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PMID:20843790

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Citation

Cho, YD, Yoon, WJ, Woo, KM, Baek, JH, Park, JC and Ryoo, HM (2010) The canonical BMP signaling pathway plays a crucial part in stimulation of dentin sialophosphoprotein expression by BMP-2. J. Biol. Chem. 285:36369-76

Abstract

Dentin sialophosphoprotein (DSPP), a typical dentin-specific protein, is mainly expressed in the dentin extracellular matrix and plays a role in dentin mineralization. BMP-2 provides a strong signal for differentiation and mineralization of odontoblasts and osteoblasts. Previously, BMP-2 treatment is reported to stimulate Dspp expression in the MD10-F2 pre-odontoblast cells through activation of the heterotrimeric transcription factor Y (NF-Y). The canonical BMP signaling pathway is known to contribute greatly to biomineralization, however, it is not known whether it is involved in Dspp expression. Here, we investigated this question. Activation of the canonical BMP-2 signaling pathway in MDPC-23, preodontoblast cell, by overexpression of constitutively active Smad1/5 or downstream transcription factors Dlx5 and Runx2 stimulated Dspp expression. Conversely, knockdown of each element with siRNA significantly blocked the BMP-2-induced Dspp expression. To test whether these transcription factors downstream of BMP-2 are directly involved in regulating Dspp, we analyzed the mouse Dspp promoter. There are 5 well conserved homeodomain binding elements, H1 to H5, in Dspp proximal promoter regions (-791 to +54). A serial deletion of H1 and H2 greatly changed basal promoter activity and responsiveness to Dlx5 or Msx2. However, further deletions did not change the responsiveness to Dlx5 or Msx2. H1 and H2 sites can be suggested as specific response elements of Dlx5 and Msx2, respectively, based on their promoter activity modulation. Thus, the canonical BMP-2 signaling pathway plays a crucial part in the regulation of Dspp expression through the action of Smads, Dlx5, Runx2, and Msx2.

Links

PubMed PMC2978565 Online version:10.1074/jbc.M110.103093

Keywords

Animals; Blotting, Western; Bone Morphogenetic Protein 2/genetics; Bone Morphogenetic Protein 2/metabolism; Cell Differentiation; Cells, Cultured; Core Binding Factor Alpha 1 Subunit/antagonists & inhibitors; Core Binding Factor Alpha 1 Subunit/genetics; Core Binding Factor Alpha 1 Subunit/metabolism; Electrophoretic Mobility Shift Assay; Extracellular Matrix Proteins/genetics; Extracellular Matrix Proteins/metabolism; Gene Expression Regulation; Homeodomain Proteins/antagonists & inhibitors; Homeodomain Proteins/genetics; Homeodomain Proteins/metabolism; Luciferases/metabolism; Mice; Odontoblasts/cytology; Odontoblasts/metabolism; Phosphoproteins/genetics; Phosphoproteins/metabolism; Promoter Regions, Genetic/genetics; Protein Binding; RNA, Messenger/genetics; RNA, Small Interfering/pharmacology; Response Elements/genetics; Reverse Transcriptase Polymerase Chain Reaction; Sialoglycoproteins/genetics; Sialoglycoproteins/metabolism; Signal Transduction; Smad2 Protein/antagonists & inhibitors; Smad2 Protein/genetics; Smad2 Protein/metabolism; Smad3 Protein/antagonists & inhibitors; Smad3 Protein/genetics; Smad3 Protein/metabolism

Significance

Annotations

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

HUMAN:BMP2

involved_in

GO:0030509: BMP signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP2

involved_in

GO:0071773: cellular response to BMP stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP2

involved_in

GO:1901522: positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SMAD1

involved_in

GO:1901522: positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P97454

P

Seeded From UniProt

complete

MOUSE:DLX5

located_in

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:DLX5

involved_in

GO:0030509: BMP signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DLX5

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0000167)

Seeded From UniProt

complete

MOUSE:DLX5

enables

GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

MOUSE:DLX5

involved_in

GO:0071773: cellular response to BMP stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DLX5

involved_in

GO:1901522: positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SMAD5

involved_in

GO:1901522: positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P70340

P

Seeded From UniProt

complete

MOUSE:TYY1

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TYY1

enables

GO:0001227: DNA-binding transcription repressor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

MOUSE:MSX2

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MSX2

enables

GO:0000981: DNA-binding transcription factor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:MSX2

involved_in

GO:2000678: negative regulation of transcription regulatory region DNA binding

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RUNX2

involved_in

GO:0030509: BMP signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RUNX2

involved_in

GO:0071773: cellular response to BMP stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RUNX2

involved_in

GO:1901522: positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SMAD1

involved_in

GO:0030509: BMP signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P97454

P

Seeded From UniProt

complete

MOUSE:SMAD1

involved_in

GO:0071773: cellular response to BMP stimulus

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P97454

P

Seeded From UniProt

complete

MOUSE:SMAD1

involved_in

GO:1901522: positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P97454

P

part_of:(GO:0071773)

Seeded From UniProt

complete

MOUSE:SMAD5

involved_in

GO:0071773: cellular response to BMP stimulus

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P70340

P

Seeded From UniProt

complete

MOUSE:SMAD5

involved_in

GO:0030509: BMP signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P70340

P

Seeded From UniProt

complete

MOUSE:SMAD5

involved_in

GO:1901522: positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P70340

P

part_of:(GO:0071773)

Seeded From UniProt

complete


See also

References

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