SET Mediates TCE-induced Liver Cell Apoptosis Through Dephosphorylation and Upregulation of Nucleolin

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Apr 14

PMID 28402964

Citations 2

Authors

Xiaohu Ren

Xinfeng Huang

Xifei Yang

Yungang Liu

Wei Liu

Haiyan Huang

Desheng Wu

Fei Zou

Jianjun Liu

Affiliations

Soon will be listed here.

Abstract

Trichloroethylene (TCE) is an occupational and environmental chemical that can cause severe hepatotoxicity. While our previous studies showed that the phosphatase inhibitor SET is a key mediator of TCE-induced liver cell apoptosis, the molecular mechanisms remain elusive. Using quantitative phosphoproteomic analysis, we report here that nucleolin is a SET-regulated phosphoprotein in human liver HL-7702 cells. Functional analysis suggested that SET promoted dephosphorylation of nucleolin, decreased its binding to its transcriptional activator, c-myc, and upregulated nucleolin expression in TCE-treated cells. Importantly, TCE-induced hepatocyte apoptosis was significantly attenuated when nucleolin was downregulated with specific siRNAs. These findings indicate that TCE may induce hepatocyte apoptosis via SET-mediated dephosphorylation and overexpression of nucleolin.

Citing Articles

The Urogenital System Microbiota: Is It a New Gamechanger in Urogenital Cancers?.

Ece G, Aktas A, Caner A, Saglik I, Kula Atik T, Ulusan Bagci O Microorganisms. 2025; 13(2).

PMID: 40005682 PMC: 11858393. DOI: 10.3390/microorganisms13020315.

The next decade of SET: from an oncoprotein to beyond.

Yao H, Zhang M, Wang D J Mol Cell Biol. 2023; 16(1).

PMID: 38157418 PMC: 11267991. DOI: 10.1093/jmcb/mjad082.

Proteomic Analysis of Brain Region and Sex-Specific Synaptic Protein Expression in the Adult Mouse Brain.

Distler U, Schumann S, Kesseler H, Pielot R, Smalla K, Sielaff M Cells. 2020; 9(2).

PMID: 32012899 PMC: 7072627. DOI: 10.3390/cells9020313.

References

Ren X, Yang X, Hong W, Huang P, Wang Y, Liu W . Identification of the proteins related to SET-mediated hepatic cytotoxicity of trichloroethylene by proteomic analysis. Toxicol Lett. 2014; 227(1):12-9. DOI: 10.1016/j.toxlet.2014.02.028. View

Liu J, Huang H, Xing X, Xi R, Zhuang Z, Yuan J . Comparative proteomic analysis on human L-02 liver cells treated with varying concentrations of trichloroethylene. Toxicol Ind Health. 2008; 23(2):91-101. DOI: 10.1177/0748233707078223. View

Yang X, Jiang Y, Li J, Hong W, Wu D, Huang X . Lentivirus-mediated silencing of I2PP2A through RNA interference attenuates trichloroethylene-induced cytotoxicity in human hepatic L-02 cells. Toxicol Lett. 2012; 209(3):232-8. DOI: 10.1016/j.toxlet.2011.12.019. View

Lash L, Putt D, Huang P, Hueni S, Parker J . Modulation of hepatic and renal metabolism and toxicity of trichloroethylene and perchloroethylene by alterations in status of cytochrome P450 and glutathione. Toxicology. 2007; 235(1-2):11-26. PMC: 1976278. DOI: 10.1016/j.tox.2007.03.001. View

Ginisty H, Sicard H, Roger B, Bouvet P . Structure and functions of nucleolin. J Cell Sci. 1999; 112 ( Pt 6):761-72. DOI: 10.1242/jcs.112.6.761. View

Hong W, Yang L, Chen M, Yang X, Ren X, Fang S . Proteomic analysis of trichloroethylene-induced alterations in expression, distribution, and interactions of SET/TAF-Iα and two SET/TAF-Iα-binding proteins, eEF1A1 and eEF1A2, in hepatic L-02 cells. Toxicol Appl Pharmacol. 2012; 263(2):259-72. DOI: 10.1016/j.taap.2012.06.018. View

Sano Y, Nakashima H, Yoshioka N, Etho N, Nomiyama T, Nishiwaki Y . Trichloroethylene liver toxicity in mouse and rat: microarray analysis reveals species differences in gene expression. Arch Toxicol. 2009; 83(9):835-49. DOI: 10.1007/s00204-009-0431-1. View

Karami S, Bassig B, Stewart P, Lee K, Rothman N, Moore L . Occupational trichloroethylene exposure and risk of lymphatic and haematopoietic cancers: a meta-analysis. Occup Environ Med. 2013; 70(8):591-9. DOI: 10.1136/oemed-2012-101212. View

Belenguer P, Caizergues-Ferrer M, Labbe J, Doree M, Amalric F . Mitosis-specific phosphorylation of nucleolin by p34cdc2 protein kinase. Mol Cell Biol. 1990; 10(7):3607-18. PMC: 360797. DOI: 10.1128/mcb.10.7.3607-3618.1990. View

10.

Greasley P, Bonnard C, Amati B . Myc induces the nucleolin and BN51 genes: possible implications in ribosome biogenesis. Nucleic Acids Res. 1999; 28(2):446-53. PMC: 102507. DOI: 10.1093/nar/28.2.446. View

11.

Hansen J, Sallmen M, Selden A, Anttila A, Pukkala E, Andersson K . Risk of cancer among workers exposed to trichloroethylene: analysis of three Nordic cohort studies. J Natl Cancer Inst. 2013; 105(12):869-77. DOI: 10.1093/jnci/djt107. View

12.

Xu X, Yang R, Wu N, Zhong P, Ke Y, Zhou L . Severe hypersensitivity dermatitis and liver dysfunction induced by occupational exposure to trichloroethylene. Ind Health. 2009; 47(2):107-12. DOI: 10.2486/indhealth.47.107. View

13.

Huang H, Liu J, Xi R, Xing X, Yuan J, Yang L . An investigation of hormesis of trichloroethylene in L-02 liver cells by differential proteomic analysis. Mol Biol Rep. 2008; 36(8):2119-29. DOI: 10.1007/s11033-008-9424-z. View

14.

Fukukawa C, Shima H, Tanuma N, Ogawa K, Kikuchi K . Up-regulation of I-2(PP2A)/SET gene expression in rat primary hepatomas and regenerating livers. Cancer Lett. 2000; 161(1):89-95. DOI: 10.1016/s0304-3835(00)00598-x. View

15.

Chen X, Kube D, Cooper M, Davis P . Cell surface nucleolin serves as receptor for DNA nanoparticles composed of pegylated polylysine and DNA. Mol Ther. 2007; 16(2):333-42. DOI: 10.1038/sj.mt.6300365. View

16.

Wise J, Berkova Z, Mathur R, Zhu H, Braun F, Tao R . Nucleolin inhibits Fas ligand binding and suppresses Fas-mediated apoptosis in vivo via a surface nucleolin-Fas complex. Blood. 2013; 121(23):4729-39. PMC: 3674671. DOI: 10.1182/blood-2012-12-471094. View

17.

Gonzalez V, Hurley L . The C-terminus of nucleolin promotes the formation of the c-MYC G-quadruplex and inhibits c-MYC promoter activity. Biochemistry. 2010; 49(45):9706-14. PMC: 2976822. DOI: 10.1021/bi100509s. View

18.

Switzer C, Cheng R, Vitek T, Christensen D, Wink D, Vitek M . Targeting SET/I(2)PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy. Oncogene. 2011; 30(22):2504-13. PMC: 3107340. DOI: 10.1038/onc.2010.622. View

19.

Wu D, Zhang P, Liu R, Sang Y, Zhou C, Xu G . Phosphorylation and changes in the distribution of nucleolin promote tumor metastasis via the PI3K/Akt pathway in colorectal carcinoma. FEBS Lett. 2014; 588(10):1921-9. DOI: 10.1016/j.febslet.2014.03.047. View

20.

Tsou J, Chang K, Wang W, Tseng J, Su W, Hung L . Nucleolin regulates c-Jun/Sp1-dependent transcriptional activation of cPLA2alpha in phorbol ester-treated non-small cell lung cancer A549 cells. Nucleic Acids Res. 2007; 36(1):217-27. PMC: 2248756. DOI: 10.1093/nar/gkm1027. View