Bone resorption by osteoclasts depends on an incompletely defined sequence of cellular events beginning with attachment bo bone matrix. Matrix attachment is mediated by the integrin avbeta3 and thus, regulation of the integrin complex on the cell surface represents a logical approach to controlling the resorptive process. We find that 1,25-dihydroxyvitamin D3 (1alpha, 25(OH), 2D3), which prompts osteoclast differentiation in vivo and in vitro, transcriptionally activate expression of integrin beta3 gene promoter region. The result in an enhanced expression of alphavbeta3 on the surface of avian osteoclast precursors. CRT is a multifunctional protein that acts as a major Ca2+ binding protein in the lumen of the endoplasmic reticulum and in the nucleus. It binds to the first zinc finger of steroid hormone receptors such as VDR, and prevents them from binding to their sterid hormone response elements. As a result, CRT modulates sterid hormone receptor-mediated gene transactivation. Furthermore, we have shown direct interaction between the VDR and calreticulin. Our central hypothesis is that the interaction of calreticulin and VDR modulates VDR genomic activity. The studies in his application are designed to establish the action of calreticulin on VDR-mediated gene transactivation and to elucidate the calreticulin function through the interaction of VDR and calreticulin.
Our specific aims are to: 1 Analyze the effects of CRT on 1alpha,25(OH)2D3-mediated again beta3 gene expression in osteoclast precursors. 2) Analyze the effects of CRT on osteoclast attachment to bone matrix and bone resorption. 3) Determine the role of CRT and VDR interaction in the translation of VDR into the nucleus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK053757-01
Application #
2623988
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Margolis, Ronald N
Project Start
1997-06-20
Project End
2002-04-30
Budget Start
1997-06-20
Budget End
1998-04-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Huang, Jin; Yuan, Honglin; Lu, Chongyuan et al. (2007) Jab1 mediates protein degradation of the Rad9-Rad1-Hus1 checkpoint complex. J Mol Biol 371:514-27
Yang, Lei; Wang, Ning; Tang, Yi et al. (2006) Acute myelogenous leukemia-derived SMAD4 mutations target the protein to ubiquitin-proteasome degradation. Hum Mutat 27:897-905
Wan, Mei; Huang, Jin; Jhala, Nirag C et al. (2005) SCF(beta-TrCP1) controls Smad4 protein stability in pancreatic cancer cells. Am J Pathol 166:1379-92
Wan, Mei; Tang, Yi; Tytler, Ewan M et al. (2004) Smad4 protein stability is regulated by ubiquitin ligase SCF beta-TrCP1. J Biol Chem 279:14484-7
Bai, Shuting; Cao, Xu (2002) A nuclear antagonistic mechanism of inhibitory Smads in transforming growth factor-beta signaling. J Biol Chem 277:4176-82
Wan, Mei; Cao, Xuesong; Wu, Yalei et al. (2002) Jab1 antagonizes TGF-beta signaling by inducing Smad4 degradation. EMBO Rep 3:171-6
Wan, M; Shi, X; Feng, X et al. (2001) Transcriptional mechanisms of bone morphogenetic protein-induced osteoprotegrin gene expression. J Biol Chem 276:10119-25
Shi, X; Bai, S; Li, L et al. (2001) Hoxa-9 represses transforming growth factor-beta-induced osteopontin gene transcription. J Biol Chem 276:850-5
Yang, X; Ji, X; Shi, X et al. (2000) Smad1 domains interacting with Hoxc-8 induce osteoblast differentiation. J Biol Chem 275:1065-72
Bai, S; Shi, X; Yang, X et al. (2000) Smad6 as a transcriptional corepressor. J Biol Chem 275:8267-70

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