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Vol. 19, Issue 5, 2113-2126, May 2008

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p204 Protein Overcomes the Inhibition of Core Binding Factor -1–mediated Osteogenic Differentiation by Id Helix-Loop-Helix Proteins

Yi Luan^*,, Xiu-Ping Yu, Ning Yang^*, Sally Frenkel^*, Lin Chen, and Chuan-ju Liu^*,,

*Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003; Department of Cell Biology, New York University School of Medicine, New York, NY 10016; Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong 250012, China; and State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China

Submitted October 22, 2007; Revised January 25, 2008; Accepted February 13, 2008
Monitoring Editor: William Tansey

Id proteins play important roles in osteogenic differentiation; however, the molecular mechanism remains unknown. In this study, we established that inhibitor of differentiation (Id) proteins, including Id1, Id2, and Id3, associate with core binding factor -1 (Cbfa1) to cause diminished transcription of the alkaline phosphatase (ALP) and osteocalcin (OCL) gene, leading to less ALP activity and osteocalcin (OCL) production. Id acts by inhibiting the sequence-specific binding of Cbfa1 to DNA and by decreasing the expression of Cbfa1 in cells undergoing osteogenic differentiation. p204, an interferon-inducible protein that interacts with both Cbfa1 and Id2, overcame the Id2-mediated inhibition of Cbfa1-induced ALP activity and OCL production. We show that 1) p204 disturbed the binding of Id2 to Cbfa1 and enabled Cbfa1 to bind to the promoters of its target genes and 2) that p204 promoted the translocation from nucleus to the cytoplasm and accelerated the degradation of Id2 by ubiquitin–proteasome pathway during osteogenesis. Nucleus export signal (NES) of p204 is required for the p204-enhanced cytoplasmic translocation and degradation of Id2, because a p204 mutant lacking NES lost these activities. Together, Cbfa1, p204, and Id proteins form a regulatory circuit and act in concert to regulate osteoblast differentiation.

Address correspondence to: Chuan-ju Liu (chuanju.liu{at}med.nyu.edu).

Abbreviations used: ALP, alkaline phosphatase; BMP, bone morphogenetic protein; Cbfa1, core binding factor -1; CCD, cleidocranial dysplasia; CoIP, coimmunoprecipitation; FCS, fetal calf serum; GST, glutathione transferase; Id, inhibitor of differentiation; LMB, leptomycin B; MOI, multiplicity of infection; NES, nuclear export signal; NLS, nuclear localization signal; OCL, osteocalcin; PCR, polymerase chain reaction; pRb, retinoblastoma protein.