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Microarray profiling reveals the integrated stress response is activated by halofuginone in mammary epithelial cells

BACKGROUND: The small molecule Halofuginone (HF) is a potent regulator of extracellular matrix (ECM ) gene expression and is unique in its therapeutic potential. While the basis for HF effects is unknown, inhibition of TGFβ signaling and activation of the amino acid restriction response (AAR) have b...

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Autores principales: Kamberov, Yana G, Kim, Jihoon, Mazitschek, Ralph, Kuo, Winston P, Whitman, Malcolm
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197508/
https://www.ncbi.nlm.nih.gov/pubmed/21974968
http://dx.doi.org/10.1186/1756-0500-4-381
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author Kamberov, Yana G
Kim, Jihoon
Mazitschek, Ralph
Kuo, Winston P
Whitman, Malcolm
author_facet Kamberov, Yana G
Kim, Jihoon
Mazitschek, Ralph
Kuo, Winston P
Whitman, Malcolm
author_sort Kamberov, Yana G
collection PubMed
description BACKGROUND: The small molecule Halofuginone (HF) is a potent regulator of extracellular matrix (ECM ) gene expression and is unique in its therapeutic potential. While the basis for HF effects is unknown, inhibition of TGFβ signaling and activation of the amino acid restriction response (AAR) have been linked to HF transcriptional control of a number of ECM components and amelioration of fibrosis and alleviation of autoimmune disease by regulation of Th17 cell differentiation, respectively. The aim of this study was to generate a global expression profile of HF targets in epithelial cells to identify potential mediators of HF function in this cell type. RESULTS: We report that HF modulation of the expression of the ECM remodeling protein Mmp13 in epithelial cells is separable from previously reported effects of HF on TGFβ signal inhibition, and use microarray expression analysis to correlate this with transcriptional responses characteristic of the Integrated Stress Response (ISR). CONCLUSIONS: Our findings suggest activation of the ISR may be a common mechanism underlying HF biological effects.
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spelling pubmed-31975082011-10-21 Microarray profiling reveals the integrated stress response is activated by halofuginone in mammary epithelial cells Kamberov, Yana G Kim, Jihoon Mazitschek, Ralph Kuo, Winston P Whitman, Malcolm BMC Res Notes Research Article BACKGROUND: The small molecule Halofuginone (HF) is a potent regulator of extracellular matrix (ECM ) gene expression and is unique in its therapeutic potential. While the basis for HF effects is unknown, inhibition of TGFβ signaling and activation of the amino acid restriction response (AAR) have been linked to HF transcriptional control of a number of ECM components and amelioration of fibrosis and alleviation of autoimmune disease by regulation of Th17 cell differentiation, respectively. The aim of this study was to generate a global expression profile of HF targets in epithelial cells to identify potential mediators of HF function in this cell type. RESULTS: We report that HF modulation of the expression of the ECM remodeling protein Mmp13 in epithelial cells is separable from previously reported effects of HF on TGFβ signal inhibition, and use microarray expression analysis to correlate this with transcriptional responses characteristic of the Integrated Stress Response (ISR). CONCLUSIONS: Our findings suggest activation of the ISR may be a common mechanism underlying HF biological effects. BioMed Central 2011-10-05 /pmc/articles/PMC3197508/ /pubmed/21974968 http://dx.doi.org/10.1186/1756-0500-4-381 Text en Copyright ©2011 Kamberov et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Kamberov, Yana G
Kim, Jihoon
Mazitschek, Ralph
Kuo, Winston P
Whitman, Malcolm
Microarray profiling reveals the integrated stress response is activated by halofuginone in mammary epithelial cells
title Microarray profiling reveals the integrated stress response is activated by halofuginone in mammary epithelial cells
title_full Microarray profiling reveals the integrated stress response is activated by halofuginone in mammary epithelial cells
title_fullStr Microarray profiling reveals the integrated stress response is activated by halofuginone in mammary epithelial cells
title_full_unstemmed Microarray profiling reveals the integrated stress response is activated by halofuginone in mammary epithelial cells
title_short Microarray profiling reveals the integrated stress response is activated by halofuginone in mammary epithelial cells
title_sort microarray profiling reveals the integrated stress response is activated by halofuginone in mammary epithelial cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197508/
https://www.ncbi.nlm.nih.gov/pubmed/21974968
http://dx.doi.org/10.1186/1756-0500-4-381
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