title: The Forkhead Transcription Factor FOXP2 Is Required for Regulation of p21WAF1/CIP1 in 143B Osteosarcoma Cell Growth Arrest.
abstract: 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.
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DU United Kingdom.
authors.forename: Duncan M
authors.initials: DM
authors.lastname: Gascoyne
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DU United Kingdom.
authors.forename: Hayley
authors.initials: H
authors.lastname: Spearman
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DU United Kingdom.
authors.forename: Linden
authors.initials: L
authors.lastname: Lyne
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN United Kingdom.
authors.forename: Rathi
authors.initials: R
authors.lastname: Puliyadi
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DU United Kingdom.
authors.forename: Marta
authors.initials: M
authors.lastname: Perez-Alcantara
authors.affiliation: Academic Unit of Bone Biology, Dept of Human Metabolism, University of Sheffield, Sheffield, S10 2RX United Kingdom.
authors.forename: Les
authors.initials: L
authors.lastname: Coulton
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, and Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
authors.affiliation: Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Croucher
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DU United Kingdom.
authors.forename: Alison H
authors.initials: AH
authors.lastname: Banham
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger