GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:15150273

From GONUTS
Jump to: navigation, search
Citation

Sowa, H, Kaji, H, Hendy, GN, Canaff, L, Komori, T, Sugimoto, T and Chihara, K (2004) Menin is required for bone morphogenetic protein 2- and transforming growth factor beta-regulated osteoblastic differentiation through interaction with Smads and Runx2. J. Biol. Chem. 279:40267-75

Abstract

Menin, the product of the multiple endocrine neoplasia type 1 (MEN1) gene, is required for commitment of multipotential mesenchymal stem cells to the osteoblast lineage, however, it inhibits their later differentiation (Sowa, H., Kaji, H., Canaff, L., Hendy, G.N., Tsukamoto, T., Yamaguchi, T., Miyazono, K., Sugimoto, T., and Chihara, K. (2003) J. Biol. Chem. 278, 21058-21069). Here, we have examined the mechanism of action of menin in regulating osteoblast differentiation using the mouse bone marrow stromal ST2 and osteoblast MC3T3-E1 cell lines. In ST2 cells, reduced menin expression achieved by transfection of menin antisense DNA (AS) antagonized bone morphogenetic protein (BMP)-2-induced alkaline phosphatase activity and osteocalcin and Runx2 mRNA expression. Menin was co-immunoprecipitated with Smad1/5 in ST2 and MC3T3-E1 cells, and inactivation of menin antagonized BMP-2-induced transcriptional activity of Smad1/5 in ST2 cells, but not MC3T3-E1 cells. Menin was co-immunoprecipitated with the key osteoblast regulator, Runx2, and AS antagonized Runx2 transcriptional activity and the ability of Runx2 to stimulate alkaline phosphatase activity only in ST2 cells but not in MC3T3-E1 cells. In the osteoblast MC3T3-E1 cells, transforming growth factor-beta and its signaling molecule, Smad3, negatively regulated Runx2 transcriptional activity. Menin and Smad3 were co-immunoprecipitated, and combined menin and Smad3 overexpression antagonized, whereas menin and the dominant-negative Smad3DeltaC together enhanced BMP-2-induced transcriptional activity of Smad1/5 and Runx2. Smad3 alone had no effect. Therefore, menin interacts physically and functionally with Runx2 in uncommitted mesenchymal stem cells, but not in well differentiated osteoblasts. In osteoblasts the interaction of menin and the transforming growth factor-beta/Smad3 pathway negatively regulates the BMP-2/Smad1/5- and Runx2-induced transcriptional activities leading to inhibition of late-stage differentiation.

Links

PubMed Online version:10.1074/jbc.M401312200

Keywords

3T3 Cells; Alkaline Phosphatase/metabolism; Animals; Blotting, Western; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins/metabolism; Cell Differentiation; Cell Line; Core Binding Factor Alpha 1 Subunit; DNA/chemistry; DNA-Binding Proteins/metabolism; Genes, Reporter; Humans; Luciferases/metabolism; Mice; Models, Biological; Neoplasm Proteins/metabolism; Oligonucleotides, Antisense/chemistry; Osteoblasts/cytology; Osteoblasts/metabolism; Phosphoproteins/metabolism; Plasmids/metabolism; Precipitin Tests; Proto-Oncogene Proteins/physiology; RNA/metabolism; RNA, Messenger/metabolism; Recombinant Proteins/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Smad Proteins; Smad1 Protein; Smad3 Protein; Smad5 Protein; Subcellular Fractions; Time Factors; Trans-Activators/metabolism; Transcription Factors/metabolism; Transcription, Genetic; Transfection; Transforming Growth Factor beta/metabolism

Significance

Annotations

Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status


See also

References

See Help:References for how to manage references in GONUTS.