Wnt‐1 dependent activation of the survival factor NF‐κB in PC12 cells (original) (raw)
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Trends in Medicine, 2019
Wortmannin is an important regulator of Phosphoinositide 3-kinase (PI(3)K) signaling pathway. Changes in expression and activity of PI3-kinase and PDGF are major positive and negative regulators, respectively, of the PI3-kinase pathway, which regulates growth, survival, and proliferation. Here we have shown that cells dosed with platelet-derived-growth-factor (PDGF) and /or wortmannin, an inhibitor of PI3 kinase, proliferated at expected rates with respect to cells deprived of any additions. Cells with added platelet-derived-growth-factor (PDGF) multiplied substantially faster than naturally growing cells-some thirty percent. As anticipated, cells given only wortmannin divided over forty percent slower than cells without any dosage. Additionally, cells transfected with a luciferase reporter carrying a consensus sequences of the nuclear factor NF-κB binding site and treated with wortmannin inhibited the activation of luciferase in T98G cells. However, this inhibition was not affected by the treatment of PDFG. Our data indicate that Wortmannin and PDGF play different role in the control of expression of Phosphoinositide 3-kinase in glioma T98G cell line.
Wnt signal transduction pathway and apoptosis: a review
Cancer Cell International, 2010
The association between the wnt signaling pathway and apoptosis has become more firmly established in the recent scientific literature. Many reports indicate that the wnt signaling pathway regulates apoptosis through a variety of mechanisms. The activity of wnt signaling according to specific cellular environment stimuli can either foster or restrain the processes of apoptosis. Wnt signaling regulates the early and late stages of apoptosis in both development and cellular injury in populations of neurons, endothelial cells, vascular smooth muscle cells and cardiomyocytes. In this review I draw attention to genes and proteins of the wnt signaling pathway involved in apoptosis and describe some of their functional effects.
Dying for NF-κB? Control of cell death by transcriptional regulation of the apoptotic machinery
Current Opinion in Cell Biology, 2003
The transcription factor nuclear factor kB (NF-kB) is a pleiotropic protein complex that is activated from a sequestered, cytoplasmic form by pro-inflammatory extracellular signals and cellular stress. Several hundred cellular genes have been shown to be regulated by NF-kB, including cytokines, chemokines and adhesion molecules. Nearly eight years ago, a flurry of publications showed that loss or suppression of NF-kB results in an enhanced sensitivity to apoptosis. In the ensuing years, activation of NF-kB has become almost synonymous with enhanced cell survival, although more recent data suggests that this transcription factor plays a more complex role in the regulation of cell death.
The pro- or anti-apoptotic function of NF-κB is determined by the nature of the apoptotic stimulus
European Journal of Biochemistry, 2000
To test whether the behaviour of transcription factor NF-kB as a promoter or antagonist of apoptosis depends on the apoptotic stimulus, we determined the influence of NF-kB on cell killing elicited by a variety of inducers within a given cell type. Inhibition of NF-kB by genetic and pharmacological approaches rendered HeLa cells more susceptible to TNF-a-induced cell killing, but protected them almost completely from H 2 O 2 -and pervanadate-induced apoptosis. TNF-a was unable to protect HeLa from H 2 O 2 -and pervanadate-induced apoptosis and further enhanced the cytotoxicity induced by these two adverse agents. Supernatants from HeLa cells stably overexpressing a transdominant negative form of IkB-a selectively increased the cytotoxicity of TNF-a for HeLa cells, suggesting that the enhanced susceptibility of these cells can be attributed to one or more secretable factors. Supershift experiments showed that the various apoptotic stimuli induced the same subset of DNA-binding subunits. Therefore, the nature of the signals elicited by the respective death inducers determines whether NF-kB induction leads to apoptosis or survival, suggesting that the manipulation of NF-kB activity may provide a new approach to adjuvant therapy in cancer treatment.
Role of WT1-ZNF224 interaction in the expression of apoptosis-regulating genes
Human Molecular Genetics, 2013
The transcription factor Wilms' tumor gene 1, WT1, is implicated both in normal developmental processes and in the generation of a variety of solid tumors and hematological malignancies. Physical interactions of other cellular proteins with WT1 are known to modulate its function. We previously identified the Krü ppellike zinc-finger protein, ZNF224, as a novel human WT1-associating protein that enhances the transcriptional activation of the human vitamin D receptor promoter by WT1. Here, we have analyzed the effects of WT1 -ZNF224 interaction on the expression of apoptosis-regulating genes in the chronic myelogenous leukemia (CML) K562 cell line. The results demonstrated that ZNF224 acts in fine tuning of WT1-dependent control of gene expression, acting as a co-activator of WT1 in the regulation of proapoptotic genes and suppressing WT1 mediated transactivation of antiapoptotitc genes. Moreover, the DNA damaging drug cytosine arabinoside (ara-C) induces expression of ZNF224 in K562 cells and this induction enhances cell apoptotic response to ara-C. These findings suggest that ZNF224 can be a mediator of DNA damage-induced apoptosis in leukemia cells.
Evidence that de novo protein synthesis is dispensable for anti-apoptotic effects of NF-?B
Oncogene, 2000
The transcription factor NF-kB is a positive transcription factor for a number of genes and has been recognized as an anti-apoptotic regulator. However, the mechanism by which NF-kB blocks apoptosis is still controversial. Here, we demonstrate the evidence that NF-kB could attenuate the TNF-a-induced apoptosis without de novo protein synthesis using human pancreatic cancer cell lines, MIA PaCa-2 and Capan-2. The TNF-a-induced apoptosis was blocked by IL-1b, a potent inducer of NF-kB activation. This inhibitory eect of IL-1b was evident when cells were treated with protein synthesis inhibitors such as cycloheximide (CHX). Moreover, NF-kB decoy oligonucleotides could not block the anti-apoptotic eect of IL-1b at doses sucient to block the NF-kB-dependent transcription induced by IL-1b. To con®rm the role of NF-kB in blocking apoptosis, we generated stable cell lines expressing IkBDN, a highly stable form of IkBa, a cytoplasmic inhibitor of NF-kB. In these stable transfectants, the antiapoptotic eect of IL-1b was totally abolished, indicating that the anti-apoptotic action of IL-1b could be ascribed to the NF-kB action. These ®ndings show that de novo protein synthesis is dispensable for anti-apoptotic eects of NF-kB and support the possibility that NF-kB could exert its anti-apoptotic action through protein-protein interaction.
2010
The CCAAT-binding transcription factor NF-Y plays a central role in regulating cellular proliferation by controlling the expression of genes required for cell-cycle progression such as cyclin A, cyclin B1, cyclin B2, cdc25A, cdc25C, and cdk1. Here we show that unrestricted NF-Y activity leads to apoptosis in an E2F1-and wild-type p53 (wtp53)-dependent manner. Unrestricted NF-Y activity induced an increase in E2F1 mRNA and protein levels. Furthermore, NF-Y directly bound the E2F1 promoter and this correlated with the appearance of open chromatin marks. The ability of NF-Y to induce apoptosis was impaired in cells lacking E2F1 and wtp53. Moreover, NF-Y overexpression elicited phosphorylation of wt p53Ser18 in an E2F1-dependent manner. Our findings establish that NF-Y acts upstream of E2F1 in p53-mediated apoptosis.
Open Access REVIEW Wnt signal transduction pathway and apoptosis: a review
The association between the wnt signaling pathway and apoptosis has become more firmly established in the recent scientific literature. Many reports indicate that the wnt signaling pathway regulates apoptosis through a variety of mechanisms. The activity of wnt signaling according to specific cellular environment stimuli can either foster or restrain the processes of apoptosis. Wnt signaling regulates the early and late stages of apoptosis in both development and cellular injury in populations of neurons, endothelial cells, vascular smooth muscle cells and cardiomyocytes. In this review I draw attention to genes and proteins of the wnt signaling pathway involved in apoptosis and describe some of their functional effects.
Journal of Biomedical Science, 2008
The link of proto-oncogenic protein Wnt-1 production with NF-jB activation has been functionally demonstrated in PC12 cells, a rat pheochromocytoma cell line of neural crest lineage, while it is not yet verified in human cells. The link can be indirectly supported in our previous report that functional proteomics identifies enhanced expression of NF-jB-associated Wnt-1 production in human hepatocellular carcinoma tissues. This study aimed to further validate this link in human cells using anti-sense strategy. The effects of sequence-specific anti-sense morpholino oligonucleotides (ONs) targeting against pre-mRNA sequences of human p50 and p65 subunits of NF-jB as well as Wnt-1 genes were investigated. It revealed that all the three morpholino ONs inhibited NF-jB activation in human hepatoblastoma cell line HepG2 cells along with decreased Wnt-1 production. Chromatin immunoprecipitation assay ascertained the direct binding of NF-jB-p50 to the Wnt-1 promoter. Additionally, anti-P50 and anti-P65 morpholino ONs also repressed the phosphorylation of Ij Ba which temporarily correlated with the inhibition of NF-jB activation accompanied by decreased Wnt-1 production by HepG2 cells. In summary, NF-jB activation is critically involved in the production of Wnt-1 by HepG2 cells. These results may have important oncology implications in treating patients with NF-jBassociated Wnt-1-producing cancers. Keywords Anti-sense strategy Á Chromatin immunoprecipitation assay Á HepG2 cells Á Ij B Á Morpholino oligonucleotide Á NF-jB Á Wnt-1 protein Abbreviations ChIP Chromatin immunoprecipitation EMSA Electrophoretic mobility shift assay Ij Bs Inhibitors of NF-jB IKK IjB kinase NF-jB Nuclear transcription factor-jB ONs Oligonucleotides RNAi RNA interference Wnt-1 Wingless-type MMTV integration site gene family, member 1 Wnts Wnt proteins Electronic supplementary material The online version of this article (