生长停滞和DNA损伤诱导蛋白45α在肝再生及肝病中的研究进展

doi:10.16098/j.issn.0529-1356.2018.02.022

摘要/Abstract

摘要：

生长停滞和DNA损伤诱导蛋白45α（GADD45α）是一种应激诱导蛋白，它可诱导Gadd45α基因的表达。GADD45α在再生肝及肝硬化、肝癌、肝衰竭等肝病中表达显著上调，与多种肝病发生发展及预后密切相关。GADD45α蛋白通过与其他蛋白相互作用，在调控细胞周期、维持基因组稳定、诱导细胞凋亡等方面发挥重要作用。以下我们综述了GADD45α与肝再生关系的研究进展,为进一步了解肝再生与肝脏疾病的发生机制以及治疗和预防肝病奠定基础。

关键词: 肝再生, 生长停滞和DNA损伤诱导蛋白45α, DNA损伤修复, 细胞增殖

Abstract:

The growth arrest and DNA damage inducible 45 alpha (GADD45α) is a stress-inducible protein. Variety of stress can induce the expression of growth arrest and DNA damage inducible 45alpha(Gadd45α) gene. Gadd45α has been found to be abundantly expressed in various liver diseases, and be closely related to the development and prognosis of liver cancer, liver fibrosis and fatty liver. GADD45α protein plays an important role in regulating cell cycle, maintaining genome stability, and inducing apoptosis by interacting with other proteins. This review summarizes the progress of liver regeneration and GADD45α, and could lay a foundation for further understanding of the mechanism of liver regeneration and liver diseases, and for the treatment and prevention of liver diseases.

Key words: Liver regeneration, Growth arrest and DNA damage inducible 45α, Repair of DNA damage, Cell proliferation

杨献光李帅洪和春翠夏聪朱琳赵卫明徐存拴. 生长停滞和DNA损伤诱导蛋白45α在肝再生及肝病中的研究进展[J]. 解剖学报, 2018, 49(2): 268-272.

YANG Xian-guang LI Shuai-hong HE Chun-cui XIA Cong ZHU Lin ZHAO Wei-ming XU Cun-shuan. Research progress of growth arrest and DNA damage inducible 45α in liver regeneration and liver diseases[J]. Acta Anatomica Sinica, 2018, 49(2): 268-272.

参考文献

［1］Juza RM, Pauli EM. Clinical and surgical anatomy of the liver: a review for clinicians ［J］. Clin Anat, 2014, 27(5): 764-769.

［2］Frenzel C,Teschke R. Herbal Hepatotoxicity: clinical characteristics and listing compilation ［J］. Inte J Mole Sciences, 2016, 17(5): E588.

［3］Klimczak A, Kozlowska U. Mesenchymal stromal cells and tissue-specific progenitor cells: their role in tissue homeostasis ［J］. Stem Cells Int, 2016, 2016: 4285215.

［4］Wang FS, Fan JG, Zhang Z, et al. The global burden of liver disease: the major impact of China ［J］. Hepatology, 2014, 60(6): 2099-2108.

［5］Jonscher KR, Alfonso-Garcia A, Suhalim JL, et al. Spaceflight Activates Lipotoxic Pathways in Mouse Liver ［J］. PLoS One, 2016, 11(4): E0152877.

［6］Wang P, Petrella F, Nicosia L, et al. Molecular imaging of stem cell transplantation for liver diseases: monitoring, clinical translation, and theranostics ［J］. Stem cells Int, 2016, 2016: 4058656.

［7］Russo FP, Ferrarese A, Zanetto A. Recent advances in understanding and managing liver transplantation ［J］. F1000Research, 2016, 5(F1000 Faculty Rev): 2895.

［8］Tessitore A, Cicciarelli G, Del Vecchio F, et al. MicroRNA expression analysis in high fat diet-induced NAFLD-NASH-HCC progression: study on C57BL/6J mice ［J］. BMC Cancer, 2016, 16(1): 3

［9］Chauhan A, Legewie S, Westermark PO, et al. A mesoscale model of G1/S phase transition in liver regeneration ［J］. J Theor Biol, 2008, 252(3): 465-473.

［10］Espanol-Suner R, Carpentier R, Van Hul N, et al. Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice ［J］. Gastroenterology, 2012, 143(6): 1564-1575.

［11］Mao SA, Glorioso JM, Nyberg SL. Liver regeneration ［J］. Transl Res, 2014, 163(4): 352-362.

［12］Xu CS, Zhao WM, Hao YP, et al. Comparative analysis of gene expression profiles of acute hepatic failure and that of liver regeneration in rat ［J］. Gene, 2013, 528(2): 59-66.

［13］Fitz Gerald MJ, Webber EM, Donovan JR. Rapid DNA binding by nuclear factor kappa B in hepatocytes at the start of liver regeneration ［J］. Cell Growth Differ, 1995, 6(4):417-427.

［14］Taub R. Liver regeneration: from myth to mechanism［J］. Nat Revi Mole Cell Biol, 2004, 5(10):836-847.

［15］Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice ［J］. Science, 1996, 274(5291):1379-1383.

［16］Hayashi H, Nagaki M, Imose M, et al. Normal liver regeneration and liver cell apoptosis after partial hepatectomy in tumor necrosis factor-alpha-deficient mice［J］.Liver Int, 2005, 25(1):162-170.

［17］Johnen H，González-Silva L，Carramolino L，et al．Gadd45g is essential for primary sex determination，male fertility and testis development［J］.PLoS One, 2013, 8(3): e58751.

［18］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.

［19］Vairapandi M, Balliet AG, Hoffman B, et al. GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress ［J］. J Cell Physiol, 2002, 192(3): 327-338.

［20] Bulavin DV, Kovalsky O, Hollander MC, et al. Loss of oncogenic H-ras-induced cell cycle arrest and p38 mitogen-activated protein kinase activation by disruption of GADD45α［J］. Mol Cell Biol, 2003, 23(11): 3859-3871.

［21］Zerbini LF, Wang Y, Czibere A, et al. NF-kappa B-mediated repression of growth arrest-and DNA-damage-inducible proteins 45alpha and gamma is essential for cancer cell survival ［J］. PNAS USA, 2004, 101(37): 13618-13623.

［22］Gupta SK, Gupta M, Hoffman B, et al. Hematopoietic cells from GADD45α-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation ［J］. Oncogene, 2006, 25(40): 5537-5546.

［23］Yang Z, Song L, Huang C. Gadd45 proteins as critical signal transducers linking NF-kappaB to MAPK cascades ［J］. Curr Cancer Drug Targets, 2009, 9(8): 915-930.

［24］Zhang D, Zhang W, Li D, et al. GADD45αinhibits autophagy by regulating the interaction between BECN1 and PIK3C3 ［J］. Autophagy, 2015, 11(12): 2247-2258.

［25］Wang XW, Zhan Q, Coursen JD, et al. GADD45 induction of a G2/M cell cycle checkpoint［J］. PNAS USA, 1999, 96(7):3706-3711.

［26］Jin S, Antinore MJ, Lung FD, et al. The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression［J］. J Biol Chem, 2000, 275(22):16602-16608.［27］Ramachandran K, Gopisetty G, Gordian E, et al. Methylation-mediated repression of GADD45α in prostate cancer and its role as a potential therapeutic target ［J］. Cancer Res, 2009, 69(4): 1527-1535.

［28］Srivastava AK, Bhatnagar P, Singh M, et al. Synthesis of PLGA nanoparticles of tea polyphenols and their strong in vivo protective effect against chemically induced DNA damage ［J］. Int J Nanomedicine, 2013, 8: 1451-1462.

［29］Chen Y, Ma X, Zhang M, et al. GADD45α regulates hematopoietic stem cell stress responses in mice ［J］. Blood, 2014, 123(6): 851-862.

［30］Zhang W, Hoffman B, Liebermann DA. Ectopic expression of MyD118/Gadd45/CR6 (Gadd45beta/alpha/gamma) sensitizes neoplastic cells to genotoxic stress-induced apoptosis ［J］. Int J Oncol, 2001, 18(4): 749-757.

［31］Wingert S, Thalheimer FB, Haetscher N, et al. DNA-damage response gene GADD45α induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival ［J］. Stem Cells, 2016, 34(3): 699-710.

［32］Zhan Q, Chen IT, Antinore MJ, et al. Tumor suppressor p53 can participate in transcriptional induction of the GADD45 promoter in the absence of direct DNA binding. ［J］. Mol Cell Biol, 1998, 18 (5):2768-2778.

［33］Fan W, Jin S, Tong T, et al. BRCA1 regulates GADD45 through its interactions with the OCT-1 and CAAT motifs ［J］. Biol Chem,2002,277 (10): 8061-8067.

［34］Yang XG, Zhu L, Zhao WM, et al. Regulatory role of GADD45α in rat liver regeneration［J］.Acta Anatomica Sinica,2016,47(3):323-329.(in Chinese)

杨献光,朱琳,赵卫明,等.GADD45α对大鼠部分肝切除后肝脏再生的调控作用［J］. 解剖学报,2016,47(3):323-329.

［35］Hong L, Sun QF, Xu TY, et al. New role and molecular mechanism of GADD45α in hepatic fibrosis ［J］. World J Gastroenterol, 2016, 22(9): 2779-2788.

［36］Kadar B, Gombos K, Szele E, et al. Effects of isoflurane on NF kappa B p65, GADD45α and JNK1 expression in the vital organs of CBA/CA mice ［J］. In Vivo, 2011, 25(2): 241-244.

［37］Wang J, Che B, Zhang LW, et al. Comparative genotoxicity of silver nanoparticles in human liver HepG2 and lung epithelial A549 cells ［J］. J Appli Toxicol JAT, 2017, 37(4): 495-501.

［38］Chen L, Tian H, Li M, et al. Derivate isocorydine inhibits cell proliferation in hepatocellular carcinoma cell lines by inducing G2/M cell cycle arrest and apoptosis ［J］. Tumour Biol, 2016, 37(5): 5951-5961.

［39］Notas G, Alexaki VI, Kampa M, et al. APRIL binding to BCMA activates a JNK2-FOXO3-GADD45 pathway and induces a G2/M cell growth arrest in liver cells ［J］. J Immunol, 2012, 189(10): 4748-4758.

［40］Gramantieri L, Chieco P, Giovannini C, et al. GADD45-alpha expression in cirrhosis and hepatocellular carcinoma: relationship with DNA repair and proliferation ［J］. Hum Pathol, 2005, 36(11): 1154-1162.

［41］Cheng D, Zhao L, Zhang L, et al. p53 controls hepatitis C virus non-structural protein 5A-mediated down regulation of GADD45alpha expression via the NF-kappa B and PI3K-Akt pathways ［J］. J Gen Virol, 2013, 94(Pt 2): 326-335.

[1]	赵卫明李晓余国营王改平常翠芳 . 丝氨酸肽酶抑制因子Kazal型1对肝癌细胞增殖的影响及其机制 [J]. 解剖学报, 2023, 54(6): 695-702.
[2]	薛奇杰常翠芳王子慧臧夏炎林凯琳张春博韩璐叶丙雨徐存拴 . 大鼠肝再生的肝细胞周期启动及终止中骨髓瘤基因mRNA与其他非编码RNA的表达变化与作用[J]. 解剖学报, 2023, 54(4): 414-419.
[3]	林凯琳杨献光王子慧臧夏炎薛奇杰韩璐张春博赵志虎徐存拴. 大鼠肝再生的肝细胞凋亡中Kruppel样因子4 mRNA、微小RNA-881-3p、环状RNA_20298和环状RNA_14826的表达变化与作用[J]. 解剖学报, 2023, 54(4): 420-424.
[4]	王子慧郭建林臧夏炎薛奇杰林凯琳张春博韩璐林俊堂徐存拴 . 大鼠肝再生的肝细胞干性变化中性别决定区转录因子2 mRNA和其他非编码RNA的表达变化与作用[J]. 解剖学报, 2023, 54(2): 202-207.
[5]	张春博王改平王子慧臧夏炎薛奇杰林凯琳韩璐王棋文徐存拴. 大鼠肝再生的肝脏炎症反应中骨髓瘤基因mRNA、微小RNA-540-3p、环状RNA_04996的表达变化与作用[J]. 解剖学报, 2023, 54(1): 70-74.
[6]	王澍尹璐刘宏斌徐加志赵吉波潘云志孙玉荣. 咪喹莫特下调STAT3/核因子κB信号通路抑制脑胶质细胞瘤U87细胞的增殖[J]. 解剖学报, 2022, 53(3): 323-329.
[7]	郭建林王雪晴徐存拴. MiR-429生物学功能的研究进展[J]. 解剖学报, 2022, 53(2): 266-272.
[8]	闫婷赵继凯王恩华. MEX3A通过PI3K/Akt信号通路促进结直肠癌细胞的增殖和迁移[J]. 解剖学报, 2022, 53(2): 196-202.
[9]	江红黄艳丽邢辉汪黎明郭红 . MiR-515-5p通过调控硫酸软骨素蛋白聚糖4表达对卵巢癌A2780细胞增殖和转移的影响及其机制[J]. 解剖学报, 2022, 53(1): 42-49.
[10]	臧夏炎王子慧李亚霏郭建林靳伟常翠芳徐存拴. 大鼠肝再生启动阶段肝细胞CCAAT增强子结合蛋白α mRNA、微小RNA-144-3p和3种环状RNA的表达和作用[J]. 解剖学报, 2021, 52(6): 901-908.
[11]	臧夏炎王子慧高寒郭建林靳伟常翠芳徐存拴. 大鼠肝再生终止阶段肝细胞CCAAT增强子结合蛋白α mRNA、微小RNA-144-3p和3种环状RNA的表达和作用[J]. 解剖学报, 2021, 52(6): 909-912.
[12]	白格王子慧宋亚萍臧夏炎李亚霏叶丙雨赵志虎徐存拴 . 大鼠肝再生启动阶段肝细胞CCAAT增强子结合蛋白β mRNA、微小RNA-369-3p和rno-Rmdn2_0006的表达和作用[J]. 解剖学报, 2021, 52(6): 913-916.
[13]	李亚霏王子慧臧夏炎靳伟常翠芳郭建林徐存拴 . 大鼠肝再生启动阶段肝细胞CCAAT 增强子结合蛋白δ mRNA、微小RNA-3553和rno-Acad8_0002的表达和作用[J]. 解剖学报, 2021, 52(6): 917-920.
[14]	高寒王子慧臧夏炎靳伟常翠芳郭建林徐存拴. 大鼠肝再生启动阶段肝细胞CCAAT增强子结合蛋白ζ mRNA、微小RNA-136-3p和4种环状RNA的表达和作用[J]. 解剖学报, 2021, 52(6): 921-624.
[15]	王棋文姚奋杰杨卓菲郭学强穆萌萌周运徐存拴. 大鼠肝再生中环状RNA表达谱的变化及其对自噬的影响[J]. 解剖学报, 2021, 52(4): 581-588.