Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to clarify mechanisms underlying dopaminergic neuronal death in Parkinson's disease (PD), a gene expression profiling study was performed in a rodent model of PD. In this model, mice are intrastriatally injected with 6-hydroxydopamine (6-OHDA) and dopaminergic neurons in the substantia nigra (SN) gradually die by retrograde degeneration. The SN were removed 2 h, 24 h, or 14 days after 6-OHDA administration. Levels of mRNAs related to cell death or survival were quantified using adaptor-tagged competitive PCR (ATAC-PCR). The cyclin D1 gene showed an immediate increase in mRNA expression. After 24 h, when dopaminergic neurons were under intense degeneration, levels of caspase 8 mRNA and p53 apoptosis effecter related to pmp 22 (PERP) mRNA increased and, conversely, FAS mRNA decreased. After 14 days, when the degeneration was attenuated, levels of PERP mRNA and serum- and glucocorticoid-regulated kinase (SGK) mRNA still increased. SGK has a similarity to AKT, which is an important molecule involved in nerve growth factor signal transduction. AKT mRNA levels are low in dopaminergic neurons. These results suggest that an increase in cyclin D1 mRNA triggers dopaminergic neurons to enter an abnormal cell cycle, which leads to neuronal degeneration and cell death, possibly induced by PERP and caspase 8. In addition to cell death-related genes, several survival-related genes are activated. SGK might function as a key enzyme for the survival of dopaminergic neurons.
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PMID:Gene expression profiling in the midbrain of striatal 6-hydroxydopamine-injected mice. 1469 15

Here, we demonstrated that inhibition of mTOR with rapamycin has negative effects on adipocyte differentiation and insulin signaling. Rapamycin significantly reduced expression of most adipocyte marker genes including PPARgamma, adipsin, aP2, ADD1/SREBP1c, and FAS, and decreased intracellular lipid accumulation in 3T3-L1 and 3T3-F442A cells, suggesting that rapamycin would affect both lipogenesis and adipogenesis. Contrary to the previous report that suppressive effect of rapamycin on adipogenesis is limited to the clonal expansion, we revealed that its inhibitory effect persisted throughout the process of adipocyte differentiation. Thus, it is likely that constitutive activation of mTOR might be required for the execution of adipogenic programming. In differentiated 3T3-L1 adipocytes, chronic treatment of rapamycin blunted the phosphorylation of AKT and GSK, which is stimulated by insulin, and reduced insulin-dependent glucose uptake activity. Taken together, these results suggest that rapamycin not only prevents adipocyte differentiation by decrease of adipogenesis and lipogenesis but also downregulates insulin action in adipocytes, implying that mTOR would play important roles in adipogenesis and insulin action.
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PMID:Regulation of adipocyte differentiation and insulin action with rapamycin. 1535 18

The relationship between breast cancer-associated fatty acid synthase (FAS; oncogenic antigen-519) and chemotherapy-induced cell damage has not been studied. We examined the ability of C75, a synthetic slow-binding inhibitor of FAS activity, to modulate the cytotoxic activity of the microtubule-interfering agent Taxol (paclitaxel) in SK-Br3, MDA-MB-231, MCF-7 and multidrug-resistant MDR-1 (P-Glycoprotein)-overexpressing MCF-7/AdrR breast cancer cells. When the combination of C75 with Taxol in either concurrent (C75 + Taxol 24 hr) or sequential (C75 24 hr --> Taxol 24 hr) schedules were tested for synergism, addition or antagonism using the isobologram and the median-effect plot analyses, co-exposure of C75 and Taxol mostly demonstrated synergistic effects, whereas sequential exposure to C75 followed by Taxol mainly showed additive or antagonistic interactions. Because the nature of the cytotoxic interactions was definitely schedule-dependent in MCF-7 cells, we next evaluated the effects of C75 on Taxol-induced apoptosis as well as Taxol-activated cell death and cell survival-signaling pathways in this breast cancer cell model. An ELISA for histone-associated DNA fragments demonstrated that C75 and Taxol co-exposure caused a synergistic enhancement of apoptotic cell death, whereas C75 pre-treatment did not enhance the apoptosis-inducing activity of Taxol. Co-exposure to C75 and Taxol induced a remarkable nuclear accumulation of activated p38 mitogen-activated protein kinase (p38 MAPK), which was accompanied by a synergistic nuclear accumulation of the p53 tumor-suppressor protein that was phosphorylated at Ser46, a p38 MAPK-regulated pro-apoptotic modification of p53. As single agents, FAS blocker C75 and Taxol induced a significant stimulation of the proliferation and cell survival mitogen-activated protein kinase extracellular signal-regulated kinase (ERK1/ERK2 MAPK) activity, whereas, in combination, they interfered with ERK1/ERK2 activation. Moreover, the combined treatment of C75 and Taxol inactivated the anti-apoptotic AKT (protein kinase B) kinase more than either agent alone, as evidenced by a synergistic down-regulation of AKT phosphorylation at its activating site Ser(473) without affecting AKT protein levels. To rule out a role for non-FAS C75-mediated effects, we finally used the potent and highly sequence-specific mechanism of RNA interference (RNAi) to block FAS-dependent signaling. Importantly, SK-Br3 and multi-drug resistant MCF-7/AdrR cells transiently transfected with sequence-specific double-stranded RNA oligonucleotides targeting FAS gene demonstrated hypersensitivity to Taxol-induced apoptotic cell death. Our findings establish for the first time that FAS blockade augments the cytotoxicity of anti-mitotic drug Taxol against breast cancer cells and that this chemosensitizing effect is schedule-dependent. We suggest that the alternate activation of both the pro-apoptotic p38 MAPK-p53 signaling and the cytoprotective MEK1/2 --> ERK1/2 cascade, as well as the inactivation of the anti-apoptotic AKT activity may explain, at least in part, the sequence-dependent enhancement of Taxol-induced cytotoxicity and apoptosis that follows inhibition of FAS activity in breast cancer cells. If chemically stable FAS inhibitors demonstrate systemic anticancer effects of FAS inhibition in vivo, these findings may render FAS as a valuable molecular target to enhance the efficacy of taxanes-based chemotherapy in human breast cancer.
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PMID:Pharmacological and small interference RNA-mediated inhibition of breast cancer-associated fatty acid synthase (oncogenic antigen-519) synergistically enhances Taxol (paclitaxel)-induced cytotoxicity. 1565

Previous studies have demonstrated that the NZM2410/NZW 'z' allele of Sle1 on telomeric murine chromosome 1 led to lymphoproliferative autoimmunity, when acting in concert with the FAS(lpr) defect on the C57BL/6 background. The present report shows that the Sle1b sub-locus, harboring the NZM2410/NZW 'z' allele of SLAM, in epistasis with FAS(lpr), may be sufficient to induce lymphoproliferative autoimmunity. Disease in this simplified genetic model is accompanied by significant activation of the AKT signaling axis in both B- and T cells, as evidenced by increased phosphorylation of AKT, mTOR, 4EBP-1 and p70S6K, resulting from increased PI3K and reduced PTEN activity. In addition, blocking this axis using RAD001, an mTOR inhibitor, ameliorated lymphoproliferation and modulated serum IgG anti-nuclear auto-antibodies. Finally, mTOR inhibition also dampened signaling via parallel axes, including the MAPK and NFkB pathways. Hence, hypersignaling via the PI3K/AKT/mTOR axis appears to be an important mechanism underlying autoimmune lymphoproliferative disease, presenting itself as a potential target for therapeutic intervention.
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PMID:PI3K/AKT/mTOR hypersignaling in autoimmune lymphoproliferative disease engendered by the epistatic interplay of Sle1b and FASlpr. 1736 92

Differential expression of apoptotic genes may influence the susceptibility of activated lymphocytes to expand and induce acute relapse and persistent inflammation in patients with relapsing-remitting multiple sclerosis (RRMS). The exact relationship between alterations in apoptotic-related gene expression and clinical disease activity has not been broadly evaluated. In this study we studied peripheral blood mononuclear cells (PBMCs) expression of pro- and antiapoptotic genes in RRMS patients during acute relapse in comparison to patients in remission. Using cDNA Affymetrix microarrays platform (U133A2 microarrays) we analyzed the gene expression profile of PBMC derived from 22 RRMS patients in acute relapse (15 females, mean age 34.6 +/- 1.8 years, disease duration 5.6 +/- 0.8 years) in comparison to 20 sex- and age-matched RRMS patients in remission. One thousand five hundred seventy-eight gene transcripts significantly differentiated acute multiple sclerosis (MS) relapse from remission. This characteristic gene expression signature was enriched by an apoptotic-related pathway. The 1578 gene transcripts that significantly differentiated acute relapse from remission were enriched by 55 apoptotic-related genes in that reflected different operating pathways during the acute phase of the disease. These genes mainly involved the caspase-dependent pathway and included overexpression of the negative regulator of FAS-induced apoptosis (TOSO) and the BCL2 antiapoptotic family members (BCL2, BCL2 AA) as well as downexpression of proapoptotic genes like BAX, apoptotic protease-activating factor 1 (APAF1) and caspases 1, 2, 8, 9. and 10. An additional group of antiapoptotic genes related to T cell receptor-mediated apoptosis was also found to be overexpressed in acute relapse and included TCR-binding CD3E antigen, antiapoptotic serine threonin kinase (AKT), and NF kappa B-associated genes like reticuloendotheliosis viral oncogene homolog A (RELA) and human T cell leukemia virus type I-binding protein (Tax1BP) known to inhibit tumor necrosis factor (TNF)-induced apoptosis. Our findings demonstrate impaired apoptotic mechanisms in peripheral lymphocytes from RRMS patients during acute relapse. This suggests that the inflammatory process in active disease is targeted by inhibition of proapoptotic and repression of antiapoptotic genes that allow prolonged abnormal immune responses.
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PMID:Impaired expression of peripheral blood apoptotic-related gene transcripts in acute multiple sclerosis relapse. 1780 43

Prior studies have noted that inhibitors of mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2) enhanced geldanamycin lethality in malignant hematopoietic cells by promoting mitochondrial dysfunction. The present studies focused on defining the mechanism(s) by which these agents altered survival in carcinoma cells. MEK1/2 inhibitors [PD184352; AZD6244 (ARRY-142886)] interacted in a synergistic manner with geldanamycins [17-allylamino-17-demethoxygeldanamycin (17AAG) and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin] to kill hepatoma and pancreatic carcinoma cells that correlated with inactivation of extracellular signal-regulated kinase 1/2 and AKT and with activation of p38 MAPK; p38 MAPK activation was reactive oxygen species dependent. Treatment of cells with MEK1/2 inhibitors and 17AAG reduced expression of c-FLIP-s that was mechanistically connected to loss of MEK1/2 and AKT function; inhibition of caspase-8 or overexpression of c-FLIP-s abolished cell killing by MEK1/2 inhibitors and 17AAG. Treatment of cells with MEK1/2 inhibitors and 17AAG caused a p38 MAPK-dependent plasma membrane clustering of CD95 without altering the levels or cleavage of FAS ligand. In parallel, treatment of cells with MEK1/2 inhibitors and 17AAG caused a p38 MAPK-dependent association of caspase-8 with CD95. Inhibition of p38 MAPK or knockdown of BID, FAS-associated death domain, or CD95 expression suppressed MEK1/2 inhibitor and 17AAG lethality. Similar correlative data were obtained using a xenograft flank tumor model system. Our data show that treatment of tumor cells with MEK1/2 inhibitors and 17AAG induces activation of the extrinsic pathway and that suppression of c-FLIP-s expression is [Mol Cancer Ther 2008;7(9):2633-48].
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PMID:Mitogen-activated protein kinase kinase 1/2 inhibitors and 17-allylamino-17-demethoxygeldanamycin synergize to kill human gastrointestinal tumor cells in vitro via suppression of c-FLIP-s levels and activation of CD95. 1879 Jul 46

Susceptibility to cell death is a prerequisite for the elimination of tumour cells by cytotoxic immune cells, chemotherapy or irradiation. Activation of the death receptor Fas is critical for the regulation of immune cell homeostasis and efficient killing of tumour cells by apoptosis. To define the molecular changes that occur during selection for insensitivity to Fas-induced apoptosis, a resistant variant of the U937 cell line was established. Individual resistant clones were isolated and characterized. The most frequently observed defect in the resistant cells was reduced Fas expression, which correlated with decreased FAS transcription. Clones with such reduced Fas expression also displayed partial cross-resistance to tumour necrosis factor-alpha stimulation, but the mRNA expression of tumour necrosis factor receptors was not decreased. Reintroduction of Fas conferred susceptibility to Fas but not to tumour necrosis factor-alpha stimulation, suggesting that several alterations could be present in the clones. The reduced Fas expression could not be explained by mutations in the FAS coding sequence or promoter region, or by silencing through methylations. Protein kinase B and extracellular signal-regulated kinase, components of signalling pathways downstream of Ras, were shown to be activated in some of the resistant clones, but none of the three RAS genes was mutated, and experiments using chemical inhibitors could not establish that the activation of these proteins was the cause of Fas resistance as described in other systems. Taken together, the data illustrate that Fas resistance can be caused by reduced Fas expression, which is a result of an unidentified mode of regulation.
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PMID:Reduced FAS transcription in clones of U937 cells that have acquired resistance to Fas-induced apoptosis. 1907 18

The PIK3/AKT pathway plays an important role in both the inhibition of the apoptotic cascade and the promotion of cell growth and proliferation. Multiple apoptosis-related targets of phosphatidylinositide 3-kinase (PIK3) and protein kinase B (AKT) have been identified, including the antiapoptotic protein XIAP. By phosphorylating XIAP, AKT was previously shown to prevent the ubiquitinization and degradation of XIAP. First-trimester trophoblast cells express high levels of XIAP, which protects them from certain apoptotic stimuli. In this study, we determine that the inhibition of the PIK3/AKT pathway induces XIAP inactivation and the activation of caspase 3 in first-trimester trophoblast cells. Using a specific AKT inhibitor and a XIAP mutant construct, which mimics the AKT phosphorylated form of XIAP, we also demonstrate that these effects are dependent on the phosphorylation of XIAP by AKT. Finally, we show that the selective inhibition of AKT renders normally resistant first-trimester trophoblast cells sensitive to FAS-mediated apoptosis by regulating XIAP expression. Our findings may provide a link between AKT, XIAP, and the regulation of the FAS apoptotic cascade in first-trimester trophoblast cells and contribute to our current knowledge of the molecular mechanisms mediating normal trophoblast physiology during pregnancy.
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PMID:AKT controls human first trimester trophoblast cell sensitivity to FAS-mediated apoptosis by regulating XIAP expression. 1972 36

Recent evidence suggests that breast cancer and other solid tumors possess a rare population of cells capable of extensive self-renewal that contribute to metastasis and treatment resistance. We report here the development of a strategy to target these breast cancer stem cells (CSCs) through blockade of the IL-8 receptor CXCR1. CXCR1 blockade using either a CXCR1-specific blocking antibody or repertaxin, a small-molecule CXCR1 inhibitor, selectively depleted the CSC population in 2 human breast cancer cell lines in vitro. Furthermore, this was followed by the induction of massive apoptosis in the bulk tumor population via FASL/FAS signaling. The effects of CXCR1 blockade on CSC viability and on FASL production were mediated by the FAK/AKT/FOXO3A pathway. In addition, repertaxin was able to specifically target the CSC population in human breast cancer xenografts, retarding tumor growth and reducing metastasis. Our data therefore suggest that CXCR1 blockade may provide a novel means of targeting and eliminating breast CSCs.
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PMID:CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. 2005 26

Small-cell lung carcinomas account for about 15-20% of lung cancer and are characterized by an intrinsic resistance to apoptosis. Increasing evidence suggests that alteration in apoptosis/antiapoptosis balance could lead to fundamental resistance of small-cell lung cancer to chemotherapy and radiation. These molecular alterations include alteration of mitochondrial pathways (BCL2 and BCLXL overexpression, activation of stress protein such as HSP 90 and HSP70, activation of PI3K/AKT/mTOR pathway). Others abnormalities could inhibit activation of extrinsic pathway such as caspase-8 and FAS underexpression as well as C-FLIP overexpression. New therapies targeting some of these abnormalities are under clinical evaluation and predictive factors of response are needed to personalize these therapies.
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PMID:[Anti-apoptotic mechanisms in small-cell lung carcinoma]. 2022 50


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