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)

While pancreatic protein synthesis and the initiation of translation are regulated by hormones and neurotransmiters, whether the elongation process is also regulated is unknown. Stimulatory doses of cholecystokinin (CCK) (100 pM), bombesin (10 nM), and carbachol (10 microM) increased elongation rates (measured as ribosomal half-transit time) in pancreatic acini in vitro. At the same time these secretagogues reduced elongation factor 2 (eEF2) phosphorylation, the main factor known to regulate elongation, and increased the phosphorylation of the eEF2 kinase. The mTOR inhibitor rapamycin reversed the dephosphorylation of eEF2 induced by CCK, as did treatment with the p38 MAPK inhibitor SB202190, the MEK inhibitor PD98059, and the phosphatase inhibitor calyculin A. Neither rapamycin, SB202190, PD98059 nor calyculin A had an effect on CCK mediated eEF2 kinase phosphorylation. Translation elongation in pancreatic acinar cells is likely regulated by eEF2 through the mTOR, p38, and MEK pathways, and modulated through PP2A.
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PMID:Regulation of translation elongation and phosphorylation of eEF2 in rat pancreatic acini. 1515 53

Cardiac hypertrophy involves increased mass (growth) of the heart and a cardinal feature of this condition is increased rates of protein synthesis. Several signaling pathways have been implicated in cardiac hypertrophy including the phosphatidylinositol 3-kinase (PI3K) and Ras/Raf/MEK/Erk pathways. PI3K lies upstream of the mammalian target of rapamycin (mTOR), an important positive regulator of protein synthesis and cell growth. However, recent data suggest that, in response to certain hypertrophic agents, signaling via Ras and MEK/Erk, as well as mTOR, is required for activation of protein synthesis, indicating new connections between these key signaling pathways.
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PMID:Ras, PI3-kinase and mTOR signaling in cardiac hypertrophy. 1527 65

Recently, we showed that autocrine transforming growth factor alpha (TGFalpha) controls the epidermal growth factor receptor (EGFR)-mediated basal expression of integrin alpha2, cell adhesion and motility in highly progressed HCT116 colon cancer cells. We also reported that the expression of basal integrin alpha2 and its biological effects are critically controlled by the constitutive activation of the ERK/MAPK pathway (Sawhney, R. S., Sharma, B., Humphrey, L. E., and Brattain, M. G. (2003) J. Biol. Chem. 278, 19861-19869). In the present report, we further examine the downstream signaling mechanisms underlying EGFR/ERK signaling and integrin alpha2 function in HCT116 cells. Selective MEK inhibitors attenuated TGFalpha-mediated basal activation of p70S6K (S6K) specifically at Thr-389, indicating that this S6K site is downstream of ERK/MAPK signaling. Cells were treated with the selective protein kinase C (PKC) inhibitor bisindolylmaleimide to determine the role of PKC in S6K activation. The Thr-421 and Ser-424 phosphorylation sites of S6K were specifically inhibited by bisindolylmaleimide, which also blocked integrin alpha2 expression, cell adhesion, and motility. These data establish a novel cell motility function of S6K via PKC activation in a cancer cell. In addition, we examined whether mammalian target of rapamycin signaling controls S6K activation. Rapamycin inhibited constitutive S6K phosphorylation specifically at Thr-389, Thr-421, and Ser-424 sites. The assignment of these phosphorylation sites on S6K to biological functions was unequivocally confirmed by transfection of cells with specific single phosphorylation site dominant negative mutants. These experiments show for the first time that autocrine TGFalpha regulates cell adhesion function by multiple signaling pathways via specific phosphorylation sites of S6K in cancer cells.
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PMID:Autocrine transforming growth factor alpha regulates cell adhesion by multiple signaling via specific phosphorylation sites of p70S6 kinase in colon cancer cells. 1530

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of many diseases and in cancer therapy. Although the unfolded protein response is known to alleviate ER stress by reducing the accumulation of misfolded proteins, the exact survival elements and their downstream signaling pathways that directly counteract ER stress-stimulated apoptotic signaling remain elusive. Here, we have shown that endogenous Akt and ERK are rapidly activated and act as downstream effectors of phosphatidylinositol 3-kinase in thapsigargin- or tunicamycin-induced ER stress. Introduction of either dominant-negative Akt or MEK1 or the inhibitors LY294002 and U0126 sensitized cells to ER stress-induced cell death in different cell types. Reverse transcription-PCR analysis of gene expression during ER stress revealed that cIAP-2 and XIAP, members of the IAP family of potent caspase suppressors, were strongly induced. Transcription of cIAP-2 and XIAP was up-regulated by the phosphatidylinositol 3-kinase/Akt pathway as shown by its reversal by dominant-negative Akt or LY294002. Ablation of these IAPs by RNA interference sensitized cells to ER stress-induced death, which was reversed by the caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone. The protective role of IAPs in ER stress coincided with Smac release from mitochondria to the cytosol. Furthermore, it was shown that mTOR was not required for Akt-mediated survival. These results represent the first demonstration that activation of endogenous Akt/IAPs and MEK/ERK plays a critical role in controlling cell survival by resisting ER stress-induced cell death signaling.
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PMID:Critical role of endogenous Akt/IAPs and MEK1/ERK pathways in counteracting endoplasmic reticulum stress-induced cell death. 1533 11

Interactions between the Chk1 inhibitor UCN-01 and the farnesyltransferase inhibitor L744832 were examined in human leukemia cells. Combined exposure of U937 cells to subtoxic concentrations of UCN-01 and L744832 resulted in a dramatic increase in mitochondrial dysfunction, apoptosis, and loss of clonogenicity. Similar interactions were noted in other leukemia cells (HL-60, Raji, Jurkat) and primary acute myeloid leukemia (AML) blasts. Coadministration of L744832 blocked UCN-01-mediated phosphorylation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK), leading to down-regulation of phospho-cyclic adenosine monophosphate responsive element-binding protein (phospho-CREB) and -p90(RSK) and activation of p34(cdc2) and stress-activated protein kinase/ERK kinase/c-Jun N-terminal kinase (SEK/JNK). Combined treatment also resulted in pronounced reductions in levels of phospho-Akt, -glycogen synthase kinase-3 (-GSK-3), -p70(S6K), -mammalian target of rapamycin (-mTOR), -forkhead transcription factor (-FKHR), -caspase-9, and -Bad. Ectopic expression of Bcl-2 or Bcl-xL but not dominant-negative caspase-8 blocked UCN-01/L744832-mediated mitochondrial dysfunction and apoptosis but did not prevent activation of p34(cdc2) and JNK or inactivation of MEK/ERK and Akt. Enforced expression of myristoylated Akt but not constitutively active MEK significantly attenuated UCN-01/L744832-induced apoptosis. However, dual transfection with Akt and MEK resulted in further protection from UCN-01/L744832-mediated lethality. Finally, down-regulation of JNK1 by siRNA significantly reduced the lethality of the UCN-01/L744832 regimen. Together, these findings suggest that farnesyltransferase inhibitors interrupt the cytoprotective Akt and MAPK pathways while reciprocally activating SAPK/JNK in leukemia cells exposed to UCN-01 and, in so doing, dramatically increase mitochondria-dependent apoptosis.
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PMID:Farnesyltransferase inhibitors interact synergistically with the Chk1 inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both Akt and MEK/ERK pathways and activation of SEK1/JNK. 1549 23

Bone marrow stromal cells are essential for the differentiation, survival and proliferation of normal and leukemic human B-lineage cells. Leukemic cells require stromal cell support for optimal proliferation and apoptotic resistance. Stromal cell contact can promote resistance to chemotherapeutic agents. In this study, we have made use of small molecular weight inhibitors and an established stromal cell-dependent pre-B-ALL cell line, BLIN-2, to investigate the role of the MAP kinase, PI3K/Akt, JAK/STAT and mTOR pathways in the promotion of leukemic cell growth in the presence of stromal cell support. Treatment with PI3K+JAK, PI3K+MEK, or MEK+JAK inhibitor combinations resulted in an inhibition of proliferation as measured by DNA synthesis. However, only inhibition of both PI3K and MEK or both mTOR and MEK resulted in a dramatic increase in the number of annexinV(+)/PI(+) apoptotic events within a 24 h period. Our data suggest that stromal cell-mediated apoptotic protection in B-lineage ALL is mediated by PI3K/mTOR and MEK via a synergistic mechanism(s).
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PMID:Inhibition of PI3K, mTOR and MEK signaling pathways promotes rapid apoptosis in B-lineage ALL in the presence of stromal cell support. 1549 72

Interleukins (IL)-2 and IL-15 regulate natural killer (NK) cell proliferation, survival, and cytolytic activity. Ets1 is a transcription factor expressed early in NK cell differentiation. Because IL-2Rbeta, IL-2Rgamma, IL-15, and Ets1 knock-out mice similarly lack NK cells, we explored a molecular connection between IL-2R signaling and Ets1. Here we report the post-transcriptional regulation of Ets1 by IL-2R signaling in human NK cells. IL-2 and IL-15 stimulation leads to increased Ets1 protein levels with no significant change in mRNA levels. Pulse and pulse-chase experiments show that IL-2 stimulation results in both a marked increase in the nascent translation of Ets1 and an increased protein half-life. Pharmacological inhibition of MEK specifically blocks IL-2- and IL-15-induced translation, whereas p38, phosphatidylinositol 3-kinase, and mTOR inhibitors had no effect on Ets1 levels. Fli1, an Ets family member, exhibited a different mechanism of regulation, illustrating the specificity of IL-2R beta and gamma subunit signaling on the regulation of Ets1 expression. Expression of a dominant negative form of MNK1, a regulator of the translation initiation factor eIF4E, blocks the expression of Ets1 as do the dominant negative forms of the common IL-2R beta and gamma chains. Expression of Ets1 is regulated similarly in normal peripheral human NK cells. Taken together, our findings provide a direct link between IL-2R subunit signaling and Ets1 expression and helps to explain the interdependence of the IL-2R subunits and Ets1 for NK cell development and function.
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PMID:Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. 1556 72

Whereas most mammalian cells require extracellular signals to suppress apoptosis, preimplantation embryos can survive and develop to the blastocyst stage in defined medium without added serum or growth factors. Since cells of these embryos are capable of undergoing apoptosis, it has been suggested that their lack of dependence upon exogenous growth factors results from the production of endogenous growth factors that suppress apoptosis by an autocrine signaling mechanism. In the present study, we have examined the growth factor requirements and intracellular signaling pathways that suppress apoptosis in both mouse preimplantation embryos and embryonic stem (ES) cells, which are derived from the blastocyst inner cell mass. Cultured ES cells, in contrast to intact embryos, required serum growth factors to prevent apoptosis. Suppression of ES cell apoptosis by serum growth factors required the phosphatidylinositol 3-kinase (PI 3-kinase) signaling pathway, since apoptosis was rapidly induced by inhibition of PI 3-kinase with LY294002. In contrast, inhibition of MEK/ERK signaling with U0126 or of mTOR with rapamycin had no detectable effect on ES cell survival. Thus, like most mammalian cells, the survival of ES cells is mediated by growth factor stimulation of PI 3-kinase signaling. Treatment with LY294002 (but not with U0126 or rapamycin) similarly induced apoptosis of mouse blastocysts in serum-free medium, indicating that intact preimplantation embryos are also dependent upon PI 3-kinase signaling for survival. These results demonstrate that PI 3-kinase signaling is required to suppress apoptosis of both ES cells and intact preimplantation embryos, consistent with the hypothesis that survival of preimplantation embryos is maintained by endogenous growth factors that stimulate the PI 3-kinase pathway.
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PMID:Mouse embryonic stem cells and preimplantation embryos require signaling through the phosphatidylinositol 3-kinase pathway to suppress apoptosis. 1562 1

The macrolide antibiotic rapamycin inhibits the mammalian target of rapamycin protein (mTOR) kinase resulting in the global inhibition of cap-dependent protein synthesis, a blockade in ribosome component biosynthesis, and G1 cell cycle arrest. G1 arrest may occur by inhibiting the protein synthesis of critical factors required for cell cycle progression. Hypersensitivity to mTOR inhibitors has been demonstrated in cells having elevated levels of AKT kinase activity, whereas cells containing quiescent AKT activity are relatively resistant. Our previous data suggest that low AKT activity induces resistance by allowing continued cap-independent protein synthesis of cyclin D1 and c-Myc proteins. In support of this notion, the current study demonstrates that the human cyclin D1 mRNA 5' untranslated region contains an internal ribosome entry site (IRES) and that both this IRES and the c-myc IRES are negatively regulated by AKT activity. Furthermore, we show that cyclin D1 and c-myc IRES function is enhanced following exposure to rapamycin and requires both p38 MAPK and RAF/MEK/ERK signaling, as specific inhibitors of these pathways reduce IRES-mediated translation and protein levels under conditions of quiescent AKT activity. Thus, continued IRES-mediated translation initiation may permit cell cycle progression upon mTOR inactivation in cells in which AKT kinase activity is relatively low.
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PMID:Cyclin D1 and c-myc internal ribosome entry site (IRES)-dependent translation is regulated by AKT activity and enhanced by rapamycin through a p38 MAPK- and ERK-dependent pathway. 1563 85

B-lineage acute leukemia (B-ALL) cells often require stromal cell support for optimal proliferation and apoptotic resistance. In addition, stromal cell contact can promote resistance to chemotherapeutic agents. However, the precise biochemical pathways within the leukemic cell that are activated by the bone marrow microenvironment which result promotion of cell proliferation and apoptotic protection are not fully characterized. We have recently reported that simultaneous inhibition of the MEK and PI3K pathways or the MEK and mTOR pathways promote rapid apoptosis of the stromal cell dependent B-lineage ALL cell line BLIN-2 in the presence of stromal cell support. These data indicated that stromal cell induced apoptotic protection is mediated by PI3K/mTOR and MEK in a mechanism(s) that suggests cross-talk or points of convergence. The EGF receptor (EGFR) has been reported to activate both MEK and PI3K. We report herein that use of the EGFR inhibitor, AG1478, inhibits BLIN-2 survival in the presence of stromal cells. FACS analysis revealed that EGFR is expressed on the surface of BLIN-2 cells. The addition of EGF to BLIN-2 cultures in the absence of stromal cells prolongs BLIN-2 survival. Similarly, introduction of a constitutively active form of EGFR, v-ErbB, into BLIN-2 prolongs the survival of BLIN-2 cells in the absence of stromal cell support. These data provide evidence that stimulation of the EGFR pathway is one mechanism by which the bone marrow microenvironment may contribute to the growth and survival of B-cell acute leukemia.
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PMID:Activated EGFR promotes the survival of B-lineage acute leukemia in the absence of stromal cells. 1570 73


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