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mot-2–Mediated Cross Talk between Nuclear Factor-κB and p53 Is Involved in Arsenite-Induced Tumorigenesis of Human Embryo Lung Fibroblast Cells

BACKGROUND: Inactivation of p53 is involved in arsenite-induced tumorigenesis; however, the molecular mechanisms remain poorly understood. OBJECTIVE: We investigated the molecular mechanisms underlying the inactivation of p53 and neoplastic transformation induced by arsenite in human embryo lung fib...

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Autores principales: Li, Yuan, Xu, Yuan, Ling, Min, Yang, Ye, Wang, Shoulin, Li, Zhong, Zhou, Jianwei, Wang, Xinru, Liu, Qizhan
Formato: Texto
Lenguaje:English
Publicado: National Institute of Environmental Health Sciences 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920912/
https://www.ncbi.nlm.nih.gov/pubmed/20199942
http://dx.doi.org/10.1289/ehp.0901677
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author Li, Yuan
Xu, Yuan
Ling, Min
Yang, Ye
Wang, Shoulin
Li, Zhong
Zhou, Jianwei
Wang, Xinru
Liu, Qizhan
author_facet Li, Yuan
Xu, Yuan
Ling, Min
Yang, Ye
Wang, Shoulin
Li, Zhong
Zhou, Jianwei
Wang, Xinru
Liu, Qizhan
author_sort Li, Yuan
collection PubMed
description BACKGROUND: Inactivation of p53 is involved in arsenite-induced tumorigenesis; however, the molecular mechanisms remain poorly understood. OBJECTIVE: We investigated the molecular mechanisms underlying the inactivation of p53 and neoplastic transformation induced by arsenite in human embryo lung fibroblast (HELF) cells. METHODS: Anchorage-independent growth assays were performed, and tumorigenicity in intact animals was assessed to confirm arsenite-induced neoplastic transformation. We determined the levels and functions of p53, nuclear factor-kappa B (NF-κB; a key transcriptional regulator), and mot-2 (a p53 inhibitor) and their relationships in arsenite-induced transformed HELF cells by two-dimensional electrophoresis, reverse-transcriptase polymerase chain reaction, Western blot, immunofluorescence, and co-immunoprecipitation assays. RESULTS: Exposure of HELF cells to low levels of arsenite increased their proliferation rate and anchorage-independent growth and disrupted normal contact inhibition. When introduced into nude mice, transformed cells were tumorigenic. We used proteomic analysis to identify proteins with altered expression between untreated and arsenite-exposed cells. We found decreased expression of NF-κB repressing factor (NKRF; an inhibitor of NF-κB–mediated gene transcription), increased expression of mot-2, and increased activation of NF-κB. Changes in cells exposed to 1.0 μM arsenite were more marked than changes in cells exposed to 0.5 or 2.0 μM arsenite. Inactivation of NF-κB prevented malignant transformation induced by 1.0 μM arsenite. Moreover, we also identified a mechanism whereby NF-κB regulated p53. Specifically, activation of NF-κB up-regulated mot-2 expression, which prevented nuclear translocation of p53 and switched the binding preference of the p53 and NF-κB coactivator CBP [cyclic AMP-responsive element binding protein (CREB) binding protein] from p53 to NF-κB. CONCLUSIONS: mot-2–mediated cross talk between NF-κB and p53 appears to be involved in arsenite-induced tumorigenesis of HELF cells.
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spelling pubmed-29209122010-08-13 mot-2–Mediated Cross Talk between Nuclear Factor-κB and p53 Is Involved in Arsenite-Induced Tumorigenesis of Human Embryo Lung Fibroblast Cells Li, Yuan Xu, Yuan Ling, Min Yang, Ye Wang, Shoulin Li, Zhong Zhou, Jianwei Wang, Xinru Liu, Qizhan Environ Health Perspect Research BACKGROUND: Inactivation of p53 is involved in arsenite-induced tumorigenesis; however, the molecular mechanisms remain poorly understood. OBJECTIVE: We investigated the molecular mechanisms underlying the inactivation of p53 and neoplastic transformation induced by arsenite in human embryo lung fibroblast (HELF) cells. METHODS: Anchorage-independent growth assays were performed, and tumorigenicity in intact animals was assessed to confirm arsenite-induced neoplastic transformation. We determined the levels and functions of p53, nuclear factor-kappa B (NF-κB; a key transcriptional regulator), and mot-2 (a p53 inhibitor) and their relationships in arsenite-induced transformed HELF cells by two-dimensional electrophoresis, reverse-transcriptase polymerase chain reaction, Western blot, immunofluorescence, and co-immunoprecipitation assays. RESULTS: Exposure of HELF cells to low levels of arsenite increased their proliferation rate and anchorage-independent growth and disrupted normal contact inhibition. When introduced into nude mice, transformed cells were tumorigenic. We used proteomic analysis to identify proteins with altered expression between untreated and arsenite-exposed cells. We found decreased expression of NF-κB repressing factor (NKRF; an inhibitor of NF-κB–mediated gene transcription), increased expression of mot-2, and increased activation of NF-κB. Changes in cells exposed to 1.0 μM arsenite were more marked than changes in cells exposed to 0.5 or 2.0 μM arsenite. Inactivation of NF-κB prevented malignant transformation induced by 1.0 μM arsenite. Moreover, we also identified a mechanism whereby NF-κB regulated p53. Specifically, activation of NF-κB up-regulated mot-2 expression, which prevented nuclear translocation of p53 and switched the binding preference of the p53 and NF-κB coactivator CBP [cyclic AMP-responsive element binding protein (CREB) binding protein] from p53 to NF-κB. CONCLUSIONS: mot-2–mediated cross talk between NF-κB and p53 appears to be involved in arsenite-induced tumorigenesis of HELF cells. National Institute of Environmental Health Sciences 2010-07 2010-03-03 /pmc/articles/PMC2920912/ /pubmed/20199942 http://dx.doi.org/10.1289/ehp.0901677 Text en http://creativecommons.org/publicdomain/mark/1.0/ Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, ?Reproduced with permission from Environmental Health Perspectives?); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright.
spellingShingle Research
Li, Yuan
Xu, Yuan
Ling, Min
Yang, Ye
Wang, Shoulin
Li, Zhong
Zhou, Jianwei
Wang, Xinru
Liu, Qizhan
mot-2–Mediated Cross Talk between Nuclear Factor-κB and p53 Is Involved in Arsenite-Induced Tumorigenesis of Human Embryo Lung Fibroblast Cells
title mot-2–Mediated Cross Talk between Nuclear Factor-κB and p53 Is Involved in Arsenite-Induced Tumorigenesis of Human Embryo Lung Fibroblast Cells
title_full mot-2–Mediated Cross Talk between Nuclear Factor-κB and p53 Is Involved in Arsenite-Induced Tumorigenesis of Human Embryo Lung Fibroblast Cells
title_fullStr mot-2–Mediated Cross Talk between Nuclear Factor-κB and p53 Is Involved in Arsenite-Induced Tumorigenesis of Human Embryo Lung Fibroblast Cells
title_full_unstemmed mot-2–Mediated Cross Talk between Nuclear Factor-κB and p53 Is Involved in Arsenite-Induced Tumorigenesis of Human Embryo Lung Fibroblast Cells
title_short mot-2–Mediated Cross Talk between Nuclear Factor-κB and p53 Is Involved in Arsenite-Induced Tumorigenesis of Human Embryo Lung Fibroblast Cells
title_sort mot-2–mediated cross talk between nuclear factor-κb and p53 is involved in arsenite-induced tumorigenesis of human embryo lung fibroblast cells
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920912/
https://www.ncbi.nlm.nih.gov/pubmed/20199942
http://dx.doi.org/10.1289/ehp.0901677
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