Document Detail


Ectopic expression of human MutS homologue 2 on renal carcinoma cells is induced by oxidative stress with interleukin-18 promotion via p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) signaling pathways.
MedLine Citation:
PMID:  22493490     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Human MutS homologue 2 (hMSH2), a crucial element of the highly conserved DNA mismatch repair system, maintains genetic stability in the nucleus of normal cells. Our previous studies indicate that hMSH2 is ectopically expressed on the surface of epithelial tumor cells and recognized by both T cell receptor γδ (TCRγδ) and natural killer group 2 member D (NKG2D) on Vδ2 T cells. Ectopically expressed hMSH2 could trigger a γδ T cell-mediated cytolysis. In this study, we showed that oxidative stress induced ectopic expression of hMSH2 on human renal carcinoma cells. Under oxidative stress, both p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) pathways have been confirmed to mediate the ectopic expression of hMSH2 through the apoptosis-signaling kinase 1 (ASK1) upstream and activating transcription factor 3 (ATF3) downstream of both pathways. Moreover, renal carcinoma cell-derived interleukin (IL)-18 in oxidative stress was a prominent stimulator for ectopically induced expression of hMSH2, which was promoted by interferon (IFN)-γ as well. Finally, oxidative stress or pretreatment with IL-18 and IFN-γ enhanced γδ T cell-mediated cytolysis of renal carcinoma cells. Our results not only establish a mechanism of ectopic hMSH2 expression in tumor cells but also find a biological linkage between ectopic expression of hMSH2 and activation of γδ T cells in stressful conditions. Because γδ T cells play an important role in the early stage of innate anti-tumor response, γδ T cell activation triggered by ectopically expressed hMSH2 may be an important event in immunosurveillance for carcinogenesis.
Authors:
Chen Mo; Yumei Dai; Ning Kang; Lianxian Cui; Wei He
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-04-09
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-04     Completed Date:  2012-08-20     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  19242-54     Citation Subset:  IM    
Affiliation:
Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Peking Union Medical College, Beijing 100005, China.
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MeSH Terms
Descriptor/Qualifier:
Activating Transcription Factor 3 / genetics,  immunology,  metabolism
Carcinoma, Renal Cell / genetics,  immunology,  metabolism*,  pathology
Gene Expression Regulation, Neoplastic / genetics
Humans
Immunity, Cellular / genetics
Interferon-gamma / genetics,  immunology,  metabolism
Interleukin-18 / genetics,  immunology,  metabolism*
JNK Mitogen-Activated Protein Kinases / genetics,  immunology,  metabolism*
Jurkat Cells
K562 Cells
Kidney Neoplasms / genetics,  immunology,  metabolism*,  pathology
Lymphocyte Activation / genetics
MAP Kinase Kinase Kinase 5 / genetics,  immunology,  metabolism
MAP Kinase Signaling System*
MutS Homolog 2 Protein / biosynthesis*,  genetics,  immunology
Oxidative Stress*
Receptors, Antigen, T-Cell, gamma-delta / genetics,  immunology,  metabolism
T-Lymphocytes / immunology,  metabolism,  pathology
p38 Mitogen-Activated Protein Kinases / genetics,  immunology,  metabolism*
Chemical
Reg. No./Substance:
0/ATF3 protein, human; 0/Activating Transcription Factor 3; 0/Interleukin-18; 0/Receptors, Antigen, T-Cell, gamma-delta; 82115-62-6/Interferon-gamma; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 2.7.11.25/MAP Kinase Kinase Kinase 5; EC 2.7.11.25/MAP3K5 protein, human; EC 3.6.1.3/MSH2 protein, human; EC 3.6.1.3/MutS Homolog 2 Protein
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