Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CIZ (Cas interacting zinc finger protein), also called Nmp4 (nuclear matrix protein 4), is a nucleo-cytoplasmic shuttling transcription factor that regulates the expression of collagen and matrix metalloproteinases. CIZ/Nmp4 was originally cloned by its binding to p130(Cas), a focal adhesion protein, and was recently shown to suppress BMP2 (bone mophogenetic protein 2) signalling. To explore the physiological role of CIZ/Nmp4, we disrupted CIZ/Nmp4-gene by inserting beta-galactosidase and neomycin resistance genes into the 2nd exon of CIZ/Nmp4-gene, which is utilized by all the sequenced alternative forms. CIZ-/- mice were born and grew to adulthood. Although they tend to be smaller than wild-type mice, no pathological abnormality was observed except in the testis. Histological analysis of the testes revealed variable degrees of spermatogenic cell degeneration within the seminiferous tubules of CIZ-/- mice, resembling the histology of the 'Germinal-cell aplasia with focal spermatogenesis'. Some of the CIZ-/- male mice developed infertility. TUNEL assay on testis sections revealed an increased occurrence of apoptosis of spermatogenic cells in the testes of CIZ-/- mice. CIZ/Nmp4 was co-localized with Smad1 in the testis, suggesting that a disregulation of BMP signalling could cause these phenotypes. These results suggest that CIZ/Nmp4 plays roles in the progress and the maintenance of spermatogenesis.
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PMID:Impaired spermatogenesis and male fertility defects in CIZ/Nmp4-disrupted mice. 1518 50

Bone marrow-derived mesenchymal stem cells (BMDMSC) hold promise for targeted osteogenic differentiation and can be augmented by delivery of genes encoding bone morphogenetic proteins (BMP). The feasibility of promoting osteogenic differentiation of BMDMSC was investigated using two BMP genes in monolayer and three-dimensional alginate culture systems. Cultured BMDMSC were transduced with E1-deleted adenoviral vectors containing either human BMP2 or BMP6 coding sequence under cytomegalovirus (CMV) promoter control [17:1 multiplicities of infection (moi)] and either sustained in monolayer or suspended in 1 mL 1.2% alginate beads for 22 days. Adenovirus (Ad)-BMP-2 and Ad-BMP-6 transduction resulted in abundant BMP-2 and BMP-6 mRNA and protein expression in monolayer culture and BMP-2 protein expression in alginate cultures. Ad-BMP-2 and Ad-BMP-6 transduced BMDMSC in monolayer had earlier and robust alkaline phosphatase-positive staining and mineralization and were sustained for a longer duration with better morphology scores than untransduced or Ad-beta-galactosidase-transduced cells. Ad-BMP-2- and, to a lesser degree, Ad-BMP-6-transduced BMDMSC suspended in alginate demonstrated greater mineralization than untransduced cells. Gene expression studies at day 2 confirmed an inflammatory response to the gene delivery process with upregulation of interleukin 8 and CXCL2. Upregulation of genes consistent with response to BMP exposure and osteogenic differentiation, specifically endochondral ossification and extracellular matrix proteins, occurred in BMP-transduced cells. These data support that transduction of BMDMSC with Ad-BMP-2 or Ad-BMP-6 can accelerate osteogenic differentiation and mineralization of stem cells in culture, including in three-dimensional culture. BMP-2-transduced stem cells suspended in alginate culture may be a practical carrier system to support bone formation in vivo. BMP-6 induced a less robust cellular response than BMP-2, particularly in alginate culture.
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PMID:Gene-mediated osteogenic differentiation of stem cells by bone morphogenetic proteins-2 or -6. 1664 80

Progress in FGF-2 gene therapy has been hampered by the difficulty in achieving therapeutic levels of FGF-2 secretion. This study tested whether the addition of BMP2/4 hybrid secretion signal to the FGF-2 gene and mutation of cys-70 and cys-88 to serine and asparagine, respectively, would increase the stability and secretion of active FGF-2 protein in mammalian cells using MLV-based vectors. Single or double mutations of cys-70 and cys-88 to ser-70 and asp-88, respectively, markedly increased the amounts of FGF-2 protein in conditioned media and cell lysates, which may be due to glycosylation, particularly at the mutated asp-88 residue. Addition of BMP2/4 secretion signal increased FGF-2 secretion, but also suppressed FGF-2 biosynthesis. The combination of BMP2/4 secretion signal and double cys-70 and cys-88 mutations increased the total amount of secreted FGF-2 protein >60-fold. The modifications did not alter its ability to stimulate cell proliferation and Erk1/2 phosphorylation in marrow stromal cells or its ability to bind heparin in vitro, suggesting that the modified FGF-2 protein was functionally as effective as the unmodified FGF-2. An ex vivo application of rat skin fibroblasts (RSF) transduced with the modified FGF-2 vector in a subcutaneous implant model showed that rats with implants containing cells transduced with the modified FGF-2 vector increased serum FGF-2 level >15-fold, increased growth of the implant, and increased vascularization within the implant, compared to rats that received implants containing beta-galactosidase- or wild-type FGF-2-transduced control cells. This modified vector may be useful in FGF-2 gene therapy investigations.
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PMID:Modifications of the fibroblast growth factor-2 gene led to a marked enhancement in secretion and stability of the recombinant fibroblast growth factor-2 protein. 1724 99

Embryonic stem (ES) cells have the capacity to differentiate into all cells of the developing embryo and may provide a renewable resource for future cell replacement therapies. The addition of bone morphogenetic protein 4 (BMP4) to serum-free ES cell culture has previously been shown to induce transcription factors, signaling molecules, and cell adhesion proteins expressed during mesoderm specification of the embryo. Here, we show the dynamics of primitive streak mesoderm differentiation in ES cells is comparable between serum and serum-free embryoid body (EB) cultures, supplemented with BMP4. Furthermore, we show a delayed wave of expression of a cohort of genes (Pax2, WT1, podocalyxin, pod-1, and nephrin), which play important roles during embryonic kidney development. The paired box transcription factor, Pax2, is one of the earliest genes expressed during kidney organogenesis and is required for normal urogenital development. ES cell lines containing either a modified Pax2 promoter-lacZ or bacterial artificial chromosome-green fluorescent protein (GFP) transgene were generated, which enabled the quantitative analysis of kidney rather than neuronal Pax2 expression within EBs. Both beta-galactosidase activity and GFP expression were detected by immunohistochemical and flow cytometric analysis following 16 days of EB culture, which correlated with an increase in Pax2 transcript levels. Together, these results suggest a spontaneous kidney gene expression program develops in mature EBs grown in both serum and serum-free conditions, when supplemented with BMP4. Further, the recombinant growth factors BMP2, BMP4, and BMP7 strongly influence gene expression within mesoderm induced EBs. BMP4 promotes ventral (blood) and intermediate (kidney) mesoderm gene expression, whereas BMP2 and BMP7 promote kidney outcomes at the expense of hematopoietic commitment. This induction assay and these unique ES cell lines will be useful for the generation of mesoderm-derived cell populations with implications for future cell therapeutic/integration assays.
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PMID:In vitro differentiation of murine embryonic stem cells toward a renal lineage. 1728 99

We determined the feasibility of using scaffolds of adenoviral human BMP2 gene (AdBMP2)-modified human bone marrow mesenchymal stem cells (hBMSCs) and antigen-free bovine cancellous bone (BCB) to construct bone tissue. hMSCs were infected with AdBMP-2. Expression of BMP-2 and alkaline phosphatase confirmed successful secretion of active BMP-2. The osteogenic capability of a composite of AdBMP2-modified hMSCs with BCB was evaluated in athymic mice (group A). BCB (group B), hMSCs/BCB (group C), adenoviral beta-galactosidase genes (Adbetagal)-transfected hMSCs/BCB (group D) were controls. Formation of bone tissue was assessed by histological methods 4 weeks and 8 weeks after implantation. Implanted cells were identified by human Y-chromosome-specific fluorescence in-situ hybridization (FISH). hMSCs differentiated into osteogenic cells, and bone formation was observed. Obvious bone formation was not noted at any time point in control groups. We hypothesize that the described method is a promising method for bone regeneration.
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PMID:Ectopic osteogenesis of hBMP-2 gene-transduced human bone mesenchymal stem cells/BCB. 2017 10