Regulation of the activity of the transcription factor Runx2 by two homeobox proteins, Msx2 and Dlx5.
BACKGROUND
Runx2, formerly called PEBP2alphaA or Cbfa1, is a transcription factor whose deletion causes a complete lack of ossification. It directly regulates the expression of osteoblast-specific genes through the osteoblast-specific cis-acting element found in the promoter region of these genes.


RESULTS
In this study, we have found conditions in which induction of the expression of Runx2 is not accompanied by expression of an osteoblast-specific gene, osteocalcin in C2C12 cells. This finding suggests the existence of a repressor of the activity of Runx2. We have then found that the homeobox protein Msx2 is able to repress the transcription activity of Runx2 by interacting with it. Furthermore, our results have shown that the other homeobox protein Dlx5 has an activity which interferes with both abilities of Msx2 to interact with Runx2 and repress its transcription activity. It has previously been shown that a missense mutation of Msx2 (P148H) causes Boston-type craniosynostosis in humans. Interestingly, while this mutant form of Msx2 was able to bind to Runx2 and repress its activity, these abilities of Msx2 (P148H) were not subject to regulation by Dlx5.


CONCLUSIONS
These results suggest that regulation of the activity of Runx2 by Msx2 and Dlx5 plays an important role in the mammalian skull development.
Shirakabe
K
K
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Terasawa
K
K
Miyama
K
K
Shibuya
H
H
Nishida
E
E
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit; D003398:Craniosynostoses / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; C100596:DLX5 protein, human; D004268:DNA-Binding Proteins; C501120:Dlx5 protein, mouse; D018398:Homeodomain Proteins; C084119:MSX2 protein; D009363:Neoplasm Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D015675:Osteocalcin