A RUNX2/PEBP2αA/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia

Yu Wen Zhang, Natsuo Yasui, Kosei Ito, Gang Huang, Makiko Fujii, Jun Ichi Hanai, Hiroshi Nogami, Takahiro Ochi, Kohei Miyazono, Yoshiaki Ito

Research output: Contribution to journalArticlepeer-review

308 Scopus citations

Abstract

Cleidocranial dysplasia (CCD), an autosomal-dominant human bone disease, is thought to be caused by heterozygous mutations in runt-related gene 2 (RUNX2)/polyomavirus enhancer binding protein 2αA (PEBP2αA)/core-binding factor A1 (CBFA1). To understand the mechanism underlying the pathogenesis of CCD, we studied a novel mutant of RUNX2, CCDαA376, originally identified in a CCD patient. The nonsense mutation, which resulted in a truncated RUNX2 protein, severely impaired RUNX2 transactivation activity. We show that signal transducers of transforming growth factor β superfamily receptors, Smads, interact with RUNX2 in vivo and in vitro and enhance the transactivation ability of this factor. The truncated RUNX2 protein failed to interact with and respond to Smads and was unable to induce the osteoblast-like phenotype in C2C12 myoblasts on stimulation by bone morphogenetic protein. Therefore, the pathogenesis of CCD may be related to the impaired Smad signaling of transforming growth factor β/bone morphogenetic protein pathways that target the activity of RUNX2 during bone formation.

Original languageEnglish (US)
Pages (from-to)10549-10554
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number19
DOIs
StatePublished - Sep 12 2000
Externally publishedYes

ASJC Scopus subject areas

  • General

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