The Forkhead Transcription Factor FOXP2 Is Required for Regulation of p21WAF1/CIP1 in 143B Osteosarcoma Cell Growth Arrest

• Published in: PloS one 2015-06, Vol.10 (6), p.e0128513-e0128513
• Main Authors: Gascoyne, Duncan M, Spearman, Hayley, Lyne, Linden, Puliyadi, Rathi, Perez-Alcantara, Marta, Coulton, Les, Fisher, Simon E, Croucher, Peter I, Banham, Alison H
• Format: Article
• Language: English
• 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
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0128513

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.