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4-Hydroxynonenal induces G2/M phase cell cycle arrest by activation of the ataxia telangiectasia mutated and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) signaling pathway.
J Biol Chem 2013; 288(28):20532-46JB

Abstract

4-Hydroxynonenal (HNE) has been widely implicated in the mechanisms of oxidant-induced toxicity, but the detrimental effects of HNE associated with DNA damage or cell cycle arrest have not been thoroughly studied. Here we demonstrate for the first time that HNE caused G2/M cell cycle arrest of hepatocellular carcinoma HepG2 (p53 wild type) and Hep3B (p53 null) cells that was accompanied with decreased expression of CDK1 and cyclin B1 and activation of p21 in a p53-independent manner. HNE treatment suppressed the Cdc25C level, which led to inactivation of CDK1. HNE-induced phosphorylation of Cdc25C at Ser-216 resulted in its translocation from nucleus to cytoplasm, thereby facilitating its degradation via the ubiquitin-mediated proteasomal pathway. This phosphorylation of Cdc25C was regulated by activation of the ataxia telangiectasia and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) pathway. The role of HNE in the DNA double strand break was strongly suggested by a remarkable increase in comet tail formation and H2A.X phosphorylation in HNE-treated cells in vitro. This was supported by increased in vivo phosphorylation of H2A.X in mGsta4 null mice that have impaired HNE metabolism and increased HNE levels in tissues. HNE-mediated ATR/Chk1 signaling was inhibited by ATR kinase inhibitor (caffeine). Additionally, most of the signaling effects of HNE on cell cycle arrest were attenuated in hGSTA4 transfected cells, thereby indicating the involvement of HNE in these events. A novel role of GSTA4-4 in the maintenance of genomic integrity is also suggested.

Authors+Show Affiliations

Department of Molecular Biology and Immunology and Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23733185

Citation

Chaudhary, Pankaj, et al. "4-Hydroxynonenal Induces G2/M Phase Cell Cycle Arrest By Activation of the Ataxia Telangiectasia Mutated and Rad3-related Protein (ATR)/checkpoint Kinase 1 (Chk1) Signaling Pathway." The Journal of Biological Chemistry, vol. 288, no. 28, 2013, pp. 20532-46.
Chaudhary P, Sharma R, Sahu M, et al. 4-Hydroxynonenal induces G2/M phase cell cycle arrest by activation of the ataxia telangiectasia mutated and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) signaling pathway. J Biol Chem. 2013;288(28):20532-46.
Chaudhary, P., Sharma, R., Sahu, M., Vishwanatha, J. K., Awasthi, S., & Awasthi, Y. C. (2013). 4-Hydroxynonenal induces G2/M phase cell cycle arrest by activation of the ataxia telangiectasia mutated and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) signaling pathway. The Journal of Biological Chemistry, 288(28), pp. 20532-46. doi:10.1074/jbc.M113.467662.
Chaudhary P, et al. 4-Hydroxynonenal Induces G2/M Phase Cell Cycle Arrest By Activation of the Ataxia Telangiectasia Mutated and Rad3-related Protein (ATR)/checkpoint Kinase 1 (Chk1) Signaling Pathway. J Biol Chem. 2013 Jul 12;288(28):20532-46. PubMed PMID: 23733185.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 4-Hydroxynonenal induces G2/M phase cell cycle arrest by activation of the ataxia telangiectasia mutated and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) signaling pathway. AU - Chaudhary,Pankaj, AU - Sharma,Rajendra, AU - Sahu,Mukesh, AU - Vishwanatha,Jamboor K, AU - Awasthi,Sanjay, AU - Awasthi,Yogesh C, Y1 - 2013/06/03/ PY - 2013/6/5/entrez PY - 2013/6/5/pubmed PY - 2013/9/28/medline KW - 4-Hydroxynonenal KW - Cell Cycle KW - Cell Cycle Arrest KW - DNA Damage KW - Glutathione S-Tranferase KW - Lipid Peroxidation KW - Oxidative Stress KW - Signal Transduction SP - 20532 EP - 46 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 288 IS - 28 N2 - 4-Hydroxynonenal (HNE) has been widely implicated in the mechanisms of oxidant-induced toxicity, but the detrimental effects of HNE associated with DNA damage or cell cycle arrest have not been thoroughly studied. Here we demonstrate for the first time that HNE caused G2/M cell cycle arrest of hepatocellular carcinoma HepG2 (p53 wild type) and Hep3B (p53 null) cells that was accompanied with decreased expression of CDK1 and cyclin B1 and activation of p21 in a p53-independent manner. HNE treatment suppressed the Cdc25C level, which led to inactivation of CDK1. HNE-induced phosphorylation of Cdc25C at Ser-216 resulted in its translocation from nucleus to cytoplasm, thereby facilitating its degradation via the ubiquitin-mediated proteasomal pathway. This phosphorylation of Cdc25C was regulated by activation of the ataxia telangiectasia and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) pathway. The role of HNE in the DNA double strand break was strongly suggested by a remarkable increase in comet tail formation and H2A.X phosphorylation in HNE-treated cells in vitro. This was supported by increased in vivo phosphorylation of H2A.X in mGsta4 null mice that have impaired HNE metabolism and increased HNE levels in tissues. HNE-mediated ATR/Chk1 signaling was inhibited by ATR kinase inhibitor (caffeine). Additionally, most of the signaling effects of HNE on cell cycle arrest were attenuated in hGSTA4 transfected cells, thereby indicating the involvement of HNE in these events. A novel role of GSTA4-4 in the maintenance of genomic integrity is also suggested. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/23733185/4_Hydroxynonenal_induces_G2/M_phase_cell_cycle_arrest_by_activation_of_the_ataxia_telangiectasia_mutated_and_Rad3_related_protein__ATR_/checkpoint_kinase_1__Chk1__signaling_pathway_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=23733185 DB - PRIME DP - Unbound Medicine ER -