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Overexpression of Rev1 promotes the development of carcinogen-induced intestinal adenomas via accumulation of point mutation and suppression of apoptosis proportionally to the Rev1 expression level

Cancer development often involves mutagenic replication of damaged DNA by the error-prone translesion synthesis (TLS) pathway. Aberrant activation of this pathway plays a role in tumorigenesis by promoting genetic mutations. Rev1 controls the function of the TLS pathway, and Rev1 expression levels a...

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Autores principales: Sasatani, Megumi, Xi, Yang, Kajimura, Junko, Kawamura, Toshiyuki, Piao, Jinlian, Masuda, Yuji, Honda, Hiroaki, Kubo, Kei, Mikamoto, Takahiro, Watanabe, Hiromitsu, Xu, Yanbin, Kawai, Hidehiko, Shimura, Tsutomu, Noda, Asao, Hamasaki, Kanya, Kusunoki, Yoichiro, Zaharieva, Elena Karamfilova, Kamiya, Kenji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872566/
https://www.ncbi.nlm.nih.gov/pubmed/28498946
http://dx.doi.org/10.1093/carcin/bgw208
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author Sasatani, Megumi
Xi, Yang
Kajimura, Junko
Kawamura, Toshiyuki
Piao, Jinlian
Masuda, Yuji
Honda, Hiroaki
Kubo, Kei
Mikamoto, Takahiro
Watanabe, Hiromitsu
Xu, Yanbin
Kawai, Hidehiko
Shimura, Tsutomu
Noda, Asao
Hamasaki, Kanya
Kusunoki, Yoichiro
Zaharieva, Elena Karamfilova
Kamiya, Kenji
author_facet Sasatani, Megumi
Xi, Yang
Kajimura, Junko
Kawamura, Toshiyuki
Piao, Jinlian
Masuda, Yuji
Honda, Hiroaki
Kubo, Kei
Mikamoto, Takahiro
Watanabe, Hiromitsu
Xu, Yanbin
Kawai, Hidehiko
Shimura, Tsutomu
Noda, Asao
Hamasaki, Kanya
Kusunoki, Yoichiro
Zaharieva, Elena Karamfilova
Kamiya, Kenji
author_sort Sasatani, Megumi
collection PubMed
description Cancer development often involves mutagenic replication of damaged DNA by the error-prone translesion synthesis (TLS) pathway. Aberrant activation of this pathway plays a role in tumorigenesis by promoting genetic mutations. Rev1 controls the function of the TLS pathway, and Rev1 expression levels are associated with DNA damage induced cytotoxicity and mutagenicity. However, it remains unclear whether deregulated Rev1 expression triggers or promotes tumorigenesis in vivo. In this study, we generated a novel Rev1-overexpressing transgenic (Tg) mouse and characterized its susceptibility to tumorigenesis. Using a small intestinal tumor model induced by N-methyl-N-nitrosourea (MNU), we found that transgenic expression of Rev1 accelerated intestinal adenoma development in proportion to the Rev1 expression level; however, overexpression of Rev1 alone did not cause spontaneous development of intestinal adenomas. In Rev1 Tg mice, MNU-induced mutagenesis was elevated, whereas apoptosis was suppressed. The effects of hREV1 expression levels on the cytotoxicity and mutagenicity of MNU were confirmed in the human cancer cell line HT1080. These data indicate that dysregulation of cellular Rev1 levels leads to the accumulation of mutations and suppression of cell death, which accelerates the tumorigenic activities of DNA-damaging agents.
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spelling pubmed-58725662018-04-05 Overexpression of Rev1 promotes the development of carcinogen-induced intestinal adenomas via accumulation of point mutation and suppression of apoptosis proportionally to the Rev1 expression level Sasatani, Megumi Xi, Yang Kajimura, Junko Kawamura, Toshiyuki Piao, Jinlian Masuda, Yuji Honda, Hiroaki Kubo, Kei Mikamoto, Takahiro Watanabe, Hiromitsu Xu, Yanbin Kawai, Hidehiko Shimura, Tsutomu Noda, Asao Hamasaki, Kanya Kusunoki, Yoichiro Zaharieva, Elena Karamfilova Kamiya, Kenji Carcinogenesis Original Manuscript Cancer development often involves mutagenic replication of damaged DNA by the error-prone translesion synthesis (TLS) pathway. Aberrant activation of this pathway plays a role in tumorigenesis by promoting genetic mutations. Rev1 controls the function of the TLS pathway, and Rev1 expression levels are associated with DNA damage induced cytotoxicity and mutagenicity. However, it remains unclear whether deregulated Rev1 expression triggers or promotes tumorigenesis in vivo. In this study, we generated a novel Rev1-overexpressing transgenic (Tg) mouse and characterized its susceptibility to tumorigenesis. Using a small intestinal tumor model induced by N-methyl-N-nitrosourea (MNU), we found that transgenic expression of Rev1 accelerated intestinal adenoma development in proportion to the Rev1 expression level; however, overexpression of Rev1 alone did not cause spontaneous development of intestinal adenomas. In Rev1 Tg mice, MNU-induced mutagenesis was elevated, whereas apoptosis was suppressed. The effects of hREV1 expression levels on the cytotoxicity and mutagenicity of MNU were confirmed in the human cancer cell line HT1080. These data indicate that dysregulation of cellular Rev1 levels leads to the accumulation of mutations and suppression of cell death, which accelerates the tumorigenic activities of DNA-damaging agents. Oxford University Press 2017-05 2017-05-09 /pmc/articles/PMC5872566/ /pubmed/28498946 http://dx.doi.org/10.1093/carcin/bgw208 Text en © The Author 2017. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Manuscript
Sasatani, Megumi
Xi, Yang
Kajimura, Junko
Kawamura, Toshiyuki
Piao, Jinlian
Masuda, Yuji
Honda, Hiroaki
Kubo, Kei
Mikamoto, Takahiro
Watanabe, Hiromitsu
Xu, Yanbin
Kawai, Hidehiko
Shimura, Tsutomu
Noda, Asao
Hamasaki, Kanya
Kusunoki, Yoichiro
Zaharieva, Elena Karamfilova
Kamiya, Kenji
Overexpression of Rev1 promotes the development of carcinogen-induced intestinal adenomas via accumulation of point mutation and suppression of apoptosis proportionally to the Rev1 expression level
title Overexpression of Rev1 promotes the development of carcinogen-induced intestinal adenomas via accumulation of point mutation and suppression of apoptosis proportionally to the Rev1 expression level
title_full Overexpression of Rev1 promotes the development of carcinogen-induced intestinal adenomas via accumulation of point mutation and suppression of apoptosis proportionally to the Rev1 expression level
title_fullStr Overexpression of Rev1 promotes the development of carcinogen-induced intestinal adenomas via accumulation of point mutation and suppression of apoptosis proportionally to the Rev1 expression level
title_full_unstemmed Overexpression of Rev1 promotes the development of carcinogen-induced intestinal adenomas via accumulation of point mutation and suppression of apoptosis proportionally to the Rev1 expression level
title_short Overexpression of Rev1 promotes the development of carcinogen-induced intestinal adenomas via accumulation of point mutation and suppression of apoptosis proportionally to the Rev1 expression level
title_sort overexpression of rev1 promotes the development of carcinogen-induced intestinal adenomas via accumulation of point mutation and suppression of apoptosis proportionally to the rev1 expression level
topic Original Manuscript
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872566/
https://www.ncbi.nlm.nih.gov/pubmed/28498946
http://dx.doi.org/10.1093/carcin/bgw208
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