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)

Astrocytic tumors frequently exhibit defects in the expression or activity of proteins that control cell-cycle progression. Inhibition of kinase activity associated with cyclin/cyclin-dependent kinase co-complexes by cyclin-dependent kinase inhibitors is an important mechanism by which the effects of growth signals are down-regulated. We undertook the present study to determine the role of p57(KIP2) (p57) in human astrocytomas. We demonstrate here that whereas p57 is expressed in fetal brain tissue, specimens of astrocytomas of varying grade and permanent astrocytoma cell lines do not express p57, and do not contain mutations of the p57 gene by multiplex-heteroduplex analysis. However, the inducible expression of p57 in three well-characterized human astrocytoma cell lines (U343 MG-A, U87 MG, and U373 MG) using the tetracycline repressor system leads to a potent proliferative block in G(1) as determined by growth curve and flow cytometric analyses. After the induction of p57, retinoblastoma protein, p107, and E2F-1 levels diminish, and retinoblastoma protein is shifted to a hypophosphorylated form. Morphologically, p57-induced astrocytoma cells became large and flat with an expanded cytoplasm. The inducible expression of p57 leads to the accumulation of senescence-associated beta-galactosidase marker within all astrocytoma cell lines such that approximately 75% of cells were positive at 1 week after induction. Induction of p57 in U373 astrocytoma cells generated a small population of cells ( approximately 15%) that were nonviable, contained discrete nuclear fragments on Hoechst 33258 staining, and demonstrated ultrastructural features characteristic of apoptosis. Examination of bax and poly-(ADP ribose) polymerase levels showed no change in bax, but decreased expression of poly-(ADP ribose) polymerase after p57 induction in all astrocytoma cell lines. These data demonstrate that the proliferative block imposed by p57 on human astrocytoma cells results in changes in the expression of a number of cell cycle regulatory factors, cell morphology, and a strong stimulus to cell senescence.
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PMID:Expression of p57(KIP2) potently blocks the growth of human astrocytomas and induces cell senescence. 1098 Jan 31

Cellular senescence has been proposed to be an in vitro and in vivo block that cells must overcome in order to immortalize and become tumorigenic. To characterize these pathways, we focused on changes in the cyclin-dependent kinase inhibitors and their binding partners that underlie the cell cycle arrest at senescence. As a model, we utilized normal human prostate epithelial cell (HPEC) and human uroepithelial cell (HUC) cultures. After 30-40 population doublings cells became growth-arrested in G0/1 with a threefold decrease in Cdk2-associated activity, a point defined as pre-senescence. Temporally following this growth arrest, the cells develop a senescence morphology and express senescence-associated beta-galactosidase (SA-beta-gal). Levels of p16(INK4a) and p57(KIP2) rise in HUCs during progressive passages, whereas only p16 increases in HPEC cultures. The induced expression of p57, similar to p16, produces a senescent-like phenotype. pRB, cyclin D, p19(INK4d) and p27(KIP1) decrease in both cell types. We find that p53, p21(CIP1) and p15(INK4b) are transiently elevated in HPECs and HUCs at the pre-senescent growth arrest, then return to low proliferating levels at terminal senescence. Analysis of p53, p21(CIP1), p15(INK4b), p16(INK4a), and p57(KIP2) reveals altered expression in immortalized, non-tumorigenic HPV16 E6 and E7 prostate lines and in tumorigenic prostate cancer cells. These results indicate: (i) the existence of a subset of growth inhibiting genes elevated at the onset of the senescence, (ii) a distinct class of genes involved in the maintenance of senescence, and (iii) the frequent inactivation of these pathways during immortalization.
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PMID:Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. 1178 34

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

5-Bromo-2-deoxyuridine (BrdU) is a thymidine analogue that is incorporated into replicating DNA. Although originally designed as a chemotherapeutic agent, sublethal concentrations of BrdU have long been known to alter the growth and phenotype of a wide range of cell types. Mechanisms underlying these BrdU-mediated effects remain unknown, however. We have characterized the effects of BrdU on A549 lung cancer cells by examining DNA damage responses, cell cycle effects and phenotypic changes. A549 cells express wild-type p53, but are p16-null. Sublethal concentrations of BrdU evoke a DNA damage response in these cells that involves the activation of Chk1, Chk2 and p53. Increased numbers of enlarged nuclei and multinucleated cells are evident in the treated populations. Cell cycle inhibition occurs, resulting in reduced proliferation and accumulation of cells in the S, G2/M and G0 phases. BrdU induces an early inhibition of p21 expression that coincides with nuclear localization of proliferating cell nuclear antigen. Subsequently, p21 levels increase, whereas proliferating cell nuclear antigen levels decrease compared with control cells. Upregulation of p27 and p57 expression also occurs. By day 7 of exposure to BrdU, treated cells acquire a senescent-like phenotype with an increase in cell size, granularity and beta-galactosidase activity. We conclude that BrdU induces a DNA damage response in A549 cells, which results in reduced proliferation mitotic exit and phenotypic changes that resemble senescence.
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PMID:5-Bromo-2-deoxyuridine activates DNA damage signalling responses and induces a senescence-like phenotype in p16-null lung cancer cells. 1770 56

Nurse cell (NC), formed from skeletal muscle cells upon infection with parasitic nematode trichina, presents a rare system of long-term suspension in the cell cycle. Signaling pathways and general biological functions of Trichinella spiralis NC, inferred from network analysis of competitive expression microarray data (NC vs. C2C12 myoblasts and myotubes), performed in Ingenuity Pathways Analysis (IPA) software and confirmed by Real-Time PCR, are presented. Assuming 4N DNA content in NC nuclei, its cell cycle arrest is identified herein as a hypermitogenic of G(1)-like type, accompanied by induction of senescence, underpinned by increased expression of p15, p16 and p57 cell cycle inhibitors, as well as overexpression of senescence-associated, beta-galactosidase and numerous secretory factors. Growth factor signaling, with predominant role of EGF, cytokine signaling and G-protein-coupled receptor signaling, are suggested as dominant NC signal transduction pathways. Fos, FosB, STAT6, CREBL2, ID4 and retinoic acid dependent nuclear receptors appear to be the main factors determining NC specific gene transcription. Antigen presentation, complement signaling and beta-amyloid processing pathways are also identified as operating in NC. In general, NC pathology is found to pertain to cancer, as well as other, including immunological and neurological, disorders.
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PMID:Nurse cell of Trichinella spp. as a model of long-term cell cycle arrest. 1863 64