Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of NF-kappaB and autophagy are two processes involved in the regulation of cell death, but the possible cross-talk between these two signaling pathways is largely unknown. Here, we show that NF-kappaB activation mediates repression of autophagy in tumor necrosis factor-alpha (TNFalpha)-treated Ewing sarcoma cells. This repression is associated with an NF-kappaB-dependent activation of the autophagy inhibitor mTOR. In contrast, in cells lacking NF-kappaB activation, TNFalpha treatment up-regulates the expression of the autophagy-promoting protein Beclin 1 and subsequently induces the accumulation of autophagic vacuoles. Both of these responses are dependent on reactive oxygen species (ROS) production and can be mimicked in NF-kappaB-competent cells by the addition of H2O2. Small interfering RNA-mediated knockdown of beclin 1 and atg7 expression, two autophagy-related genes, reduced TNFalpha- and reactive oxygen species-induced apoptosis in cells lacking NF-kappaB activation and in NF-kappaB-competent cells, respectively. These findings demonstrate that autophagy may amplify apoptosis when associated with a death signaling pathway. They are also evidence that inhibition of autophagy is a novel mechanism of the antiapoptotic function of NF-kappaB activation. We suggest that stimulation of autophagy may be a potential way bypassing the resistance of cancer cells to anti-cancer agents that activate NF-kappaB.
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PMID:NF-kappaB activation represses tumor necrosis factor-alpha-induced autophagy. 1747 Oct 12

The downregulation of macroautophagy observed in cancer cells is associated with tumor progression. The regulation of macroautophagy by signaling pathways overlaps with the control of cell growth, proliferation, cell survival and death. Several tumor suppressor genes (PTEN, TSC2 and p53) involved in the mTOR signaling network have been shown to stimulate autophagy. In contrast, the oncoproteins involved in this network have the opposite effect. These findings, together with the discovery that haploinsufficiency of the tumor suppressor beclin 1 promotes tumorigenesis in various tissues in transgenic mice, give credibility to the idea that autophagy is a tumor suppressor mechanism. The induction of macroautophagy by cancer treatments may also contribute to cell eradication. However, cancer cells sometimes mobilize autophagic capacities in response to various stimuli without a fatal outcome, suggesting that they can also exploit macroautophagy for their own benefit.
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PMID:Autophagy signaling and the cogwheels of cancer. 1687 41

Autophagy is a tightly regulated catabolic mechanism that degrades proteins and organelles. Autophagy mediates programmed cell death under certain conditions. To determine the role of autophagy in T cells, we examined, in mouse CD4+ T cells, conditions under which autophagy is induced and alterations of the cell fate when autophagy is blocked. We have found that resting naive CD4+ T cells do not contain detectable autophagosomes. Autophagy can be observed in activated CD4+ T cells upon TCR stimulation, cytokine culturing, and prolonged serum starvation. Induction of autophagy in T cells requires JNK and the class III PI3K. Autophagy is inhibited by caspases and mammalian target of rapamycin in T cells. Interestingly, more Th2 cells than Th1 cells undergo autophagy. Th2 cells become more resistant to growth factor-withdrawal cell death when autophagy is blocked using either chemical inhibitors 3-methyladenine, or by RNA interference knockdown of beclin 1 and Atg7. Therefore, autophagy is an important mechanism that controls homeostasis of CD4+ T cells.
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PMID:Autophagy is induced in CD4+ T cells and important for the growth factor-withdrawal cell death. 1701 1

Autophagy is an intracellular bulk degradation process for proteins and organelles. In the heart, autophagy is stimulated by myocardial ischemia. However, the causative role of autophagy in the survival of cardiac myocytes and the underlying signaling mechanisms are poorly understood. Glucose deprivation (GD), which mimics myocardial ischemia, induces autophagy in cultured cardiac myocytes. Survival of cardiac myocytes was decreased by 3-methyladenine, an inhibitor of autophagy, suggesting that autophagy is protective against GD in cardiac myocytes. GD-induced autophagy coincided with activation of AMP-activated protein kinase (AMPK) and inactivation of mTOR (mammalian target of rapamycin). Inhibition of AMPK by adenine 9-beta-d-arabinofuranoside or dominant negative AMPK significantly reduced GD-induced autophagy, whereas stimulation of autophagy by rapamycin failed to cause an additive effect on GD-induced autophagy, suggesting that activation of AMPK and inhibition of mTOR mediate GD-induced autophagy. Autophagy was also induced by ischemia and further enhanced by reperfusion in the mouse heart, in vivo. Autophagy resulting from ischemia was accompanied by activation of AMPK and was inhibited by dominant negative AMPK. In contrast, autophagy during reperfusion was accompanied by upregulation of Beclin 1 but not by activation of AMPK. Induction of autophagy and cardiac injury during the reperfusion phase was significantly attenuated in beclin 1(+/-) mice. These results suggest that, in the heart, ischemia stimulates autophagy through an AMPK-dependent mechanism, whereas ischemia/reperfusion stimulates autophagy through a Beclin 1-dependent but AMPK-independent mechanism. Furthermore, autophagy plays distinct roles during ischemia and reperfusion: autophagy may be protective during ischemia, whereas it may be detrimental during reperfusion.
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PMID:Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. 1747 Oct 15

Cell differentiation is often associated with decreased cell growth, indicating an altered rate of macromolecule synthesis and degradation. In this study, we present evidence that autophagy, a process for bulk degradation of cytoplasm, is activated during retinoic acid-induced neuronal differentiation of neuroblastoma N2a cells. Chemical inhibitors of autophagy, including 3-MA and LY294002, abrogate cell differentiation. RNA interference of autophagy gene beclin 1 markedly delays the process of differentiation. We also find that cell differentiation is accompanied by decreased activity of mTOR, a major controller of cell growth and a negative regulator of autophagy. However, completely inhibiting mTOR by rapamycin decreases neurite outgrowth, cell size and the immunoreactivity for neuronal markers. Our study suggests that an appropriate level of mTOR activity is important in cell differentiation for a balance between macromolecule synthesis and degradation.
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PMID:Roles of autophagy and mTOR signaling in neuronal differentiation of mouse neuroblastoma cells. 1820 67

Autophagy has been shown to contribute to defense against intracellular bacteria and parasites. In comparison, the ability of such pathogens to manipulate host cell autophagy to their advantage has not been examined. Here we present evidence that infection by Toxoplasma gondii, an intracellular protozoan parasite, induces host cell autophagy in both HeLa cells and primary fibroblasts, via a mechanism dependent on host Atg5 but independent of host mammalian target of rapamycin suppression. Infection led to the conversion of LC3 to the autophagosome-associated form LC3-II, to the accumulation of LC3-containing vesicles near the parasitophorous vacuole, and to the relocalization toward the vacuole of structures labeled by the phosphatidylinositol 3-phosphate indicator YFP-2xFYVE. The autophagy regulator beclin 1 was concentrated in the vicinity of the parasitophorous vacuole in infected cells. Inhibitor studies indicated that parasite-induced autophagy is dependent on calcium signaling and on abscisic acid. At physiologically relevant amino acid levels, parasite growth became defective in Atg5-deficient cells, indicating a role for host cell autophagy in parasite recovery of host cell nutrients. A flow cytometric analysis of cell size as a function of parasite content revealed that autophagy-dependent parasite growth correlates with autophagy-dependent consumption of host cell mass that is dependent on parasite progression. These findings indicate a new role for autophagy as a pathway by which parasites may effectively compete with the host cell for limiting anabolic resources.
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PMID:Host cell autophagy is induced by Toxoplasma gondii and contributes to parasite growth. 1902 80

Cystatin C (CysC) expression in the brain is elevated in human patients with epilepsy, in animal models of neurodegenerative conditions, and in response to injury, but whether up-regulated CysC expression is a manifestation of neurodegeneration or a cellular repair response is not understood. This study demonstrates that human CysC is neuroprotective in cultures exposed to cytotoxic challenges, including nutritional-deprivation, colchicine, staurosporine, and oxidative stress. While CysC is a cysteine protease inhibitor, cathepsin B inhibition was not required for the neuroprotective action of CysC. Cells responded to CysC by inducing fully functional autophagy via the mTOR pathway, leading to enhanced proteolytic clearance of autophagy substrates by lysosomes. Neuroprotective effects of CysC were prevented by inhibiting autophagy with beclin 1 siRNA or 3-methyladenine. Our findings show that CysC plays a protective role under conditions of neuronal challenge by inducing autophagy via mTOR inhibition and are consistent with CysC being neuroprotective in neurodegenerative diseases. Thus, modulation of CysC expression has therapeutic implications for stroke, Alzheimer's disease, and other neurodegenerative disorders.
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PMID:Induction of autophagy by cystatin C: a mechanism that protects murine primary cortical neurons and neuronal cell lines. 2035 8

Autophagy is a regulated catabolic process triggered in cells deprived of nutrients or growth factors that govern nutrient uptake. Here, we report that autophagy is induced by cetuximab, a therapeutic antibody that blocks epidermal growth factor receptor function. Cancer cell treatment with cetuximab triggered autophagosome formation, conversion of microtubule-associated protein 1 light chain 3 from its cytoplasmic to membrane-associated form, and increased acidic vesicular organelle formation. Autophagy occurred when cetuximab inhibited the class I phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin pathway, but not when it inhibited only the mitogen-activated protein/extracellular signal-regulated kinase kinase/Erk pathway, and it was accompanied by decreased levels of hypoxia inducible factor-1 alpha (HIF-1alpha) and Bcl-2. Stable overexpression of a HIF-1alpha mutant prevented cetuximab-induced autophagy and decrease in Bcl-2 levels. Knockdown of autophagy regulator beclin 1 or cell treatment with autophagy inhibitor 3-methyladenine, a class III PI3K (hVps34) inhibitor, also inhibited cetuximab-induced autophagy. Furthermore, knockdown of beclin 1 or Atg7 or treatment with the lysosome inhibitor chloroquine sensitized cancer cells to cetuximab-induced apoptosis. Mechanistic analysis argued that cetuximab acted by promoting an association between beclin 1 and hVps34, which was inhibited by overexpression of Bcl-2. Our findings suggest that the autophagy protects cancer cells from the proapoptotic effects of cetuximab.
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PMID:The epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1alpha and Bcl-2 and activating the beclin 1/hVps34 complex. 2063 5

Arsenic trioxide (As(2)O(3)) exhibits potent antitumor effects in vitro and in vivo, but the precise mechanisms by which it generates such responses are not well understood. We provide evidence that As(2)O(3) is a potent inducer of autophagy in leukemia cells. Such induction of autophagy by As(2)O(3) appears to require activation of the MEK/ERK pathway but not the AKT/mammalian target of rapamycin or JNK pathways. In efforts to understand the functional relevance of arsenic-induced autophagy, we found that pharmacological inhibitors of autophagy or molecular targeting of beclin 1 or Atg7 results in reversal of the suppressive effects of As(2)O(3) on leukemic cell lines and primary leukemic progenitors from acute myelogenous leukemia patients. Altogether, our data provide direct evidence that autophagic cell death is critical for the generation of the effects of As(2)O(3) on acute myelogenous leukemia cells and raise the potential of modulation of elements of the autophagic machinery as an approach to enhance the antitumor properties of As(2)O(3) and possibly other heavy metal derivatives.
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PMID:Autophagy is a critical mechanism for the induction of the antileukemic effects of arsenic trioxide. 2065 87

Cetuximab is an epidermal growth factor receptor (EGFR)-blocking antibody that is approved to treat several types of solid cancers in patients. We recently showed that cetuximab can induce autophagy in cancer cells by both inhibiting the class I phosphatidylinositol 3-kinase (PtdIns3K)/Akt/mammalian target of rapamycin (mTOR) pathway and activating the class III PtdIns3K (hVps34)/beclin 1 pathway. In the current study, we investigated the relationship between cetuximab-induced autophagy and apoptosis and the biological roles of autophagy in cetuximab-mediated cancer therapy. We found that cetuximab induced autophagy in cancer cells that show strong or weak induction of apoptosis after cetuximab treatment but not in those that show only cytostatic growth inhibition. Inhibition of cetuximab-induced apoptosis by a caspase inhibitor prevented the induction of autophagy. Conversely, inhibition of cetuximab-induced autophagy by silencing the expression of autophagy-related genes (Atg) or treating the cancer cells with lysosomal inhibitors enhanced the cetuximab-induced apoptosis, suggesting that autophagy was a protective cellular response to cetuximab treatment. On the other hand, cotreatment of cancer cells with cetuximab and the mTOR inhibitor rapamycin resulted in an Atg-dependent and lysosomal inhibition-sensitive death of cancer cells that show only growth inhibition or weak apoptosis after cetuximab treatment, indicating that cell death may be achieved by activating the autophagy pathway in these cells. Together, our findings may guide the development of novel clinical strategies for sensitizing cancer cells to EGFR-targeted therapy.
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PMID:Roles of autophagy in cetuximab-mediated cancer therapy against EGFR. 2086 11


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