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)

The signal transduction cascade initiated by the activation of phosphoinositide 3-kinase (PI-3 kinase) is implicated in mitogenic and antiapoptotic signaling generated by growth factors in a variety of cell types. We have examined the consequences of an inhibition of this pathway in human diploid fibroblasts. We find that a specific PI-3 kinase inhibitor (LY294002) causes growth arrest in these cells accompanied by changes in gene expression that are similar to those seen during cellular senescence. A second inhibitor, PD58029, which is specific for the mitogen-activated protein kinase kinase 1 (MEK-1), also induces a growth arrest but does not induce the same spectrum of gene expression. The pattern of gene expression in the presence the MEK-1 inhibitor is similar to that seen during growth arrest induced by serum starvation. The specific phenotypic changes seen following inhibition of PI-3 kinase are: an increase in beta-galactosidase activity; a decrease in EPC-1 gene expression; and a dramatic increase in collagenase gene expression. Thus, growth arrest with a PI-3 kinase inhibitor induces a senescent-like phenotype that is not seen when cells are growth arrested by either serum starvation or a MEK-1 inhibitor.
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PMID:A phosphatidylinositol 3-kinase inhibitor induces a senescent-like growth arrest in human diploid fibroblasts. 981 8

The proteasome constitutes the main non-lysosomal cellular protease activity, and plays a crucial role not only in the disposal of unwanted material, but also in the regulation of numerous cellular processes. Previously, we have reported that during the replicative senescence of WI-38 fibroblasts there is a significant impairment in proteasome activity, which probably has important implications in the control of MAPK signaling and cellular proliferation. In this study, we report the potential role of the proteasome in the generation of the senescent phenotype in WI-38 fibroblasts. Our results indicate that inhibition of proteasome activity leads to an impairment in cell proliferation, and a shortening of the life span. The results also indicate that inhibition of the proteasome in young cells induces a premature senescent-like phenotype, as indicated by the increase in senescence-associated beta-galactosidase (SA beta-gal) activity and the abundance of both p21 and collagenase mRNAs, as well as a decreased level of EPC-1 mRNA known markers of cellular senescence, not previously shown to depend on proteasome activity. Together, our results suggest a molecular mechanism for the lack of responsiveness of human cells to growth factors, and point towards a role for the proteasome in the control of the life span of both cells and organisms.
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PMID:Proteasome inhibitors shorten replicative life span and induce a senescent-like phenotype of human fibroblasts. 1652 93

PEDF is one of the most potent inhibitor of angiogenesis. Loss of PEDF was found in human prostate tumors and associated with the progression toward a metastatic phenotype. To test the therapeutic potential of PEDF, we constructed a replication-defective adenoviral vector capable of efficient transduction and expression of PEDF (Ad-PEDF) in PC-3 prostate carcinoma cells. As controls, we used adenoviruses expressing beta-galactosidase (Ad-LacZ). We showed that overexpression of PEDF inhibited proliferation of cells and augmented apoptosis in serum-starved cells, in comparison with Ad-LacZ. Furthermore, Ad-PEDF suppresses anchorage-independent growth cells in soft agar and tumor formation in athymic nude mice associated with decreased microvessel density. Microarray analysis showed that 56 out of 8464 genes were found to be upregulated and downregulated in the PC-3 infected with Ad-PEDF as compared with Ad-LacZ. The differentially expressed genes cover a broad range of functional activities including catalytic activity, protein binding, signal transduction activity and cell invasion. Among them, PAI-2 and DRHC were confirmed to be upregulated with real-time PCR and Western blot, suggesting a possible association with PEDF-induced signaling for cell motility and metastasis. These results can contribute to our understanding of the molecular mechanisms of treatment strategies of PEDF for prostate cancer.
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PMID:Adenovirus-mediated PEDF expression inhibits prostate cancer cell growth and results in augmented expression of PAI-2. 1747 Oct 21