The Forkhead Transcription Factor FOXP2 Is Required for Regulation of p21WAF1/CIP1 in 143B Osteosarcoma Cell Growth Arrest
Mutations of the forkhead transcription factor FOXP2 gene have been implicated in inherited speech-and-language disorders, and specific Foxp2 expression patterns in neuronal populations and neuronal phenotypes arising from Foxp2 disruption have been described. However, molecular functions of FOXP2 a...
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description | Mutations of the forkhead transcription factor FOXP2 gene have been implicated in inherited speech-and-language disorders, and specific Foxp2 expression patterns in neuronal populations and neuronal phenotypes arising from Foxp2 disruption have been described. However, molecular functions of FOXP2 are not completely understood. Here we report a requirement for FOXP2 in growth arrest of the osteosarcoma cell line 143B. We observed endogenous expression of this transcription factor both transiently in normally developing murine osteoblasts and constitutively in human SAOS-2 osteosarcoma cells blocked in early osteoblast development. Critically, we demonstrate that in 143B osteosarcoma cells with minimal endogenous expression, FOXP2 induced by growth arrest is required for up-regulation of p21WAF1/CIP1. Upon growth factor withdrawal, FOXP2 induction occurs rapidly and precedes p21WAF1/CIP1 activation. Additionally, FOXP2 expression could be induced by MAPK pathway inhibition in growth-arrested 143B cells, but not in traditional cell line models of osteoblast differentiation (MG-63, C2C12, MC3T3-E1). Our data are consistent with a model in which transient upregulation of Foxp2 in pre-osteoblast mesenchymal cells regulates a p21-dependent growth arrest checkpoint, which may have implications for normal mesenchymal and osteosarcoma biology. |
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However, molecular functions of FOXP2 are not completely understood. Here we report a requirement for FOXP2 in growth arrest of the osteosarcoma cell line 143B. We observed endogenous expression of this transcription factor both transiently in normally developing murine osteoblasts and constitutively in human SAOS-2 osteosarcoma cells blocked in early osteoblast development. Critically, we demonstrate that in 143B osteosarcoma cells with minimal endogenous expression, FOXP2 induced by growth arrest is required for up-regulation of p21WAF1/CIP1. Upon growth factor withdrawal, FOXP2 induction occurs rapidly and precedes p21WAF1/CIP1 activation. Additionally, FOXP2 expression could be induced by MAPK pathway inhibition in growth-arrested 143B cells, but not in traditional cell line models of osteoblast differentiation (MG-63, C2C12, MC3T3-E1). Our data are consistent with a model in which transient upregulation of Foxp2 in pre-osteoblast mesenchymal cells regulates a p21-dependent growth arrest checkpoint, which may have implications for normal mesenchymal and osteosarcoma biology.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0128513</identifier><identifier>PMID: 26034982</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amino acids ; Animal models ; Animals ; Apoptosis ; Biocompatibility ; Biology ; Blotting, Western ; Bone cancer ; Bone Neoplasms - genetics ; Bone Neoplasms - metabolism ; Bone Neoplasms - pathology ; Cell culture ; Cell Cycle ; Cell Proliferation ; Cells, Cultured ; Chromatin Immunoprecipitation ; Cyclin-dependent kinase inhibitor p21 ; Cyclin-Dependent Kinase Inhibitor p21 - genetics ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; Cyclin-dependent kinases ; Forkhead protein ; Forkhead Transcription Factors - antagonists & inhibitors ; Forkhead Transcription Factors - genetics ; Forkhead Transcription Factors - metabolism ; Foxp2 protein ; Gene expression ; Gene Expression Regulation, Neoplastic ; Humans ; Immunoenzyme Techniques ; Kinases ; Laboratories ; Lymphocytes ; Male ; MAP kinase ; Medicine ; Mesenchyme ; Mice ; Mice, Inbred C57BL ; Molecular chains ; Multiple myeloma ; Mutation ; Osteoblastogenesis ; Osteoblasts ; Osteoblasts - cytology ; Osteoblasts - metabolism ; Osteosarcoma ; Osteosarcoma - genetics ; Osteosarcoma - metabolism ; Osteosarcoma - pathology ; Osteosarcoma cells ; Pathogenesis ; Phosphatase ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; Sarcoma ; Stem cells ; Transcription factors</subject><ispartof>PloS one, 2015-06, Vol.10 (6), p.e0128513-e0128513</ispartof><rights>2015 Gascoyne et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Gascoyne et al 2015 Gascoyne et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5073-af22f7ab3883ae5903f1b7b00f7508b2c9d193e7fd00cf6e66be95c9376803553</citedby><cites>FETCH-LOGICAL-c5073-af22f7ab3883ae5903f1b7b00f7508b2c9d193e7fd00cf6e66be95c9376803553</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452790/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452790/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26034982$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Vanacker, Jean-Marc</contributor><creatorcontrib>Gascoyne, Duncan M</creatorcontrib><creatorcontrib>Spearman, Hayley</creatorcontrib><creatorcontrib>Lyne, Linden</creatorcontrib><creatorcontrib>Puliyadi, Rathi</creatorcontrib><creatorcontrib>Perez-Alcantara, Marta</creatorcontrib><creatorcontrib>Coulton, Les</creatorcontrib><creatorcontrib>Fisher, Simon E</creatorcontrib><creatorcontrib>Croucher, Peter I</creatorcontrib><creatorcontrib>Banham, Alison H</creatorcontrib><title>The Forkhead Transcription Factor FOXP2 Is Required for Regulation of p21WAF1/CIP1 in 143B Osteosarcoma Cell Growth Arrest</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Mutations of the forkhead transcription factor FOXP2 gene have been implicated in inherited speech-and-language disorders, and specific Foxp2 expression patterns in neuronal populations and neuronal phenotypes arising from Foxp2 disruption have been described. 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Our data are consistent with a model in which transient upregulation of Foxp2 in pre-osteoblast mesenchymal cells regulates a p21-dependent growth arrest checkpoint, which may have implications for normal mesenchymal and osteosarcoma biology.</description><subject>Amino acids</subject><subject>Animal models</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biocompatibility</subject><subject>Biology</subject><subject>Blotting, Western</subject><subject>Bone cancer</subject><subject>Bone Neoplasms - genetics</subject><subject>Bone Neoplasms - metabolism</subject><subject>Bone Neoplasms - pathology</subject><subject>Cell culture</subject><subject>Cell Cycle</subject><subject>Cell Proliferation</subject><subject>Cells, Cultured</subject><subject>Chromatin Immunoprecipitation</subject><subject>Cyclin-dependent kinase inhibitor p21</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</subject><subject>Cyclin-dependent kinases</subject><subject>Forkhead protein</subject><subject>Forkhead Transcription Factors - antagonists & inhibitors</subject><subject>Forkhead Transcription Factors - genetics</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Foxp2 protein</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Immunoenzyme Techniques</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Lymphocytes</subject><subject>Male</subject><subject>MAP kinase</subject><subject>Medicine</subject><subject>Mesenchyme</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Molecular chains</subject><subject>Multiple myeloma</subject><subject>Mutation</subject><subject>Osteoblastogenesis</subject><subject>Osteoblasts</subject><subject>Osteoblasts - cytology</subject><subject>Osteoblasts - metabolism</subject><subject>Osteosarcoma</subject><subject>Osteosarcoma - genetics</subject><subject>Osteosarcoma - metabolism</subject><subject>Osteosarcoma - pathology</subject><subject>Osteosarcoma cells</subject><subject>Pathogenesis</subject><subject>Phosphatase</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - 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genetics</topic><topic>Bone Neoplasms - metabolism</topic><topic>Bone Neoplasms - pathology</topic><topic>Cell culture</topic><topic>Cell Cycle</topic><topic>Cell Proliferation</topic><topic>Cells, Cultured</topic><topic>Chromatin Immunoprecipitation</topic><topic>Cyclin-dependent kinase inhibitor p21</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</topic><topic>Cyclin-dependent kinases</topic><topic>Forkhead protein</topic><topic>Forkhead Transcription Factors - antagonists & inhibitors</topic><topic>Forkhead Transcription Factors - genetics</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Foxp2 protein</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Immunoenzyme Techniques</topic><topic>Kinases</topic><topic>Laboratories</topic><topic>Lymphocytes</topic><topic>Male</topic><topic>MAP kinase</topic><topic>Medicine</topic><topic>Mesenchyme</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Molecular chains</topic><topic>Multiple myeloma</topic><topic>Mutation</topic><topic>Osteoblastogenesis</topic><topic>Osteoblasts</topic><topic>Osteoblasts - 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However, molecular functions of FOXP2 are not completely understood. Here we report a requirement for FOXP2 in growth arrest of the osteosarcoma cell line 143B. We observed endogenous expression of this transcription factor both transiently in normally developing murine osteoblasts and constitutively in human SAOS-2 osteosarcoma cells blocked in early osteoblast development. Critically, we demonstrate that in 143B osteosarcoma cells with minimal endogenous expression, FOXP2 induced by growth arrest is required for up-regulation of p21WAF1/CIP1. Upon growth factor withdrawal, FOXP2 induction occurs rapidly and precedes p21WAF1/CIP1 activation. Additionally, FOXP2 expression could be induced by MAPK pathway inhibition in growth-arrested 143B cells, but not in traditional cell line models of osteoblast differentiation (MG-63, C2C12, MC3T3-E1). Our data are consistent with a model in which transient upregulation of Foxp2 in pre-osteoblast mesenchymal cells regulates a p21-dependent growth arrest checkpoint, which may have implications for normal mesenchymal and osteosarcoma biology.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26034982</pmid><doi>10.1371/journal.pone.0128513</doi><oa>free_for_read</oa></addata></record> |
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subjects | Amino acids Animal models Animals Apoptosis Biocompatibility Biology Blotting, Western Bone cancer Bone Neoplasms - genetics Bone Neoplasms - metabolism Bone Neoplasms - pathology Cell culture Cell Cycle Cell Proliferation Cells, Cultured Chromatin Immunoprecipitation Cyclin-dependent kinase inhibitor p21 Cyclin-Dependent Kinase Inhibitor p21 - genetics Cyclin-Dependent Kinase Inhibitor p21 - metabolism Cyclin-dependent kinases Forkhead protein Forkhead Transcription Factors - antagonists & inhibitors Forkhead Transcription Factors - genetics Forkhead Transcription Factors - metabolism Foxp2 protein Gene expression Gene Expression Regulation, Neoplastic Humans Immunoenzyme Techniques Kinases Laboratories Lymphocytes Male MAP kinase Medicine Mesenchyme Mice Mice, Inbred C57BL Molecular chains Multiple myeloma Mutation Osteoblastogenesis Osteoblasts Osteoblasts - cytology Osteoblasts - metabolism Osteosarcoma Osteosarcoma - genetics Osteosarcoma - metabolism Osteosarcoma - pathology Osteosarcoma cells Pathogenesis Phosphatase Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics Sarcoma Stem cells Transcription factors |
title | The Forkhead Transcription Factor FOXP2 Is Required for Regulation of p21WAF1/CIP1 in 143B Osteosarcoma Cell Growth Arrest |
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