Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated phosphatidylinositol 3-kinase (PI3K)-dependent survival signalling pathways using several cytokines in three different hemopoietic cell lines, MC/9, FDC-P1, and TF-1. Cytokines caused PI3K- and PKB-dependent phosphorylation of FOXO3a (previously known as FKHRL1) at three distinct sites. Following cytokine withdrawal or PI3K inhibition, both of which are known to lead to apoptosis, there was a loss of FOXO3a phosphorylation, and a resulting increase in forkhead transcriptional activity, along with increased expression of Fas Ligand (FasL), which could be detected at the cell surface. Concurrently, an increase in cell surface expression of Fas was also detected. Despite the presence of both FasL and Fas, there was no detectable evidence that activation of Fas-mediated apoptotic events was contributing to apoptosis resulting from cytokine starvation or inhibition of PI3K activity. Thus, inhibition of FOXO3a activity is mediated by the PI3K-PKB pathway, but regulation of FasL is not the primary means by which cell survival is regulated in cytokine-dependent hemopoietic cells. We were also able to confirm increased expression of known FOXO3a targets, Bim and p27kip1. Together, these results support the conclusion that mitochondrial-mediated signals play the major role in apoptosis of hemopoietic cells due to loss of cytokine signalling.
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PMID:Cytokine-mediated FOXO3a phosphorylation suppresses FasL expression in hemopoietic cell lines: investigations of the role of Fas in apoptosis due to cytokine starvation. 1760 40

Airway smooth muscle (ASM) cells are characterized by phenotypic plasticity and can switch between differentiated and proliferative phenotypes. In rabbit tracheal ASM cells that had been differentiated in vitro by serum starvation, readdition of FBS caused initiation of proliferation and induction of nuclear and transcriptionally active hypoxia-inducible factor (HIF)-1alpha. In addition, FBS stimulated the induction of HIF-1alpha by the hypoxia mimetic cobalt. Treatment with actinomycin D, cycloheximide, the phosphatidylinositol 3-kinase inhibitors LY-294002 and wortmannin or the reactive oxygen species scavenger diphenyleneiodonium inhibited the FBS-dependent induction of HIF-1alpha. These data indicate that, in differentiated ASM cells, FBS upregulates HIF-1alpha by a transcription-, translation-, phosphatidylinositol 3-kinase-, and reactive oxygen species-dependent mechanism. Interestingly, addition of FBS and cobalt also induced HIF-1alpha in organ cultures of rabbit trachea strips and synergistically increased their contractile response to ACh, suggesting that HIF-1alpha might be implicated in airway hypercontractility.
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PMID:Exposure of differentiated airway smooth muscle cells to serum stimulates both induction of hypoxia-inducible factor-1{alpha} and airway responsiveness to ACh. 1766 Mar 26

Astrocyte elevated gene-1 (AEG-1) displays oncogenic properties. Its expression is elevated in diverse neoplastic states and it cooperates with Ha-ras to promote cellular transformation. Overexpression of AEG-1 augments invasion and anchorage-independent growth of transformed cells, while AEG-1 siRNA inhibits Ha-ras-mediated colony formation, supporting a potential functional role in tumorigenesis. Additionally, oncogenic Ha-ras induces AEG-1 expression through the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. In the present study, we investigated whether AEG-1 could induce serum-independent cell growth, another property of oncogenes. Overexpression of AEG-1 inhibited serum starvation-induced apoptosis through activation of PI3K-Akt signaling, one of the effector pathways induced by activated Ras. AEG-1 also affected the phosphorylation state of Akt substrates that are implicated in apoptosis suppression, including glycogen synthase kinase 3beta, c-Myc, murine double minute 2, p53, p21/mda-6 and Bad. Additionally, AEG-1 blocked the activity of serum starvation-induced caspases. Taken together, these observations provide evidence that AEG-1 is an oncogene cooperating with Ha-ras as well as functioning as a downstream target gene of Ha-ras and may perform a central role in Ha-ras-mediated carcinogenesis. Activation of survival pathways may be one mechanism by which AEG-1 exerts its oncogenic properties.
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PMID:Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling. 1770 8

Glutamine, the most abundant amino acid in the bloodstream, is the preferred fuel source for enterocytes and plays a vital role in the maintenance of mucosal growth. The molecular mechanisms regulating the effects of glutamine on intestinal cell growth and survival are poorly understood. Here, we show that addition of glutamine (1 mmol/l) enhanced rat intestinal epithelial (RIE)-1 cell growth; conversely, glutamine deprivation increased apoptosis as noted by increased DNA fragmentation and caspase-3 activity. To delineate signaling pathways involved in the effects of glutamine on intestinal cells, we assessed activation of extracellular signal-related kinase (ERK), protein kinase D (PKD), and phosphatidylinositol 3-kinase (PI3K)/Akt, which are important pathways in cell growth and survival. Addition of glutamine activated ERK and PKD in RIE-1 cells after a period of glutamine starvation; inhibition of ERK, but not PKD, increased cell apoptosis. Conversely, glutamine starvation alone increased phosphorylated Akt; inhibition of Akt enhanced RIE-1 cell DNA fragmentation. The role of ERK was further delineated using RIE-1 cells stably transfected with an inducible Ras. Apoptosis was significantly increased following ERK inhibition, despite Ras activation. Taken together, these results identify a critical role for the ERK signaling pathways in glutamine-mediated intestinal homeostasis. Furthermore, activation of PI3K/Akt during periods of glutamine deprivation likely occurs as a protective mechanism to limit apoptosis associated with cellular stress. Importantly, our findings provide novel mechanistic insights into the antiapoptotic effects of glutamine in the intestine.
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PMID:Molecular mechanisms contributing to glutamine-mediated intestinal cell survival. 1791 48

Previously, we showed that retinol inhibited all-trans-retinoic acid (ATRA)-resistant human colon cancer cell invasion via a retinoic acid receptor-independent mechanism. Because phosphatidylinositol 3-kinase (PI3K) regulates cell invasion, the objective of the current study was to determine if retinol affected PI3K activity. Following 24 h of serum starvation, the ATRA resistant human colon cancer cell lines HCT-116 and SW620 were treated with 0, 1, or 10 microM retinol. Thirty minutes of retinol treatment resulted in a significant decrease in PI3K activity in both cell lines. To determine the mechanism by which retinol reduces PI3K activity, the levels and heterodimerization of the regulatory subunit, p85, and the catalytic subunit, p110, of PI3K were examined. Retinol treatment did not alter p85 or p110 protein levels or the heterodimerization of these subunits at any time point examined. To determine if retinol affected the ability of PI3K to phosphorylate the substrate, phosphatidylinositol (PI), PI3K was immunoprecipitated from control cells and incubated with 10 microg PI and increasing concentrations of retinol or 10 microg retinol and increasing concentrations of PI. Retinol decreased PI3K activity in a dose-responsive manner and increased PI suppressed the inhibitory effect of retinol on PI3K activity. Finally, the PI3K inhibitor, LY294002, mimicked the ability of retinol to decrease cell invasion. Computational modeling revealed that retinol may inhibit PI3K activity in a manner similar to that of wortmannin. Thus, a decrease in PI3K activity due to retinol treatment may confer the ability of retinol to inhibit ATRA-resistant colon cancer cell invasion.
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PMID:Retinol decreases phosphatidylinositol 3-kinase activity in colon cancer cells. 1791 8

Autophagy is an intracellular system for the bulk degradation of cytoplasmic components enclosed within double-membrane structures known as autophagosomes. To date, many autophagy-related (Atg) genes have been identified by independent genetic screens for autophagy-defective mutants in yeast; however, the molecular machinery required for the biogenesis of autophagosomes in mammalian systems has yet to be determined.(1,2) Recently, we have reported that Bif-1 interacts with Beclin 1 through UVRAG and promotes the activation of class III phosphatidylinositol 3-kinase (PI3KC3) and the formation of autophagosomes.(3) Moreover, we have found that loss of Bif-1 promotes starvation-induced caspase activation, but prolongs cell survival by suppressing autophagydependent cell death, and enhances spontaneous tumorigenesis in mice. Bif-1 is a member of the endophilin family, which possesses membrane binding and liposome tubulation activities.(4) During nutrient deprivation, Bif-1 accumulates in punctate foci where it co-localizes with LC3, Atg5 and Atg9. Time-lapse microscopy analyses reveal that Bif-1-positive small vesicles expand by recruiting and fusing with Atg9-positive small membranes to form autophagosomes. Taken together, our findings highlight Bif-1 as a potential regulator of autophagosome biogenesis and as a tumor suppressor.
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PMID:BARgaining membranes for autophagosome formation: Regulation of autophagy and tumorigenesis by Bif-1/Endophilin B1. 1803 18

Apoptosis is an important cell death system that deletes damaged and mutated cells to prevent cancer. We have previously reported that a certain dose of UVB irradiation inhibited the apoptosis induced by serum starvation and cell detachment, leading to cell transformation. This antiapoptotic effect was partially inhibited by phosphatidylinositol 3-kinase (PI3-kinase) inhibitors. UVB irradiation is known to cause the phosphorylation of Akt via the activation of PI3-kinase; however, the Akt isoform-specific relationship has not yet been clarified. Notably, the role in antiapoptotic effect of UVB has yet to be elucidated. In this study, the role of Akt1 in the UVB-induced inhibition of apoptosis was examined by Akt1 knockdown using small interfering RNA (siRNA). NIH3T3 cells showed typical apoptotic cell death by serum starvation and cell detachment, which was significantly inhibited by UVB irradiation. Akt1 knockdown decreased the antiapoptotic effect of UVB. Hydrogen peroxide-induced suppression of cell death was also decreased in Akt1 knockdown cells. An antioxidant, N-acetylcysteine, inhibited the antiapoptotic effect by UVB irradiation, whereas no inhibition was observed in Akt1 knockdown cells. Furthermore, UVB-induced intracellular peroxidation was not observed in the knockdown cells, indicating that Akt1 played an important role in mediating the intracellular redox status. Treatment with insulin had a similar antiapoptotic effect as UVB irradiation involving intracellular peroxidation, which was also attenuated in Akt1 knockdown cells. These findings suggest that appropriate intracellular oxidation after UVB irradiation prevented apoptosis, a process which might be partially regulated by the production of reactive oxygen species mediated by Akt1.
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PMID:Akt1-mediated intracellular oxidation after UVB irradiation suppresses apoptotic cell death induced by cell detachment and serum starvation. 1817 15

The nectin-afadin complex is involved in the formation of cell-cell junctions, such as adherens junctions (AJs) and tight junctions (TJs). Nectins are Ca(2+)-independent immunoglobulin-like cell-cell adhesion molecules, whereas afadin is an intracellular nectin-binding protein that connects nectins to the cadherin-catenin system at AJs and to the claudin-zona-occludens (ZO) protein system at TJs. Afadin(-/-) mice show embryonic lethality, resulting from impaired migration and improper differentiation of cells due to disorganization of cell-cell junctions during gastrulation. However, it remains to be elucidated whether disruption of afadin affects apoptosis. In the present study, we first found that embryoid bodies derived from afadin-knockout embryonic stem (ES) cells contained many more apoptotic cells than those derived from wild-type ES cells. We also revealed that apoptosis induced by serum starvation or Fas-ligand stimulation was increased in cultured NIH3T3 cells when afadin or nectin-3 was knocked down. The nectin-afadin complex was involved in the platelet-derived growth factor (PDGF)-induced activation of phosphatidylinositol 3-kinase (PI3K)-Akt signaling for cell survival. This complex was associated with PDGF receptor on the plasma membrane at cell-cell adhesion sites. Thus, the nectin-afadin complex is involved in PDGF-induced cell survival, at least through the PI3K-Akt signaling pathway.
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PMID:Involvement of the nectin-afadin complex in PDGF-induced cell survival. 1850 95

Elucidating the cross-talk between inflammatory and cell proliferation pathways might provide important insights into the pathogenesis of inflammation-induced cancer. Here, we show that the receptor-interacting protein 1 (RIP1)-an essential mediator of inflammation-induced nuclear factor-kappaB (NF-kappaB) activation-regulates p27(Kip1) levels and cell-cycle progression. RIP1 regulates p27(Kip1) levels by an NF-kappaB-independent signal that involves activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-forkhead pathway. Mouse embryonic fibroblasts (MEFs) from RIP1-knockout mice express high levels of p27(Kip1). Reconstitution of MEFs with RIP1 downregulates p27(Kip1) levels in a PI3K-dependent manner. RIP1 regulates p27(Kip1) at the messenger RNA level by regulating the p27(Kip1) promoter through the forkhead transcription factors. RIP1 expression blocks accumulation of cells in G(1) in response to serum starvation and favours cell-cycle progression. Finally, we show that overexpression of p27(Kip1) blocks the effects of RIP1 on the cell cycle. Thus, our study provides a new insight into how components of inflammatory and immune signalling pathways regulate cell-cycle progression.
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PMID:The death domain-containing kinase RIP1 regulates p27(Kip1) levels through the PI3K-Akt-forkhead pathway. 1856 99

Resistance to cell death is a hallmark of cancer. Autophagy is a survival mechanism activated in response to nutrient deprivation; however, excessive autophagy will ultimately induce cell death in a nonapoptotic manner. The present study demonstrates that CCL2 protects prostate cancer PC3 cells from autophagic death, allowing prolonged survival in serum-free conditions. Upon serum starvation, CCL2 induced survivin up-regulation in PC3, DU 145, and C4-2B prostate cancer cells. Both cell survival and survivin expression were stunted in CCL2-stimulated PC3 cells when treated either with the phosphatidylinositol 3-kinase inhibitor LY294002 (2 microm) or the Akt-specific inhibitor-X (Akti-X; 2.5 microm). Furthermore, CCL2 significantly reduced light chain 3-II (LC3-II) in serum-starved PC3; in contrast, treatment with LY294002 or Akti-X reversed the effect of CCL2 on LC3-II levels, suggesting that CCL2 signaling limits autophagy in these cells. Upon serum deprivation, the analysis of LC3 localization by immunofluorescence revealed a remarkable reduction in LC3 punctate after CCL2 stimulation. CCL2 treatment also resulted in a higher sustained mTORC1 activity as measured by an increase in phospho-p70S6 kinase (Thr389). Rapamycin, an inducer of autophagy, both down-regulated survivin and decreased PC3 cell viability in serum-deprived conditions. Treatment with CCL2, however, allowed cells to partially resist rapamycin-induced death, which correlated with survivin protein levels. In two stable transfectants expressing survivin-specific short hairpin RNA, generated from PC3, survivin protein levels controlled both cell viability and LC3 localization in response to CCL2 treatment. Altogether, these findings indicate that CCL2 protects prostate cancer PC3 cells from autophagic death via the phosphatidylinositol 3-kinase/Akt/survivin pathway and reveal survivin as a critical molecule in this survival mechanism.
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PMID:CCL2 protects prostate cancer PC3 cells from autophagic death via phosphatidylinositol 3-kinase/AKT-dependent survivin up-regulation. 1861 60


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