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First published online 20 March 2007
doi: 10.1242/jcs.000067

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Comparative roles of Twist-1 and Id1 in transcriptional regulation by BMP signaling

¹ Division of Gene Therapy Science, Graduate School of Medicine, Osaka University 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
² Department of Orthopedic Surgery, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
³ Department of Orthopedic Surgery, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan

^* Author for correspondence (e-mail: kaneday{at}gts.med.osaka-u.ac.jp)

Accepted 12 February 2007

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.

Key words: Twist-1, Id1, BMP, Smad, HDAC

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