Systems analysis of ATF3 in stress response and cancer reveals opposing effects on pro-apoptotic genes in p53 pathway.

Stress-inducible transcription factors play a pivotal role in cellular adaptation to environment to maintain homeostasis and integrity of the genome. Activating transcription factor 3 (ATF3) is induced by a variety of stress and inflammatory conditions and is over-expressed in many kinds of cancer c...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Yujiro Tanaka, Aya Nakamura, Masaki Suimye Morioka, Shoko Inoue, Mimi Tamamori-Adachi, Kazuhiko Yamada, Kenji Taketani, Junya Kawauchi, Miki Tanaka-Okamoto, Jun Miyoshi, Hiroshi Tanaka, Shigetaka Kitajima
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a0e9837255b24ba09c67ef0bf2d79f3b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:a0e9837255b24ba09c67ef0bf2d79f3b
record_format	dspace
spelling	oai:doaj.org-article:a0e9837255b24ba09c67ef0bf2d79f3b2021-11-18T07:35:41ZSystems analysis of ATF3 in stress response and cancer reveals opposing effects on pro-apoptotic genes in p53 pathway.1932-620310.1371/journal.pone.0026848https://doaj.org/article/a0e9837255b24ba09c67ef0bf2d79f3b2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22046379/?tool=EBIhttps://doaj.org/toc/1932-6203Stress-inducible transcription factors play a pivotal role in cellular adaptation to environment to maintain homeostasis and integrity of the genome. Activating transcription factor 3 (ATF3) is induced by a variety of stress and inflammatory conditions and is over-expressed in many kinds of cancer cells. However, molecular mechanisms underlying pleiotropic functions of ATF3 have remained elusive. Here we employed systems analysis to identify genome-wide targets of ATF3 that is either induced by an alkylating agent methyl methanesulfonate (MMS) or over-expressed in a prostate tumour cell line LNCaP. We show that stress-induced and cancer-associated ATF3 is recruited to 5,984 and 1,423 targets, respectively, in the human genome, 89% of which are common. Notably, ATF3 targets are highly enriched for not only ATF/CRE motifs but also binding sites of several other stress-inducible transcription factors indicating an extensive network of stress response factors in transcriptional regulation of target genes. Further analysis of effects of ATF3 knockdown on these targets revealed that stress-induced ATF3 regulates genes in metabolic pathways, cell cycle, apoptosis, cell adhesion, and signalling including insulin, p53, Wnt, and VEGF pathways. Cancer-associated ATF3 is involved in regulation of distinct sets of genes in processes such as calcium signalling, Wnt, p53 and diabetes pathways. Notably, stress-induced ATF3 binds to 40% of p53 targets and activates pro-apoptotic genes such as TNFRSF10B/DR5 and BBC3/PUMA. Cancer-associated ATF3, by contrast, represses these pro-apoptotic genes in addition to CDKN1A/p21. Taken together, our data reveal an extensive network of stress-inducible transcription factors and demonstrate that ATF3 has opposing, cell context-dependent effects on p53 target genes in DNA damage response and cancer development.Yujiro TanakaAya NakamuraMasaki Suimye MoriokaShoko InoueMimi Tamamori-AdachiKazuhiko YamadaKenji TaketaniJunya KawauchiMiki Tanaka-OkamotoJun MiyoshiHiroshi TanakaShigetaka KitajimaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 10, p e26848 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yujiro Tanaka Aya Nakamura Masaki Suimye Morioka Shoko Inoue Mimi Tamamori-Adachi Kazuhiko Yamada Kenji Taketani Junya Kawauchi Miki Tanaka-Okamoto Jun Miyoshi Hiroshi Tanaka Shigetaka Kitajima Systems analysis of ATF3 in stress response and cancer reveals opposing effects on pro-apoptotic genes in p53 pathway.
description	Stress-inducible transcription factors play a pivotal role in cellular adaptation to environment to maintain homeostasis and integrity of the genome. Activating transcription factor 3 (ATF3) is induced by a variety of stress and inflammatory conditions and is over-expressed in many kinds of cancer cells. However, molecular mechanisms underlying pleiotropic functions of ATF3 have remained elusive. Here we employed systems analysis to identify genome-wide targets of ATF3 that is either induced by an alkylating agent methyl methanesulfonate (MMS) or over-expressed in a prostate tumour cell line LNCaP. We show that stress-induced and cancer-associated ATF3 is recruited to 5,984 and 1,423 targets, respectively, in the human genome, 89% of which are common. Notably, ATF3 targets are highly enriched for not only ATF/CRE motifs but also binding sites of several other stress-inducible transcription factors indicating an extensive network of stress response factors in transcriptional regulation of target genes. Further analysis of effects of ATF3 knockdown on these targets revealed that stress-induced ATF3 regulates genes in metabolic pathways, cell cycle, apoptosis, cell adhesion, and signalling including insulin, p53, Wnt, and VEGF pathways. Cancer-associated ATF3 is involved in regulation of distinct sets of genes in processes such as calcium signalling, Wnt, p53 and diabetes pathways. Notably, stress-induced ATF3 binds to 40% of p53 targets and activates pro-apoptotic genes such as TNFRSF10B/DR5 and BBC3/PUMA. Cancer-associated ATF3, by contrast, represses these pro-apoptotic genes in addition to CDKN1A/p21. Taken together, our data reveal an extensive network of stress-inducible transcription factors and demonstrate that ATF3 has opposing, cell context-dependent effects on p53 target genes in DNA damage response and cancer development.
format	article
author	Yujiro Tanaka Aya Nakamura Masaki Suimye Morioka Shoko Inoue Mimi Tamamori-Adachi Kazuhiko Yamada Kenji Taketani Junya Kawauchi Miki Tanaka-Okamoto Jun Miyoshi Hiroshi Tanaka Shigetaka Kitajima
author_facet	Yujiro Tanaka Aya Nakamura Masaki Suimye Morioka Shoko Inoue Mimi Tamamori-Adachi Kazuhiko Yamada Kenji Taketani Junya Kawauchi Miki Tanaka-Okamoto Jun Miyoshi Hiroshi Tanaka Shigetaka Kitajima
author_sort	Yujiro Tanaka
title	Systems analysis of ATF3 in stress response and cancer reveals opposing effects on pro-apoptotic genes in p53 pathway.
title_short	Systems analysis of ATF3 in stress response and cancer reveals opposing effects on pro-apoptotic genes in p53 pathway.
title_full	Systems analysis of ATF3 in stress response and cancer reveals opposing effects on pro-apoptotic genes in p53 pathway.
title_fullStr	Systems analysis of ATF3 in stress response and cancer reveals opposing effects on pro-apoptotic genes in p53 pathway.
title_full_unstemmed	Systems analysis of ATF3 in stress response and cancer reveals opposing effects on pro-apoptotic genes in p53 pathway.
title_sort	systems analysis of atf3 in stress response and cancer reveals opposing effects on pro-apoptotic genes in p53 pathway.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/a0e9837255b24ba09c67ef0bf2d79f3b
work_keys_str_mv	AT yujirotanaka systemsanalysisofatf3instressresponseandcancerrevealsopposingeffectsonproapoptoticgenesinp53pathway AT ayanakamura systemsanalysisofatf3instressresponseandcancerrevealsopposingeffectsonproapoptoticgenesinp53pathway AT masakisuimyemorioka systemsanalysisofatf3instressresponseandcancerrevealsopposingeffectsonproapoptoticgenesinp53pathway AT shokoinoue systemsanalysisofatf3instressresponseandcancerrevealsopposingeffectsonproapoptoticgenesinp53pathway AT mimitamamoriadachi systemsanalysisofatf3instressresponseandcancerrevealsopposingeffectsonproapoptoticgenesinp53pathway AT kazuhikoyamada systemsanalysisofatf3instressresponseandcancerrevealsopposingeffectsonproapoptoticgenesinp53pathway AT kenjitaketani systemsanalysisofatf3instressresponseandcancerrevealsopposingeffectsonproapoptoticgenesinp53pathway AT junyakawauchi systemsanalysisofatf3instressresponseandcancerrevealsopposingeffectsonproapoptoticgenesinp53pathway AT mikitanakaokamoto systemsanalysisofatf3instressresponseandcancerrevealsopposingeffectsonproapoptoticgenesinp53pathway AT junmiyoshi systemsanalysisofatf3instressresponseandcancerrevealsopposingeffectsonproapoptoticgenesinp53pathway AT hiroshitanaka systemsanalysisofatf3instressresponseandcancerrevealsopposingeffectsonproapoptoticgenesinp53pathway AT shigetakakitajima systemsanalysisofatf3instressresponseandcancerrevealsopposingeffectsonproapoptoticgenesinp53pathway
_version_	1718423238408667136

Systems analysis of ATF3 in stress response and cancer reveals opposing effects on pro-apoptotic genes in p53 pathway.

Ejemplares similares