Integration of phosphatidylinositol 3-kinase, Akt kinase, and Smad signaling pathway in BMP-2-induced osterix expression.
Osterix (Osx), a BMP-2-regulated transcription factor, controls expression of genes essential for osteoblast differentiation. Using progressive deletion of the Osx promoter, we characterized a Smad binding element (SBE) between -552 and -839 bp from its transcription start site. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay showed binding and in vivo recruitment of Smads 1 and 5 to the Osx SBE. Inactivation of PI 3-kinase by the pharmacologic inhibitor Ly294002 or by dominant negative (DN) enzyme significantly blocked BMP-2-induced Osx protein and mRNA expression and Osx transcription. Finally, both DN PI 3-kinase and DN Akt significantly attenuated Smad 5-dependent transcription of Osx, demonstrating the first evidence for a concerted action of PI 3-kinase/Akt signaling with BMP-specific Smads for expression of Osx.
Mandal
Chandi Charan
CC
Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Drissi
Hicham
H
Choudhury
Goutam Ghosh
GG
Ghosh-Choudhury
Nandini
N
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
D055396:Bone Morphogenetic Protein 2; D012333:RNA, Messenger; D051785:Smad Proteins; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt