GADD45α对大鼠部分肝切除后肝脏再生的调控作用

doi:10.16098/j.issn.0529-1356.2016.03.006

解剖学报 ›› 2016, Vol. ›› Issue (3): 323-329.doi: 10.16098/j.issn.0529-1356.2016.03.006

GADD45α对大鼠部分肝切除后肝脏再生的调控作用

杨献光^1,2 朱琳¹ 赵卫明^1,2 和春翠¹徐存拴^1,2*

1. 河南师范大学生命科学学院，河南新乡 453007; 2. 河南省一科技部共建细胞分化国家重点实验室培育基地，河南新乡 453007

收稿日期:2015-10-08 修回日期:2015-11-11 出版日期:2016-06-06 发布日期:2016-06-06
通讯作者: 徐存拴 E-mail:yangxg@htu.cn
基金资助:
国家自然科学基金项目

Regulatory role of GADD45α in rat liver regeneration

YANG Xian-guang ^1,2 ZHU Lin¹ ZHAO Wei-ming^1,2 HE Chun-cui¹XU Cun-shuan^1,2*

1. College of Life Science, He’nan Normal University, He’nan Xinxiang 453007, China; 2. State Key Laboratory Cultivation Base for Cell Differentiation Regulation, He’nan Normal University, He’nan Xinxiang 453007, China

Received:2015-10-08 Revised:2015-11-11 Online:2016-06-06 Published:2016-06-06
Contact: XU Cun-shuan E-mail:yangxg@htu.cn

摘要/Abstract

摘要：

目的探讨生长阻滞和DNA损伤诱导基因GADD45α在大鼠部分肝切除（PH）后肝再生中的作用及其调节机制。方法将114只大鼠随机分为19组，2/3肝切除9组，手术对照9组，正常对照1组，制作大鼠部分肝切除模型，然后用大鼠基因组芯片Rat Genome 230 2.0检测部分肝切除后再生肝的基因表达变化，采用实时定量PCR技术验证芯片检测结果。利用谱函数（Ep）分析基因表达变化预示的生理活动改变，进而通过Ingenuity Pathway Analysis（IPA）汇总GADD45α调控肝再生的信号通路并分析其可能的分子机制。结果 GADD45α在PH后2~6h、24h和36~72h均表达上调，GADD45α通过NF-κB、p38PRAK、p53、STAT3-p21、STAT3-Bcl-2、STAT3-cMyc等6条途径参与大鼠部分肝切除后的肝脏再生调控。谱函数分析发现，GADD45α调控的生理活动的变化情况基本与大鼠肝再生进程相符。
结论 GADD45α在大鼠肝再生中可能通过上述信号通路调控细胞增殖、细胞周期和细胞存活等生理活动，进而调节肝脏的再生。

Abstract:

Objective To explore the role and mechanism of growth arrest and DNA damage inducible gene GADD45α during liver regeneration (LR) after partial hepatectomy (PH) in rats. Methods 114 rats were randomly divided into 19 groups, 9 groups of 2/3 liver resection, 9 control groups and 1 normal control group. The rat PH model was established, rat Genome 230 2.0 array was used to detect the gene expression profiles of the regenerated liver after PH, and Real-time PCR technique was used to verify the reliability of the microarray. Expression profile function (Ep) was used to analyze the biological processes that regulated by GADD45α, and then Ingenuity Pathway Analysis (IPA) was used to summarize the signal pathway of GADD45α regulating LR and analyze its possible mechanism. Results The microarray results showed that Gadd45α was up-regulated at 2-6 hours, 24 hours and 36-72 hours after PH. The IPA results indicated that GADD45α regulated various physiological activities which were involved in rat LR via NF-κB, p38PRAK, p53, STAT3-p21, STAT3-Bcl-2 and STAT3-cMyc paths. The results revealed that changes of physiological activity were in line with the basic process of rat LR. Conclusion GADD45α may regulate cell proliferation, cell cycle and cell survival and other physiological activities during the regeneration of liver in rat through the above pathways.

杨献光朱琳赵卫明和春翠徐存拴*. GADD45α对大鼠部分肝切除后肝脏再生的调控作用[J]. 解剖学报, 2016, (3): 323-329.

YANG Xian-guang ZHU Lin ZHAO Wei-ming HE Chun-cui XU Cun-shuan*. Regulatory role of GADD45α in rat liver regeneration[J]. AAS, 2016, (3): 323-329.

参考文献

［1］Michalopoulos GK，DeFrances MC. Liver regeneration ［J］. Science，1997，276 (5309)：60-66.
［2］Best J, Manka P, Syn WK, et al. Role of liver progenitors in liver regeneration. ［J］. Hepatobiliary Surg Nutr, 2015, 4(1):48-58.
［3］Schaefer KN, Geil WM, Sweredoski MJ, et al. Oxidation of p53 through DNA charge transport involves a network of disulfides within the DNA-binding domain ［J］. Biochemistry, 2015, 54(3):932-941.
［4］Lin CR，Yang CH，Huang CE，et al. GADD45A protects against cell death in dorsal root ganglion neurons following peripheral nerve injury ［J］. J Neurosci Res，2011，89 (5)：689-699.
［5］Bockhorn M，Goralski M，Prokofiev D，et al. VEGF is important for early liver regeneration after partial hepatectomy ［J］. J Surg Res，2007，138 (2)：291-299. 
［6］van der Heide LP，Wijchers PJ，von Oerthel L，et al. FoxK2 is required for cellular proliferation and survival［J］. J Cell Physiol, 2015，230 (5)：1013-1023.
［7］Higgins GM, Anderson RM. Experimental pathology of the liver: restoration of the liver of the white rat following partial surgical removal ［J］. Arch Pathol, 1931, (12): 186-202.
［8］Wang GP，Xu CS. Reference gene selection for real-time RT-PCR in eight kinds of rat regenerating hEpatic cells ［J］. Mol Biotechnol，2010，46 (1)：49-57.
［9］Xu CS，Chen XG，Chang CF，et al. Transcriptome analysis of hepatocytes after partial hepatectomy in rats ［J］. Dev Genes Evol，2010，220 (910)：263-274.
［10］Mulrane L，RexhEpaj E，Smart V，et al. Creation of a digital slide and tissue microarray resource from a multi-institutional predictive toxicology study in the rat：an initial rEport from the PredTox group ［J］. Exp Toxicol Pathol，2008，60 (45)：235-245.
［11］Salomonis N，Hanspers K，Zambon AC，et al. GenMAPP 2：new features and resources for pathway analysis ［J］. BMC Bioinformatics，2007，24 (8)：217.
［12］Xu CSh，Jiang Y. Application of spectral function (Ep) in chip data analysis ［J］. Henan Science，2011，15 (3)：293-231. (in Chinese)
徐存拴，江云. 谱函数（Ep）在芯片数据分析中的应用研究［J］. 河南科学，2011，15 (3)：293-231.
［13］Kountouras J，Boura P，Lygidakis NJ. Liver regeneration after hepatectomy ［J］. Hepatogastroenterology，2001, 48 (38)：556-562.
［14］Jin J，Hong IH，Lewis K，et al. Cooperation of C/EBP family proteins and chromatin remodeling proteins is essential for termination of liver regeneration ［J］. Hepatology，2015， 61 (1):315-325.
［15］Xu CSh, Zhang JB. Research on the Functional Genomics of the Rat Regenerating Liver［M］. Beijing: Higher Education Press, 2009: 25-26.(in Chinese)
徐存拴，章静波. 大鼠肝再生的功能基因组学研究［M］. 北京:高等教育出版社，2009：25-26.
［16］Schmucker DL. Age-related changes in liver structure and function：implications for disease ［J］? Exp Gerontol，2005，40 (89)：650-659.
［17］Li Y，Bolderson E，Kumar R，et al. HSSB1 and hSSB2 form similar multiprotein complexes that participate in DNA damage response ［J］. J Biol Chem，2009，284 (35)：23525-23531. 
［18］Yan Y，Black CP，Cao PT，et al. Gamma-irradiation-induced DNA damage checkpoint activation involves feedback regulation between extracellular signal-regulated kinase 1/2 and BRCA1 ［J］. Cancer Res，2008，68 (13)：5113-5121.
［19］Zhan Q. Gadd45a，a p53-and BRCA1-regulated stress protein，in cellular response to DNA damage ［J］. Mutat Res，2005，569 (1-2)：133-143.
［20］Abell AN， Granger DA， Johnson GL. MEKK4 stimulation of p38 and JNK activity is negatively regulated by GSK3beta ［J］. J Biol Chem，2007，282 (42)：30476-30484.
［21］Conejo R，de Alvaro C，Benito M，et al. Insulin restores differentiation of Ras-transformed C2C12 myoblasts by inducing NF-kappaB through an AKT/P70S6K/p38-MAPK pathway ［J］. Oncogene，2002，21 (23)：3739-3753.
［22］Yoshizuka N, Chen RM, Xu Z, et al. EMBO J. A novel function of p38-regulated/activated kinase in endothelial cell migration and tumor angiogenesis ［J］. Mol Cell Biol, 2012, 32(3):606-618.
［23］Ye SY， Wu J， Zhang J，et al. Locally synthesized HSP27 in hepatocytes：Is it possibly a novel strategy against human liver ischemia/reperfusion injury ［J］? Med Hypotheses，2011，6 (2)：296-298. 
［24］Gurgis FM， Ziaziaris W， Munoz L. Mitogen-activated protein kinase-activated protein kinase 2 in neuroinflammation，heat shock protein 27 phosphorylation，and cell cycle： role and targeting ［J］. Mol Pharmacol，2014，85(2)：345-356.
［25］Feng LJ， Duan LJ， Zhang RG，et al. Comparative analysis of the role of JNK signaling pathway in cell proliferation and apoptosis of rat liver regeneration and cirrhosis ［J］. Acta Anatomica Sinica, 2012, 43 (3):352-358. （in Chinese）
冯利娟，段丽娟，张瑞刚，等. JNK 信号通路在大鼠肝再生及肝硬化的细胞增殖和凋亡中作用的比较［J］. 解剖学报，2014， 85 (2)：345-356.
［26］Briest F, Grabowski P. The p53 network as therapeutic target in gastroenteropancreatic neuroendocrine neoplasms ［J］. Cancer Treat Rev, 2015, 41(5):423-430.
［27］Yang F, Zhang W, Li D, et al. Gadd45a suppresses tumor angiogenesis via inhibition of the mTOR/STAT3 protein pathway ［J］. J Biol Chem, 2013, 288(9):6552-6560.
［28］Brazina J, Svadlenka J, Macurek L, et al. DNA damage-induced regulatory interplay between DAXX, p53, ATM kinase and Wip1 phosphatase ［J］. Cell Cycle, 2015, 14(3):375-387.
［29］Uddin N, Kim RK, Yoo KC, et al. Persistent activation of STAT3 by PIM2-driven positive feedback loop for epithelial-mesenchymal transition in breast cancer ［J］. Cancer Sci, 2015, 106(6):718-725.
［30］Barré B，Avril S，Coqueret O. Opposite regulation of myc and p21waf1 transcription by STAT3 proteins ［J］. J Biol Chem，2003, 278 (5)：2990-2996. 
［31］Valera A，Colomo L，Martínez A，et al. ALK-positive large B-cell lymphomas express a terminal B-cell differentiation program and activated STAT3 but lack MYC rearrangements ［J］. Mod Pathol，2013, 26 (10)：1329-1337.
［32］Pozo-Molina G, Ponciano-Gómez A, Rivera-González GC, et al. Arsenic-induced S phase cell cycle lengthening is associated with ROS generation, p53 signaling and CDC25A expression ［J］. Chem Biol Interact, 2015, 238(5):170-179.

GADD45α对大鼠部分肝切除后肝脏再生的调控作用

Regulatory role of GADD45α in rat liver regeneration

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