IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells

Abstract Inflammatory stimuli triggers the degradation of three inhibitory κB (IκB) proteins, allowing for nuclear translocation of nuclear factor-κB (NFκB) for transcriptional induction of its target genes. Of these three, IκBα is a well-known negative feedback regulator that limits the duration of...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Minami Ando, Shigeyuki Magi, Masahide Seki, Yutaka Suzuki, Takeya Kasukawa, Diane Lefaudeux, Alexander Hoffmann, Mariko Okada
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/29d6b7c18ef04c3094c7dd706d16a6a5
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:29d6b7c18ef04c3094c7dd706d16a6a5
record_format	dspace
spelling	oai:doaj.org-article:29d6b7c18ef04c3094c7dd706d16a6a52021-12-05T12:10:43ZIκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells10.1038/s41540-021-00204-72056-7189https://doaj.org/article/29d6b7c18ef04c3094c7dd706d16a6a52021-12-01T00:00:00Zhttps://doi.org/10.1038/s41540-021-00204-7https://doaj.org/toc/2056-7189Abstract Inflammatory stimuli triggers the degradation of three inhibitory κB (IκB) proteins, allowing for nuclear translocation of nuclear factor-κB (NFκB) for transcriptional induction of its target genes. Of these three, IκBα is a well-known negative feedback regulator that limits the duration of NFκB activity. We sought to determine whether IκBα’s role in enabling or limiting NFκB activation is important for tumor necrosis factor (TNF)-induced gene expression in human breast cancer cells (MCF-7). Contrary to our expectations, many more TNF-response genes showed reduced induction than enhanced induction in IκBα knockdown cells. Mathematical modeling was used to investigate the underlying mechanism. We found that the reduced activation of some NFκB target genes in IκBα-deficient cells could be explained by the incoherent feedforward loop (IFFL) model. In addition, for a subset of genes, prolonged NFκB activity due to loss of negative feedback control did not prolong their transient activation; this implied a multi-state transcription cycle control of gene induction. Genes encoding key inflammation-related transcription factors, such as JUNB and KLF10, were found to be best represented by a model that contained both the IFFL and the transcription cycle motif. Our analysis sheds light on the regulatory strategies that safeguard inflammatory gene expression from overproduction and repositions the function of IκBα not only as a negative feedback regulator of NFκB but also as an enabler of NFκB-regulated stimulus-responsive inflammatory gene expression. This study indicates the complex involvement of IκBα in the inflammatory response to TNF that is induced by radiation therapy in breast cancer.Minami AndoShigeyuki MagiMasahide SekiYutaka SuzukiTakeya KasukawaDiane LefaudeuxAlexander HoffmannMariko OkadaNature PortfolioarticleBiology (General)QH301-705.5ENnpj Systems Biology and Applications, Vol 7, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Minami Ando Shigeyuki Magi Masahide Seki Yutaka Suzuki Takeya Kasukawa Diane Lefaudeux Alexander Hoffmann Mariko Okada IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells
description	Abstract Inflammatory stimuli triggers the degradation of three inhibitory κB (IκB) proteins, allowing for nuclear translocation of nuclear factor-κB (NFκB) for transcriptional induction of its target genes. Of these three, IκBα is a well-known negative feedback regulator that limits the duration of NFκB activity. We sought to determine whether IκBα’s role in enabling or limiting NFκB activation is important for tumor necrosis factor (TNF)-induced gene expression in human breast cancer cells (MCF-7). Contrary to our expectations, many more TNF-response genes showed reduced induction than enhanced induction in IκBα knockdown cells. Mathematical modeling was used to investigate the underlying mechanism. We found that the reduced activation of some NFκB target genes in IκBα-deficient cells could be explained by the incoherent feedforward loop (IFFL) model. In addition, for a subset of genes, prolonged NFκB activity due to loss of negative feedback control did not prolong their transient activation; this implied a multi-state transcription cycle control of gene induction. Genes encoding key inflammation-related transcription factors, such as JUNB and KLF10, were found to be best represented by a model that contained both the IFFL and the transcription cycle motif. Our analysis sheds light on the regulatory strategies that safeguard inflammatory gene expression from overproduction and repositions the function of IκBα not only as a negative feedback regulator of NFκB but also as an enabler of NFκB-regulated stimulus-responsive inflammatory gene expression. This study indicates the complex involvement of IκBα in the inflammatory response to TNF that is induced by radiation therapy in breast cancer.
format	article
author	Minami Ando Shigeyuki Magi Masahide Seki Yutaka Suzuki Takeya Kasukawa Diane Lefaudeux Alexander Hoffmann Mariko Okada
author_facet	Minami Ando Shigeyuki Magi Masahide Seki Yutaka Suzuki Takeya Kasukawa Diane Lefaudeux Alexander Hoffmann Mariko Okada
author_sort	Minami Ando
title	IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells
title_short	IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells
title_full	IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells
title_fullStr	IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells
title_full_unstemmed	IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells
title_sort	iκbα is required for full transcriptional induction of some nfκb-regulated genes in response to tnf in mcf-7 cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/29d6b7c18ef04c3094c7dd706d16a6a5
work_keys_str_mv	AT minamiando ikbaisrequiredforfulltranscriptionalinductionofsomenfkbregulatedgenesinresponsetotnfinmcf7cells AT shigeyukimagi ikbaisrequiredforfulltranscriptionalinductionofsomenfkbregulatedgenesinresponsetotnfinmcf7cells AT masahideseki ikbaisrequiredforfulltranscriptionalinductionofsomenfkbregulatedgenesinresponsetotnfinmcf7cells AT yutakasuzuki ikbaisrequiredforfulltranscriptionalinductionofsomenfkbregulatedgenesinresponsetotnfinmcf7cells AT takeyakasukawa ikbaisrequiredforfulltranscriptionalinductionofsomenfkbregulatedgenesinresponsetotnfinmcf7cells AT dianelefaudeux ikbaisrequiredforfulltranscriptionalinductionofsomenfkbregulatedgenesinresponsetotnfinmcf7cells AT alexanderhoffmann ikbaisrequiredforfulltranscriptionalinductionofsomenfkbregulatedgenesinresponsetotnfinmcf7cells AT marikookada ikbaisrequiredforfulltranscriptionalinductionofsomenfkbregulatedgenesinresponsetotnfinmcf7cells
_version_	1718372180267368448

IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells

Ejemplares similares