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PMID:15383550

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Citation

Kim, YJ, Lee, MH, Wozney, JM, Cho, JY and Ryoo, HM (2004) Bone morphogenetic protein-2-induced alkaline phosphatase expression is stimulated by Dlx5 and repressed by Msx2. J. Biol. Chem. 279:50773-80

Abstract

Alkaline phosphatase (ALP) is a widely accepted bone marker. Its expression is stimulated by bone morphogenetic protein (BMP)-2 treatment, the activation of BMP receptors and R-Smads, and the expression of Dlx5 and Runx2. However, how BMP-2 induces ALP expression is not clearly understood. We dissected the murine ALP promoter and found within it a Dlx5-binding cis-acting element by electrophoretic mobility shift assays and site-directed mutagenesis of the element. Dlx5 and the product of its target gene, Runx2, stimulated ALP promoter activity in an additive manner. However, because Dlx5 continued to stimulate ALP expression in Runx2(-/-) cells, the ALP stimulatory activity of Dlx5 is independent of Runx2. We also found that overexpression of Msx2 suppressed the mRNA level and enzyme activity of ALP that were induced by BMP-2 stimulation, and suppressed the Dlx5-stimulated ALP promoter activity by competing with Dlx5 for the cis-acting element in the ALP promoter. Moreover, Msx2 levels are constitutively high in C2C12 myogenic cells but decrease over time after BMP-2 treatment. This may explain why BMP-2 treatment of these cells results in immediate Dlx5 expression yet ALP expression commences only 1-2 days later. In other words, Msx2 in high levels counteracts initially the transcriptional activity of Dlx5 in low levels until a threshold Dlx5:Msx2 ratio is reached to the levels that allow the ALP stimulatory activity of Dlx5 to prevail. Thus, Dlx5 transactivates ALP expression, directly by binding to its cognate response element and/or indirectly by stimulating Runx2 expression, and Msx2 counteracts the direct transactivation of Dlx5.

Links

PubMed Online version:10.1074/jbc.M404145200

Keywords

Alkaline Phosphatase/biosynthesis; Alkaline Phosphatase/metabolism; Animals; Base Sequence; Blotting, Northern; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins/metabolism; Cell Line; Cycloheximide/pharmacology; DNA/chemistry; DNA/metabolism; DNA-Binding Proteins/metabolism; Down-Regulation; Genes, Reporter; Homeodomain Proteins/metabolism; Humans; Luciferases/metabolism; Mice; Molecular Sequence Data; Mutagenesis, Site-Directed; Promoter Regions, Genetic; Protein Binding; Protein Structure, Tertiary; Protein Synthesis Inhibitors/pharmacology; RNA, Messenger/metabolism; Rats; Recombinant Proteins/chemistry; Time Factors; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transfection; Transforming Growth Factor beta/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:DLX5

involved_in

GO:0001649: osteoblast differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DLX5

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:DLX5

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MSX2

involved_in

GO:0001649: osteoblast differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MSX2

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:MSX2

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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