Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of clomiphene citrate given in vivo upon the in vitro uptake of labeled estradiol (tritiated-E2) was investigated in a 60-year-old patient with breast cancer who had had a mastectomy 10 months earlier followed by radiotherapy. Multiple subcutaneous metastatic nodules and enlargement of the liver were present but bone metastases could not be shown. A biopsy from a subcutaneous nodule, taken prior to present treatment, showed 86 fmol estradiol binding sites per mg of cytoplasmic protein with a dissociation constant of the estradiol-estradiol binding protein interaction of 2.8 X 10 -10 M. The patient was treated with 200 mg clomiphene citrate daily. Subjective symptoms improved and a reduction of skin nodule size and of liver enlargement followed. The serum enzymes alkaline phosphatase, nucleotidase, and phosphohexoseisomerase were diminished. A 2nd biopsy taken at Day 26 of treatment with clomiphene citrate showed complete inhibition of labeled estradiol tritiated-E2 uptake by the cytosol protein. This finding is thought to show the absence of free binding sites after clomiphene citrate therapy. Microscopic studies of biopsy material were unchanged. These results are thought to be the first to record human in vivo inhibition of trititated-E2 uptake for EBP by an antiestrogen compound, although similar in vitro observations have been made in human tumor specimens. There is thought to be a potential value of antiestrogenic agents, alone or with inhibitors of prolactin secretion, to replace endocrine ablations and to predict the response to endocrine therapy.
...
PMID:In vivo blockade of the estradiol-binding-protein (EBP) by clomiphene citrate in human breast cancer. 437 71

Using the c-fos enhancer as a model to analyze growth hormone (GH)-promoted gene expression, the roles of CCAAT/enhancer-binding proteins (C/EBPs) in GH-regulated transcription were investigated. In 3T3-F442A fibroblasts stably expressing the c-fos promoter mutated at the C/EBP binding site upstream of luciferase, c-fos promoter activity is stimulated by GH 6-7-fold; wild type c-fos promoter shows only a 2-fold induction by GH. This suggests that C/EBP restrains GH-stimulated expression of c-fos. Electrophoretic mobility shift assays with nuclear extracts from 3T3-F442A cells indicate that GH rapidly (2-5 min) increases binding of C/EBPbeta and C/EBPdelta, to the c-fos C/EBP binding site. Both liver activating protein (LAP) and liver inhibitory protein (LIP), forms of C/EBPbeta, are detected in 3T3-F442A cells by immunoblotting. GH increases the binding of LAP/LAP and LAP/LIP dimers. Overexpression of LIP interferes with GH-promoted reporter expression in CHO cells expressing GH receptors, consistent with the possibility that LIP restrains GH-stimulated c-fos expression. Overexpression of LAP elevates basal luciferase activity but does not influence promoter activation by GH, while overexpressed C/EBPdelta elevates basal promoter activity and enhances the stimulation by GH. GH stimulates the expression of mRNA for C/EBPbeta and -delta and increases levels of C/EBPdelta. Although C/EBPbeta is not detectably altered, GH induces a shift to more rapidly migrating forms of LIP and LAP upon immunoblotting. Treatment of extracts from GH-treated cells with alkaline phosphatase causes a shift of the slower migrating form to the rapidly migrating form, consistent with GH promoting dephosphorylation of LIP and LAP. These studies implicate C/EBPbeta and -delta in GH-regulated gene expression. They also indicate that GH stimulates the binding of C/EBPbeta and -delta to the c-fos promoter and promotes the dephosphorylation of LIP and LAP. These events may contribute to the ability of C/EBPbeta and -delta to regulate GH-stimulated expression of c-fos.
...
PMID:CCAAT/enhancer-binding protein beta (C/EBPbeta) and C/EBPdelta contribute to growth hormone-regulated transcription of c-fos. 1053 66

Intestinal epithelial cells participate in an acute phase response (APR) by responding to cytokines and by expressing acute phase protein genes. We hypothesized that butyrate, a fermentation product of the bacterial intestinal flora with deacetylase activity, affects the APR in intestinal epithelial cells. Sodium butyrate (NaBu) and Trichostatin A (TSA) induced alkaline phosphatase activity and histone H4 acetylation in IEC-6 rat intestinal epithelial cells treated with or without interleukin-1beta (IL-1). In contrast, both NaBu and TSA attenuated the IL-1-dependent induction of the acute phase protein gene haptoglobin, as well as C/EBPbeta and C/EBPdelta transcription factors mRNAs. Gel shift and supershift assays showed a strong decrease in the IL-1-induced C/EBPbeta and C/EBPdelta containing complexes binding to the HaptoA C/EBP DNA-binding site of the haptoglobin promoter, by NaBu and TSA. Furthermore, site-specific mutation of the HaptoA site abolished the NaBu- and TSA-dependent inhibition of haptoglobin, as determined by transient transfection assays. These results suggest that deacetylase inhibitors may regulate the IL-1 dependent induction of haptoglobin by down-regulating C/EBP isoforms, and that C/EBPs represent a target for the action of butyrate in the control of the APR of intestinal epithelial cells.
...
PMID:Inhibition by deacetylase inhibitors of IL-1-dependent induction of haptoglobin involves CCAAT/Enhancer-binding protein isoforms in intestinal epithelial cells. 1102 30

Bile salts are rapidly removed from the circulation by the liver-specific sodium/taurocholate cotransporter (SLC10A1). To understand factors controlling its liver-specific expression, we isolated human SLC10A1 from a YAC chromosomal clone. SLC10A1 spans approximately 23 kb distributed over five exons. The major transcription start site is at 299 bp, and a minor start site is at 395 bp from the translational start site. A 1.2-kb portion of the 5' flanking region was sequenced and shown to contain a number of liver-enriched elements, but no TATA box. Using secreted alkaline phosphatase reporter constructs liver-specific expression was examined. Transient transfection demonstrated that SLC10A1 promoter expression was selectively expressed eightfold in FAO and rat hepatocytes, while deletion mutants demonstrated liver-specific expression in a region extending from -5 to +198 bp, which contained putative sites for C/EBP and HNF3. Mutations of the C/EBP site resulted in loss of 77% of transcriptional activity. Cotransfection of C/EBP, but not other putative liver-enriched binding factors, increased SLC10A1 promoter activity. Electrophoretic mobility shift assays demonstrated specific protein-DNA interactions that involved C/EBPalpha and beta. These studies demonstrate that the TATA-less human SLC10A1 promoter exhibits liver-specific activity and its regulatory elements contain binding sites for C/EBP, which contributes specifically to its transcriptional regulation.
...
PMID:Structural and functional characterization of liver cell-specific activity of the human sodium/taurocholate cotransporter. 1103 Nov 3

Bone marrow stroma contain pluripotential cells with the potential to differentiate into various mesenchymal cell lineages. We compared the effect of cortisol and bone morphogenetic protein-2 (BMP-2) on the differentiation of murine ST-2 stromal cells into mature osteoblasts or adipocytes. ST-2 cells were cultured for 3-27 days in the presence of 10% fetal bovine serum, 100 microg/mL ascorbic acid, and 5 mmol/L beta-glycerolphosphate in the presence or absence of cortisol at 1 micromol/L or BMP-2 at 1 nmol/L. Untreated ST-2 cells expressed high levels of alkaline phosphatase activity (APA) 15 days after confluence, and this was followed by the appearance of mineralized nodules after 24 days. BMP-2 accelerated and intensified the appearance of cells expressing APA and the presence of mineralized nodules. In contrast, cortisol decreased APA, prevented the formation of mineralized nodules, and induced a cellular phenotype characteristic of adipocytes. Untreated stromal cells expressed osteocalcin, Cbfa1, type I collagen, and alkaline phosphatase mRNA. BMP-2 increased osteocalcin and alkaline phosphatase mRNA, whereas cortisol suppressed their expression, as well as Cbfa1 and type I collagen transcripts. Cortisol enhanced, and BMP-2 downregulated, peroxisome proliferator-activated receptor gamma 2 and adipsin transcripts. The C/EBP transcription factors regulate genes critical for adipocytic and osteoblastic differentiation. Cortisol increased the expression of C/EBP alpha, beta, delta, and gamma mRNA levels, whereas BMP-2 had minor effects on C/EBP expression. In conclusion, BMP-2 accelerates the differentiation of stromal cells toward an osteoblastic phenotype, whereas glucocorticoids induce their differentiation toward an adipocytic phenotype.
...
PMID:Effects of cortisol and bone morphogenetic protein-2 on stromal cell differentiation: correlation with CCAAT-enhancer binding protein expression. 1199 5

The product of the leptin gene is a 16-kDa protein secreted by adipose tissue and regulates adiposity. The leptin gene could be a potential candidate gene controlling some proportion of adipose and lean accretion in cattle, and thus, may be referred to as one of genetic factor controlling meat quality determinants such as marbling. We have isolated the bovine leptin gene including its promoter region. We have determined the exon-intron organization of the bovine leptin gene, which consisted of three exons and two introns and spanned about 18.9 kb, equivalent to that of human or mouse gene. A approximately 3-kb 5'-flanking region upstream from the putative transcription start site of the gene contained consensus Sp1 and CCAAT/enhancer-binding protein (C/EBP) motifs, and transient transfection assay with secreted alkaline phosphatase reporter confirmed the promoter activity in 3T3-L1 cells that possessed expression of the cotransfected C/EBP alpha expression plasmid. Cotransfection with C/EBP alpha caused 24-fold activation in leptin reporter expression, as compared to cotransfection with control plasmid, consistent with existence of the putative C/EBP alpha binding site in the proximal 5'-flanking region of the bovine leptin gene.
...
PMID:Genomic structure and promoter analysis of the bovine leptin gene. 1204 96

CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP/DDIT3), a member of the C/EBP family of transcription factors, plays a role in cell survival and differentiation. CHOP/DDIT3 binds to C/EBPs to form heterodimers that do not bind to consensus Cebp sequences, acting as a dominant-negative inhibitor. CHOP/DDIT3 blocks adipogenesis, and we postulated it could induce osteoblastogenesis. We investigated the effects of constitutive CHOP/DDIT3 overexpression in murine ST-2 stromal cells transduced with retroviral vectors. ST-2 cells differentiated toward osteoblasts, and CHOP/DDIT3 accelerated and enhanced the appearance of mineralized nodules, and the expression of osteocalcin and alkaline phosphatase mRNAs, particularly in the presence of bone morphogenetic protein-2. CHOP/DDIT3 overexpression opposed adipogenesis, and did not cause substantial changes in cell number. CHOP/DDIT3 overexpression did not modify C/EBPalpha or -beta mRNA levels but decreased C/EBPdelta after 24 d of culture. Electrophoretic mobility shift and supershift assays demonstrated that overexpression of CHOP/DDIT3 decreased the binding of C/EBPs to their consensus sequence by interacting with C/EBPalpha and -beta, confirming its dominant-negative role. In addition, CHOP/DDIT3 enhanced bone morphogenetic protein-2/Smad signaling. In conclusion, CHOP/DDIT3 enhances osteoblastic differentiation of stromal cells, in part by interacting with C/EBPalpha and -beta and also by enhancing Smad signaling.
...
PMID:CCAAT/enhancer binding protein homologous protein (DDIT3) induces osteoblastic cell differentiation. 1468 14

Mice deficient in the Msx2 gene manifest defects in skull ossification and a marked reduction in bone formation associated with decreases in osteoblast numbers, thus suggesting that Msx2 is involved in bone formation. However, the precise role of Msx2 during osteoblast differentiation is not fully understood. In the present study, we investigated the role of Msx2 in the regulation of osteoblast differentiation in the multipotent mesenchymal cell lines C3H10T1/2 and C2C12 and in murine primary osteoblasts. Introduction of Msx2 induced alkaline phosphatase activity in C3H10T1/2 and C2C12 cells and promoted the calcification of murine primary osteoblasts. This effect of Msx2 was also observed in mesenchymal cells isolated from Runx2-deficient mice. Interestingly the expression of Msx2 was induced by bone morphogenetic protein 2 treatment in Runx2-deficient mesenchymal cells. In contrast, Msx2 diminished peroxisome proliferator-activated receptor gamma (PPARgamma) expression and adipogenesis of the preadipocytic cell line 3T3-F442A. Moreover Msx2 inhibited the transcriptional activity of PPARgamma, CCAAT/enhancer-binding protein beta (C/EBPbeta), and C/EBPdelta and blocked adipocyte differentiation of mesenchymal cells induced by overexpression of PPARgamma, C/EBPalpha, C/EBPbeta, or C/EBPdelta. These data indicate that Msx2 promotes osteoblast differentiation independently of Runx2 and negatively regulates adipocyte differentiation through inhibition of PPARgamma and the C/EBP family.
...
PMID:Reciprocal roles of MSX2 in regulation of osteoblast and adipocyte differentiation. 1517 25

Differentiation of committed osteoblasts is controlled by complex activities involving signal transduction and gene expression, and Runx2 and Osterix function as master regulators for this process. Recently, CCAAT/enhancer-binding proteins (C/EBPs) have been reported to regulate osteogenesis in addition to adipogenesis. However, the roles of C/EBP transcription factors in the control of osteoblast differentiation have yet to be fully elucidated. Here we show that C/EBP homologous protein (CHOP; also known as C/EBPzeta) is expressed in bone as well as in mesenchymal progenitors and primary osteoblasts. Overexpression of CHOP reduces alkaline phosphatase activity in primary osteoblasts and suppresses the formation of calcified bone nodules. CHOP-deficient osteoblasts differentiate more strongly than their wild-type counterparts, suggesting that endogenous CHOP plays an important role in the inhibition of osteoblast differentiation. Furthermore, endogenous CHOP induces differentiation of calvarial osteoblasts upon bone morphogenetic protein (BMP) treatment. CHOP forms heterodimers with C/EBPbeta and inhibits the DNA-binding activity as well as Runx2-binding activity of C/EBPbeta, leading to inhibition of osteocalcin gene transcription. These findings indicate that CHOP acts as a dominant-negative inhibitor of C/EBPbeta and prevents osteoblast differentiation but promotes BMP signaling in a cell-type-dependent manner. Thus, endogenous CHOP may have dual roles in regulating osteoblast differentiation and bone formation.
...
PMID:CCAAT/enhancer-binding protein homologous protein (CHOP) regulates osteoblast differentiation. 1688 May 21

Runx2/CBFA1/AML3 is a master regulator of the osteoblast lineage and has been shown to directly control the transcription of numerous osteoblast-specific genes including alkaline phosphatase, osteopontin, and type I collagen. In its absence, ossification does not occur during development resulting in animals with cartilaginous skeletons and no osteoblasts. In humans, loss of one copy of Runx2 causes cleidocranial dysplasia characterized by malformations of the facial and cranial bones and the clavicle. Despite its important role in osteoblast biology, relatively little is known about the transcriptional regulation of the Runx2 gene. In the present study, we show that CCAAT/enhancer binding protein beta (C/EBPbeta) is a negative regulator of Runx2 expression and acts by directly binding a C/EBP element located at -591/-576 within the osteoblast-specific Runx2 P1 promoter. Ectopic expression of C/EBPbeta in C3H10T1/2 cells causes a reduction in Runx2 expression concomitant with a decrease in osteogenic potential during all-trans retinoic acid (ATRA)-induced differentiation. In nondifferentiating cells, C/EBPbeta can be found occupying the C/EBP negative response element within the Runx2 P1 promoter. ATRA, the effects of which are mediated by retinoic acid receptor alpha and gamma in C3H10T1/2 cells, stimulates the dissociation of C/EBPbeta from this element and promotes Runx2 expression. Thus, ATRA initiates osteoblastic differentiation of C3H10T1/2 cells, at least in part, by triggering the dissociation of C/EBPbeta from the Runx2 promoter.
...
PMID:CCAAT/Enhancer binding protein beta abrogates retinoic acid-induced osteoblast differentiation via repression of Runx2 transcription. 1757 10


1 2 3 Next >>

---