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Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma

Although GBP1 (guanylate binding protein 1) was among the first interferon-inducible proteins identified, its function is still largely unknown. Epidermal growth factor receptor (EGFR) activation by amplification or mutation is one of the most frequent genetic lesions in a variety of human tumors. T...

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Autores principales: Li, Ming, Mukasa, Akitake, del-Mar Inda, Maria, Zhang, Jianhua, Chin, Lynda, Cavenee, Webster, Furnari, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244036/
https://www.ncbi.nlm.nih.gov/pubmed/22162832
http://dx.doi.org/10.1084/jem.20111102
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author Li, Ming
Mukasa, Akitake
del-Mar Inda, Maria
Zhang, Jianhua
Chin, Lynda
Cavenee, Webster
Furnari, Frank
author_facet Li, Ming
Mukasa, Akitake
del-Mar Inda, Maria
Zhang, Jianhua
Chin, Lynda
Cavenee, Webster
Furnari, Frank
author_sort Li, Ming
collection PubMed
description Although GBP1 (guanylate binding protein 1) was among the first interferon-inducible proteins identified, its function is still largely unknown. Epidermal growth factor receptor (EGFR) activation by amplification or mutation is one of the most frequent genetic lesions in a variety of human tumors. These include glioblastoma multiforme (GBM), which is characterized by independent but interrelated features of extensive invasion into normal brain parenchyma, rapid growth, necrosis, and angiogenesis. In this study, we show that EGFR activation promoted GBP1 expression in GBM cell lines through a signaling pathway involving Src and p38 mitogen-activated protein kinase. Moreover, we identified YY1 (Yin Yang 1) as the downstream transcriptional regulator regulating EGFR-driven GBP1 expression. GBP1 was required for EGFR-mediated MMP1 (matrix metalloproteinase 1) expression and glioma cell invasion in vitro. Although deregulation of GBP1 expression did not affect glioma cell proliferation, overexpression of GBP1 enhanced glioma cell invasion through MMP1 induction, which required its C-terminal helical domain and was independent of its GTPase activity. Reducing GBP1 levels by RNA interference in invasive GBM cells also markedly inhibited their ability to infiltrate the brain parenchyma of mice. GBP1 expression was high and positively correlated with EGFR expression in human GBM tumors and cell lines, particularly those of the neural subtype. Together, these findings establish GBP1 as a previously unknown link between EGFR activity and MMP1 expression and nominate it as a novel potential therapeutic target for inhibiting GBM invasion.
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spelling pubmed-32440362012-06-19 Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma Li, Ming Mukasa, Akitake del-Mar Inda, Maria Zhang, Jianhua Chin, Lynda Cavenee, Webster Furnari, Frank J Exp Med Article Although GBP1 (guanylate binding protein 1) was among the first interferon-inducible proteins identified, its function is still largely unknown. Epidermal growth factor receptor (EGFR) activation by amplification or mutation is one of the most frequent genetic lesions in a variety of human tumors. These include glioblastoma multiforme (GBM), which is characterized by independent but interrelated features of extensive invasion into normal brain parenchyma, rapid growth, necrosis, and angiogenesis. In this study, we show that EGFR activation promoted GBP1 expression in GBM cell lines through a signaling pathway involving Src and p38 mitogen-activated protein kinase. Moreover, we identified YY1 (Yin Yang 1) as the downstream transcriptional regulator regulating EGFR-driven GBP1 expression. GBP1 was required for EGFR-mediated MMP1 (matrix metalloproteinase 1) expression and glioma cell invasion in vitro. Although deregulation of GBP1 expression did not affect glioma cell proliferation, overexpression of GBP1 enhanced glioma cell invasion through MMP1 induction, which required its C-terminal helical domain and was independent of its GTPase activity. Reducing GBP1 levels by RNA interference in invasive GBM cells also markedly inhibited their ability to infiltrate the brain parenchyma of mice. GBP1 expression was high and positively correlated with EGFR expression in human GBM tumors and cell lines, particularly those of the neural subtype. Together, these findings establish GBP1 as a previously unknown link between EGFR activity and MMP1 expression and nominate it as a novel potential therapeutic target for inhibiting GBM invasion. The Rockefeller University Press 2011-12-19 /pmc/articles/PMC3244036/ /pubmed/22162832 http://dx.doi.org/10.1084/jem.20111102 Text en © 2011 Li et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Li, Ming
Mukasa, Akitake
del-Mar Inda, Maria
Zhang, Jianhua
Chin, Lynda
Cavenee, Webster
Furnari, Frank
Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma
title Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma
title_full Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma
title_fullStr Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma
title_full_unstemmed Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma
title_short Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma
title_sort guanylate binding protein 1 is a novel effector of egfr-driven invasion in glioblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244036/
https://www.ncbi.nlm.nih.gov/pubmed/22162832
http://dx.doi.org/10.1084/jem.20111102
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