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

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Query: EC:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A thorough examination of the structure and plasticity of the neuromuscular system was performed in tenascin-C mutant mice deficient in tenascin-C. The study of the peripheral nerve revealed a number of abnormal features. In the motor nerve, numerous unmyelinated and myelinated fibers with degraded myelin were present. Schwann cell processes often enclosed degenerative terminals. Transgene (beta-galactosidase) expression analyzed at the ultrastructural level was found to be unequally distributed in the mutant's neuromuscular tissues. At the NMJ, preterminal disorganization was prevalent. Some axon terminals exhibited abnormal overgrowth. A surprising lack of beta-galactosidase expression at some cellular sites known to possess tenascin-C in wild type mice correlated best with marked changes in the cytoarchitecture of the peripheral nerve and NMJ. In some other -but not all- cellular sites which normally express the molecule, immunofluorescence analysis suggested the presence of significant but low levels of tenascin-C-like immunoreactivity together with beta-galactosidase expression. Messenger RNA detection by RT-PCR confirmed the presence of low amounts of tenascin-C mRNA in skeletal muscle suggesting that the mice deficient in tenascin-C are not complete knock-outs of this gene, but low-expression mutants. Following in vivo injections of botulinum type-A toxin, we observed a greatly reduced sprouting response of the motor nerves in tenascin-C mutant mice. We also observed that N-CAM and beta-catenin were overexpressed in the mutant. Our results suggest that tenascin-C is involved both in stabilization and in plasticity of the NMJ.
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PMID:The peripheral nerve and the neuromuscular junction are affected in the tenascin-C-deficient mouse. 959 87

The majority of colonic neoplasias contain mutations in either the adenomatous polyposis coli or the beta-catenin (beta-cat) gene, both of which result in elevated levels of cytoplasmic beta-cat. The oncogenic activity of beta-cat has been explored in vivo and in vitro with conflicting results. We tested the hypothesis that beta-cat is capable of immortalizing and transforming cultured epithelial cells that represent the precursors to colon cancer. A truncated form of beta-cat (deltaN89) was stably expressed in murine colonic epithelial cells that were conditionally immortalized by temperature-sensitive T antigen expression and contained a mutant ApcMin allele [Immorto-Min colonic epithelium (IMCE)]. IMCE cells, grown under nonpermissive conditions, were immortalized by expression of the truncated beta-cat protein as determined by sustained growth in culture and escape from senescence as measured by endogenous beta-galactosidase activity. IMCE neo cells at nonpermissive conditions underwent extensive apoptosis, an effect that was blocked by the expression of deltaN89 beta-catenin. IMCE beta-cat cells had significantly lower p19 and p53 protein levels compared to IMCE neo cells, suggesting that alterations in these two key genes may mediate the effects of beta-cat on both cellular senescence and apoptosis. IMCE beta-cat cells were also transformed as determined by growth in the absence of serum, anchorage-independent growth, and sustained tumor growth in nude mice. Stable beta-cat-expressing populations could not be generated in conditionally immortalized colonic epithelia cells with a wild-type Apc background. These studies demonstrated the immortalizing activity of stabilized beta-cat for the first time and extend the transforming ability of mutated beta-cat to a cell line representing a precursor to colorectal cancer.
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PMID:Stabilized beta-catenin immortalizes colonic epithelial cells. 1128 Jul 72

Lithium affects development of various organisms and cell fate through the inhibition of glycogen synthase kinase-3 beta and induction of the Wnt/beta-catenin signaling pathway. In this study, we investigated the effects of lithium on primary bovine aortic endothelial cells (BAEC). Lithium treatment of BAEC induced beta-catenin stabilization but failed to activate the transcriptional activity of the beta-catenin/T-cell factor complex. Lithium caused a sustained G(2)/M cell cycle arrest without affecting cell viability. Reversibility of this cell cycle arrest occurred up to 3 days after treatment but was reduced thereafter. Lithium-treated BAEC exhibited a senescent-like morphology with an increase in cells positive for the senescence-associated-beta-galactosidase activity. Lithium also increased the expression of p21(Cip), a cyclin-dependent kinase inhibitor, both at the protein and RNA levels. No change in p21(Cip) mRNA stability was observed, whereas the transcriptional activity of a p21(Cip) promoter-luciferase construct containing p53 binding sites was increased after lithium treatment. Furthermore, lithium caused increased transcription of a reporter gene under the control of a promoter containing the p53 consensus binding sites both in transiently transfected BAEC and in a stably transfected fibroblast cell line. Lithium caused accumulation of p53 protein in BAEC without affecting p53 mRNA levels. Finally, up-regulation of p21(Cip) in response to lithium did not occur in mouse embryonic fibroblasts that were null for p53 alleles, confirming the dependence on a p53 pathway for this lithium effect. These findings demonstrate for the first time that lithium induces also stabilization of the tumor suppressor p53 and reveal a new mechanism that may contribute to the neuroprotective effects of lithium.
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PMID:Lithium inhibits cell cycle progression and induces stabilization of p53 in bovine aortic endothelial cells. 1133 98

There is an urgent need for improved therapies for inoperable metastatic colon cancer. Gene-directed enzyme prodrug therapy (GDEPT) using adenovirus vectors works well in preclinical models of this disease, but successful clinical application is hampered by an inability to construct vectors that express at high levels in infected tumor cells but not in infected normal cells. Constitutive activation of beta-catenin-dependent gene expression is almost certainly a key causative event in the genesis of colon and some other cancers. Here we have exploited this oncogenic defect to design a synthetic promoter, CTP1, that, in contrast to currently available tumor-selective promoters, is both highly active in cancer cells and highly cancer-cell-specific. CTP1 directs high-level beta-galactosidase expression in freshly isolated biopsies of secondary colon cancer, but is not detectably active in associated normal liver tissue. We also demonstrate that CTP1 can direct high-level, tumor-specific therapeutic gene expression in vivo. Intratumoral injection of an adenovirus vector encoding Escherichia coli nitroreductase driven by CTP1 efficiently sensitized SW480 xenografts to the prodrug CB1954, whereas systemic vector and prodrug administration produced no apparent signs of toxicity. CTP1 may form the basis for effective, targeted gene therapy of metastatic colon cancer and other tumors with deregulated beta-catenin/T cell factor.
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PMID:High-level, beta-catenin/TCF-dependent transgene expression in secondary colorectal cancer tissue. 1159 40

Loss of functional adenomatous polyposis coli protein (APC) leads to uncontrolled proliferation of colonic epithelial cells, as evidenced by polyp formation, a prelude to carcinogenesis. As a tumor suppressor, APC targets the oncogene beta-catenin for proteasome-mediated cytoplasmic degradation. Recently, it was demonstrated that APC also interacts with nuclear beta-catenin, thereby reducing beta-catenin's activity as a transcription cofactor and enhancing its nuclear export. The first objective of this study was to analyze how cellular context affected APC distribution. We determined that cell density but not cell cycle influenced APC's subcellular distribution, with predominantly nuclear APC found in subconfluent MDCK and intestinal epithelial cells but both cytoplasmic and nuclear APC in superconfluent cells. Redistribution of APC protein did not depend on continual nuclear export. Focusing on the two defined nuclear localization signals in the C-terminal third of APC (NLS1(APC) and NLS2(APC)), we found that phosphorylation at the CK2 site increased and phosphorylation at the PKA site decreased NLS2(APC)-mediated nuclear translocation. Cell density-mediated redistribution of beta-galactosidase was achieved by fusion to NLS2(APC) but not to NLS1(APC). Both the CK2 and PKA sites were important for this density-mediated redistribution, and pharmacological agents that target CK2 and PKA instigated relocalization of endogenous APC. Our data provide evidence that physiological signals such as cell density regulate APC's nuclear distribution, with phosphorylation sites near NLS2(APC) being critical for this regulation.
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PMID:Cell density and phosphorylation control the subcellular localization of adenomatous polyposis coli protein. 1168 3

Wntbeta-catenin signaling plays key roles in several developmental and pathological processes. Domains of Wnt expression have been extensively investigated in the mouse, but the tissues receiving the signal remain largely unidentified. To define which cells respond to activated beta-catenin during mammalian development, we generated the beta-catenin-activated transgene driving expression of nuclear beta-galactosidase reporter (BAT-gal) transgenic mice, expressing the lacZ gene under the control of beta-cateninT cell factor responsive elements. Reporter gene activity is found in known organizing centers, such as the midhindbrain border and the limb apical ectodermal ridge. Moreover, BAT-gal expression identifies novel sites of Wnt signaling, like notochord, endothelia, and areas of the adult brain, revealing an unsuspected dynamic pattern of beta-catenin transcriptional activity. Expression of the transgene was analyzed in mutant backgrounds. In lipoprotein receptor-related protein 6-null homozygous mice, which lack a Wnt coreceptor, BAT-gal staining is absent in mutant tissues, indicating that BAT-gal mice are bona fide in vivo indicators of Wntbeta-catenin signaling. Analyses of BAT-gal expression in the adenomatous polyposis coli (multiple intestinal neoplasia+) background revealed betacatenin transcriptional activity in intestinal adenomas but surprisingly not in normal crypt cells. In summary, BAT-gal mice unveil the entire complexity of Wntbeta-catenin signaling in mammals and have broad application potentials for the identification of Wnt-responsive cell populations in development and disease.
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PMID:Mapping Wnt/beta-catenin signaling during mouse development and in colorectal tumors. 1262 57

The Wnts are a family of glycoproteins that regulate cell proliferation, fate decisions, and differentiation. In our study, we examined the contribution of Wnts to the development of ventral midbrain (VM) dopaminergic (DA) neurons. Our results show that beta-catenin is expressed in DA precursor cells and that beta-catenin signaling takes place in these cells, as assessed in TOPGAL [Tcf optimal-promoter beta-galactosidase] reporter mice. We also found that Wnt-1, -3a, and -5a expression is differentially regulated during development and that partially purified Wnts distinctively regulate VM development. Wnt-3a promoted the proliferation of precursor cells expressing the orphan nuclear receptor-related factor 1 (Nurr1) but did not increase the number of tyrosine hydroxylase-positive neurons. Instead, Wnt-1 and -5a increased the number of rat midbrain DA neurons in rat embryonic day 14.5 precursor cultures by two distinct mechanisms. Wnt-1 predominantly increased the proliferation of Nurr1+ precursors, up-regulated cyclins D1 and D3, and down-regulated p27 and p57 mRNAs. In contrast, Wnt-5a primarily increased the proportion of Nurr1+ precursors that acquired a neuronal DA phenotype and up-regulated the expression of Ptx3 and c-ret mRNA. Moreover, the soluble cysteine-rich domain of Frizzled-8 (a Wnt inhibitor) blocked endogenous Wnts and the effects of Wnt-1 and -5a on proliferation and the acquisition of a DA phenotype in precursor cultures. These findings indicate that Wnts are key regulators of proliferation and differentiation of DA precursors during VM neurogenesis and that different Wnts have specific and unique activity profiles.
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PMID:Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a. 1455 50

Beta-catenin is a critical regulator of cell behavior during embryogenesis and neoplastic processes. It also plays a crucial role in repair by modulating dermal fibroblast activity during the proliferative phase of cutaneous wound healing. We hypothesize that growth factors liberated during the initial phase of wound healing convey signals to induce activation of beta-catenin-mediated TCF-dependent signaling during the proliferative phase. Dermal fibroblasts were isolated and cultured from mice containing a beta-galactosidase reporter responsive to beta-catenin-TCF transactivation (TCF-beta-gal). Cells were stimulated with growth factors present at the initial phase of wound healing. EGF and TGF-beta1 significantly increased beta-catenin protein levels and transcriptional activity, whereas beta-catenin mRNA expression was unaffected. This increase was attributed to inactivation of GSK-3beta, a kinase important for beta-catenin destabilization. Subcutaneous injection of EGF or TGF-beta1 before wounding of TCF-beta-gal mice resulted in larger scars and fibroblasts within these wounds that strongly stained for beta-galactosidase, indicating significant beta-catenin transcriptional activity in vivo. Thus, beta-catenin-mediated signaling is activated downstream of growth factors released during the initial phase of wound repair, and may act during the proliferative phase of wound healing to integrate signals from initial phase factors into the expression of genes important during the later, remodeling phase.
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PMID:Growth factors regulate beta-catenin-mediated TCF-dependent transcriptional activation in fibroblasts during the proliferative phase of wound healing. 1472 64

In the past decades, the function of the Wnt canonical pathway during embryogenesis has been intensively investigated; however, little survey of neonatal and adult tissues has been made, and the role of this pathway remains largely unknown. To investigate its role in mature tissues, we generated two new reporter transgenic mouse lines, ins-TOPEGFP and ins-TOPGAL, that drive EGFP and beta-galactosidase expression under TCF/beta-catenin, respectively. To obtain the accurate expression pattern, we flanked these transgenes with the HS4 insulator to reduce chromosomal positional effects. Analysis of embryos showed that the reporter genes were activated in regions where canonical Wnt activity has been implicated. Furthermore, their expression patterns were consistent in both lines, indicating the accuracy of the reporter signal. In the neonatal brain, the reporter signal was detected in the mesencephalon and hippocampus. In the adult mice, the reporter signal was found in the mature pericenteral hepatocytes in the normal liver. Furthermore, during inflammation the number of T cells expressing the reporter gene increased in the adult spleen. Thus, in this research, we identified two organs, i.e., the liver and spleen, as novel organs in which the Wnt canonical signal is in motion in the adult. These transgenic lines will provide us broader opportunities to investigate the function of the Wnt canonical pathway in vivo.
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PMID:GFP transgenic mice reveal active canonical Wnt signal in neonatal brain and in adult liver and spleen. 1724 75

Wnt signaling pathways are regulated both at the intracellular and extracellular levels. During embryogenesis, the in vivo effects of the secreted frizzled-related protein (Sfrp) family of Wnt inhibitors are poorly understood. Here, we show that inactivation of Sfrp2 results in subtle limb defects in mice with mesomelic shortening and consistent shortening of all autopodal elements that is clinically manifested as brachydactyly. In addition, there is soft-tissue syndactyly of the hindlimb. The brachydactyly is caused by decreased chondrocyte proliferation and delayed differentiation in distal limb chondrogenic elements. These data suggest that Sfrp2 can regulate both chondrogenesis and regression of interdigital mesenchyme in distal limb. Sfrp2 can also repress canonical Wnt signaling by Wnt1, Wnt9a, and Wnt4 in vitro. Sfrp2-/- and TOPGAL/Sfrp2-/- mice have a mild increase in beta-catenin and beta-galactosidase staining, respectively, in some phalangeal elements. This however does not exclude a potential concurrent effect on non-canonical Wnt signaling in the growth plate. In combination with what is known about BMP and Wnt signaling in human brachydactylies, our data establish a critical role for Sfrp2 in proper distal limb formation and suggest SFPR2 could be a novel candidate gene for human brachy-syndactyly defects.
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PMID:Brachy-syndactyly caused by loss of Sfrp2 function. 1844 12


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