TY - JOUR
T1 - Integration of phosphatidylinositol 3-kinase, akt kinase, and smad signaling pathway in BMP-2-induced osterix expression
AU - Mandal, Chandi Charan
AU - Drissi, Hicham
AU - Ghosh Choudhury, Goutam
AU - Ghosh-Choudhury, Nandini
N1 - Funding Information:
This work was supported by grants from the NIH (RO1 AR52425) and VA Medical Research Service Merit Review (to N. G.-C.) and grants from the NIH (RO1 DK50190), VA Merit Review, and Juvenile Diabetes Research Foundation (to G. G. C.). G. G. C. is a recipient of the Research Career Scientist Award from the Department of Veterans Affairs.
PY - 2010/12
Y1 - 2010/12
N2 - 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.
AB - 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.
KW - Bone morphogenetic protein
KW - Gene transcription regulation
KW - Osteoblast
KW - Osterix
KW - PI 3-kinase
KW - Smad
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U2 - 10.1007/s00223-010-9419-3
DO - 10.1007/s00223-010-9419-3
M3 - Article
C2 - 20872216
AN - SCOPUS:78649324674
SN - 0171-967X
VL - 87
SP - 533
EP - 540
JO - Calcified tissue international
JF - Calcified tissue international
IS - 6
ER -