Comparative roles of Twist-1 and Id1 in transcriptional regulation by BMP signaling.
Basic helix-loop-helix (bHLH) transcription factors are known as key regulators for mesenchymal differentiation. The present study showed that overexpression of Twist-1, a bHLH transcription factor, suppresses bone morphogenetic protein (BMP)-induced osteoblast differentiation, and downregulation of endogenous Twist-1 enhances BMP signaling. Maximal inhibition of BMP signaling was observed when Twist-1 was bound to E47, which markedly enhanced the stability of Twist-1. Co-immunoprecipitation assays revealed that Twist-1 formed a complex with Smad4 and histone deacetylase (HDAC) 1 in MC3T3-E1 cells stably expressing Twist-1. With trichostatin, an HDAC inhibitor, osteogenic factors such as alkaline phosphatase, Runx2 and osteopontin increased. Those results suggested that Twist-1 inhibited BMP signaling by recruiting HDAC1 to Smad4. Furthermore, the inhibitory effects of Twist-1 on BMP signaling were overcome by Id1 through induction of Twist-1 degradation. These findings suggest that Twist-1 can act as an inhibitor of BMP signaling, and Id1 can regulate BMP signaling through a positive feedback loop repressing Twist-1 function. These two molecules may therefore regulate differentiation of mesenchymal cells into progeny such as osteoblasts by controlling BMP signaling.
Hayashi
Masanori
M
Division of Gene Therapy Science, Graduate School of Medicine, Osaka University 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Nimura
Keisuke
K
Kashiwagi
Katsunobu
K
Harada
Taku
T
Takaoka
Kunio
K
Kato
Hiroyuki
H
Tamai
Katsuto
K
Kaneda
Yasufumi
Y
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D015870:Gene Expression; D051798:Inhibitor of Differentiation Protein 1 / Q000502:physiology*; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology*; D010006:Osteoblasts / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction; D014158:Transcription, Genetic; D051879:Twist-Related Protein 1 / Q000502:physiology*
D019485:Bone Morphogenetic Proteins; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1