞极性以及细胞内运输等多种功能。然而目前对Cdc42在哺乳动物肝脏中的作用仍然知之甚少。陈正军组的袁海心等利用肝脏2/3切除手术模型,研究了Cdc42基因敲除对肝损伤后再生过程的影响。Cdc42在对照小鼠肝脏部分切除后的3小时-24小时显著激活,证明其参与了肝脏再生过程。而在缺失Cdc42蛋白后,小鼠肝脏的再生能力明显下降,主要表现为肝重回复的延迟。对分子机理的研究进一步显示在肝再生过程中,缺失Cdc42的小鼠肝脏DNA合成水平显著下降,并且细胞周期因子的表达以及数条与Cdc42相关的重要生长信号通路(如ERK、JNK和p70S6K)的激活发生延迟。此外,Cdc42的缺失还影响了脂肪转运蛋白ABCA1的细胞内定位,造成肝再生过程中脂肪代谢的异常。该项研究揭示了Cdc42在肝脏再生过程中担负的重要功能,Cdc42在肝细胞中的功能调控是一个复杂的网络,可能涉及到多种不同的细胞内功能和复杂的信号分子通路,对这些问题的阐释对于我们更深入理解肝脏的生理功能和发病机理具有重要的指导意义。

本课题在研究过程中得到丹麦哥本哈根大学Cord  Brakebusch教授和美国哈佛大学医学院的吴训伟博士的大力支持和帮助。(生物谷Bioon.com)

生物谷推荐原始出处:

Hepatology Volume 49 Issue 1, Pages 240 - 249

Hepatocyte-specific deletion of Cdc42 results in delayed liver regeneration after partial hepatectomy in mice

Haixin Yuan 1 2, Hong Zhang 1 2, Xunwei Wu 3, Zhe Zhang 1, Dan Du 1 2, Wenchao Zhou 1 2, Shuhua Zhou 1 2, Cord Brakebusch 4, Zhengjun Chen 1 *

1 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
2 Graduate School of the Chinese Academy of Sciences, Shanghai, China
3 Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
4 Biomedical Institute, BRIC, University of Copenhagen, Copenhagen, Denmark

Funded by:
 National Natural Science Foundation of China; Grant Number: 30730055, 30623002
 National Key Scientific Program of China; Grant Number: 2007CB914504
 National High Technology Research and Development Program of China; Grant Number: 2006AA02A308
 Chinese Academy of Sciences; Grant Number: KSCX2-YW-R-108

ABSTRACT

Cdc42, a member of the Rho guanosine triphosphatase (GTPase) family, plays important roles in the regulation of the cytoskeleton, cell proliferation, cell polarity, and cellular transport, but little is known about its specific function in mammalian liver. We investigated the function of Cdc42 in regulating liver regeneration. Using a mouse model with liver-specific knockout of Cdc42 (Cdc42LK), we studied liver regeneration after partial hepatectomy. Histological analysis, immunostaining, and western blot analysis were performed to characterize Cdc42LK livers and to explore the role of Cdc42 in liver regeneration. In control mouse livers, Cdc42 became activated between 3 and 24 hours after partial hepatectomy. Loss of Cdc42 led to a significant delay of liver recovery after partial hepatectomy, which was associated with reduced and delayed DNA synthesis indicated by 5-bromo-2-deoxyuridine staining. Consistent with this, expression of cyclins D1, A, and E was markedly delayed or reduced in Cdc42LK livers during regeneration. As a potential effector of Cdc42, Rac1 activation was dramatically attenuated in Cdc42LK livers after partial hepatectomy, suggesting it is regulated in a Cdc42-dependent manner. Activation of certain proliferative signaling pathways, such as extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p70S6 kinase pathways, was delayed in Cdc42LK livers. In addition, dilated bile canaliculi and excessive lipid accumulation were observed in mutant livers during liver regeneration, which may result from impaired cytoskeletal organization and intracellular trafficking in hepatocytes. Conclusion: Our results revealed important roles of Cdc42 in the regulation of proliferative signaling during liver regeneration. (HEPATOLOGY 2009:49:240-249.)

温馨提示:87%用户都在生物谷APP上阅读,扫描立刻下载! 天天精彩!


相关标签

最新会议 培训班 期刊库