Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteoblasts are differentiated cells that produce bone matrix components including the bone-specific protein osteocalcin. The osteocalcin gene promoter has become a model for understanding how genes are regulated, specifically in osteoblasts. One model for cell-specific regulation suggests that osteoblast-expressed genes are regulated through common promoter sequences which bind osteoblast-specific transcriptional activators. The phenotype suppression model suggests osteoblast-specific promoters are switched off through the action of the common transcriptional activator AP1. We previously demonstrated that a short sequence element (OSCARE-2) in the osteocalcin promoter was homologous to a repressive element in the collagen type 1 (alpha 1) promoters. In this paper we use electrophoretic mobility shift (EMS) assays to examine DNA-protein interactions in the OSCARE-2 sequence. In EMS assays, OSCARE-2 binds a complex of proteins, including AP1. This supports the role of AP1 sites in contributing to the regulation of the osteocalcin promoter. Exogenous c-JUN protein bound to OSCARE-2 and increasing c-JUN incubated with nuclear extract amounts caused a progressive increase in a higher-molecular-weight complex, consistent with c-JUN involvement in protein-protein as well as DNA-protein interactions. Anti-c-FOS antibody was capable of supershifting OSCARE-2 DNA-protein complexes produced using osteoblast-like cell nuclear extracts. In addition, EMS assays of nuclear proteins from osteoblast-like cells indicated that 1,25 (OH)2D3-inducible proteins are bound to OSCARE-2. Osteocalcin promoter constructs showed that OSCARE-2 contributed to the 1,25 (OH)2D3 response, albeit in a minor way. These data support the role of AP1 protein as a regulator of osteoblast-specific gene expression during osteoblast development.
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PMID:Identification of an osteocalcin gene promoter sequence that binds AP1. 870 85

The molecular mechanisms that couple osteoblast structure and gene expression are emerging from recent studies on the bone extracellular matrix, integrins, the cytoskeleton, and the nucleoskeleton (nuclear matrix). These proteins form a dynamic structural network, the tissue matrix, that physically links the genes with the substructure of the cell and its substrate. The molecular analog of cell structure is the geometry of the promoter. The degree of supercoiling and bending of promoter DNA can regulate transcriptional activity. Nuclear matrix proteins may render a change in cytoskeletal organization into a bend or twist in the promoter of target genes. We review the role of nuclear matrix proteins in the regulation of gene expression with special emphasis on osseous tissue. Nuclear matrix proteins bind to the osteocalcin and type I collagen promoters in osteoblasts. One such protein is Cbfa1, a recently described transcriptional activator of osteoblast differentiation. Although their mechanisms of action are unknown, some nuclear matrix proteins may act as "architectural" transcription factors, regulating gene expression by bending the promoter and altering the interactions between other trans-acting proteins. The osteoblast nuclear matrix is comprised of cell- and phenotype-specific proteins including proteins common to all cells. Nuclear matrix proteins specific to the osteoblast developmental stage and proteins that distinguish osteosarcoma from the osteoblast have been identified. Recent studies indicating that nuclear matrix proteins mediate bone cell response to parathyroid hormone and vitamin D are discussed.
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PMID:Nuclear matrix proteins and osteoblast gene expression. 949 8

Although much has been learned about growth plate development and chondrocyte gene expression during cellular maturation and matrix remodeling in the mouse, there has been a limited study of the interrelationships of gene expression between proteinases, growth factors, and other regulatory molecules in the mouse and in other species. Here we use RT-PCR of sequential transverse sections to examine the expression profiles of genes involved in chondrocyte growth, differentiation, matrix assembly, remodeling, and mineralization in the bovine proximal tibial growth plate. Specifically, we studied the expression of genes encoding COL2A1 and COL10A1, the latter a marker of cellular hypertrophy, the matrix metalloproteinases (MMP), MMP-13 and MMP-9, as well as the transcriptional factors, Sox9 and Cbfa1, the growth factors basic fibroblast growth factor (bFGF), parathyroid hormone-related peptide (PTHrP), transforming growth factor (TGF)beta1, and beta2, Indian hedgehog (Ihh), and the matrix protein osteocalcin. These were analyzed in relationship to cell division defined by cyclin B2 expression. Two peaks of gene expression activity were observed. One was transient, limited, and located immediately before and at the onset of cyclin B2 expression in the early proliferative zone. The other was generally much more pronounced and was located in the early hypertrophic zone. The upregulation of expression of COL2A1, its transcriptional activator Sox9, osteocalcin, MMP-13, and TGFbeta2 was observed immediately before and at the onset of cyclin B2 expression and also in the hypertrophic zones. The upregulation of COL10A1, Cbfa1, MMP-9, TGFbeta-1, and Ihh gene expression was associated exclusively with the terminal differentiation of chondrocytes at the time of mineral formation in the extracellular matrix. In contrast, bFGF and PTHrP expression was observed in association with the onset of cyclin B2 expression and hypertrophy. This initial cluster of gene expression associated predominantly with matrix assembly and onset of cell proliferation is therefore characterized by expression of regulatory molecules distinct from those involved at hypertrophy. Together these results identify separate phases of coordinated gene expression associated with the development of the physis in endochondral bone formation.
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PMID:Distinct phases of coordinated early and late gene expression in growth plate chondrocytes in relationship to cell proliferation, matrix assembly, remodeling, and cell differentiation. 1273 23