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)

Dysregulated signal transduction from receptor tyrosine kinases to phosphatidylinositol 3-kinase (PI3K), AKT (protein kinase B), and its effector FKBP-rapamycin-associated protein (FRAP) occurs via autocrine stimulation or inactivation of the tumor suppressor PTEN in many cancers. Here we demonstrate that in human prostate cancer cells, basal-, growth factor-, and mitogen-induced expression of hypoxia-inducible factor 1 (HIF-1) alpha, the regulated subunit of the transcription factor HIF-1, is blocked by LY294002 and rapamycin, inhibitors of PI3K and FRAP, respectively. HIF-1-dependent gene transcription is blocked by dominant-negative AKT or PI3K and by wild-type PTEN, whereas transcription is stimulated by constitutively active AKT or dominant-negative PTEN. LY294002 and rapamycin also inhibit growth factor- and mitogen-induced secretion of vascular endothelial growth factor, the product of a known HIF-1 target gene, thus linking the PI3K/PTEN/AKT/FRAP pathway, HIF-1, and tumor angiogenesis. These data indicate that pharmacological agents that target PI3K, AKT, or FRAP in tumor cells inhibit HIF-1alpha expression and that such inhibition may contribute to therapeutic efficacy.
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PMID:Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. 1074 20

Stem cell factor (SCF)/c-kit plays an important role in the regulation of hematopoiesis, melanogenesis, and spermatogenesis. In the testis, the SCF/c-kit system is believed to regulate germ cell proliferation, meiosis, and apoptosis. Studies with type A spermatogonia in vivo and in vitro have indicated that SCF induces DNA synthesis and proliferation. However, the signaling pathway for this function of SCF/c-kit has not been elucidated. We now demonstrate that SCF activates phosphoinositide 3-kinase (PI3-K) and p70 S6 kinase (p70S6K) and that rapamycin, a FRAP/mammalian target of rapamycin-dependent inhibitor of p70S6K, completely inhibited bromodeoxyuridine incorporation induced by SCF in primary cultures of spermatogonia. SCF induced cyclin D3 expression and phosphorylation of the retinoblastoma protein through a pathway that is sensitive to both wortmannin and rapamycin. Furthermore, AKT, but not protein kinase C-zeta, is used by SCF/c-kit/PI3-K to activate p70S6K. Dominant negative AKT-K179M completely abolished p70S6K phosphorylation induced by the constitutively active PI3-K catalytic subunit p110. Constitutively active v-AKT highly phosphorylated p70S6K, which was totally inhibited by rapamycin. Thus, SCF/c-kit uses a rapamycin-sensitive PI3-K/AKT/p70S6K/cyclin D3 pathway to promote spermatogonial cell proliferation.
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PMID:Stem cell factor/c-kit up-regulates cyclin D3 and promotes cell cycle progression via the phosphoinositide 3-kinase/p70 S6 kinase pathway in spermatogonia. 1084 22

The microbially derived antiproliferative agent rapamycin inhibits cell growth by interfering with the signaling functions of the mammalian target of rapamycin (mTOR). In this study, we demonstrate that interleukin-3 stimulation induces a wortmannin-sensitive increase in mTOR kinase activity in a myeloid progenitor cell line. The involvement of phosphoinositide 3'-kinase (PI3K) in the regulation of mTOR activity was further suggested by findings that mTOR was phosphorylated in vitro and in vivo by the PI3K-regulated protein kinase, AKT/PKB. Although AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. Transient transfection assays with mTOR mutants bearing Ala substitutions at Ser2448 and/or Thr2446 indicated that AKT-dependent mTOR phosphorylation was not essential for either PHAS-I phosphorylation or p70S6K activation in HEK cells. However, a deletion of amino acids 2430-2450 in mTOR, which includes the potential AKT phosphorylation sites, significantly increased both the basal protein kinase activity and in vivo signaling functions of mTOR. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a "repressor domain" that negatively regulates the catalytic activity of mTOR. Furthermore, the activation status of the PI3K-AKT pathway in cancer cells may be an important determinant of cellular sensitivity to the cytostatic effect of rapamycin.
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PMID:A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. 1091 62

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator composed of HIF-1alpha and HIF-1beta subunits. Several dozen HIF-1 targets are known, including the gene encoding vascular endothelial growth factor (VEGF). Under hypoxic conditions, HIF-1alpha expression increases as a result of decreased ubiquitination and degradation. The tumor suppressors VHL (von Hippel-Lindau protein) and p53 target HIF-1alpha for ubiquitination such that their inactivation in tumor cells increases the half-life of HIF-1alpha. Increased phosphatidylinositol 3-kinase (PI3K) and AKT or decreased PTEN activity in prostate cancer cells also increases HIF-1alpha expression by an undefined mechanism. In breast cancer, increased activity of the HER2 (also known as neu) receptor tyrosine kinase is associated with increased tumor grade, chemotherapy resistance, and decreased patient survival. HER2 has also been implicated as an inducer of VEGF expression. Here we demonstrate that HER2 signaling induced by overexpression in mouse 3T3 cells or heregulin stimulation of human MCF-7 breast cancer cells results in increased HIF-1alpha protein and VEGF mRNA expression that is dependent upon activity of PI3K, AKT (also known as protein kinase B), and the downstream kinase FRAP (FKBP-rapamycin-associated protein). In contrast to other inducers of HIF-1 expression, heregulin stimulation does not affect the half-life of HIF-1alpha but instead stimulates HIF-1alpha synthesis in a rapamycin-dependent manner. The 5'-untranslated region of HIF-1alpha mRNA directs heregulin-inducible expression of a heterologous protein. These data provide a molecular basis for VEGF induction and tumor angiogenesis by heregulin-HER2 signaling and establish a novel mechanism for the regulation of HIF-1alpha expression.
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PMID:HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. 1135 7

The FOP-fibroblast growth factor receptor 1 (FGFR1) fusion protein is expressed as a consequence of a t(6;8) (q27;p12) translocation associated with a stem cell myeloproliferative disorder with lymphoma, myeloid hyperplasia and eosinophilia. In the present report, we show that the fusion of the leucine-rich N-terminal region of FOP to the catalytic domain of FGFR1 results in conversion of murine hematopoietic cell line Ba/F3 to factor-independent cell survival via an antiapoptotic effect. This survival effect is dependent upon the constitutive tyrosine phosphorylation of FOP-FGFR1. Phosphorylation of STAT1 and of STAT3, but not STAT5, is observed in cells expressing FOP-FGFR1. The survival function of FOP-FGFR1 is abrogated by mutation of the phospholipase C gamma binding site. Mitogen-activated protein kinase (MAPK) is also activated in FOP-FGFR1-expressing cells and confers cytokine-independent survival to hematopoietic cells. These results demonstrate that FOP-FGFR1 is capable of protecting cells from apoptosis by using the same effectors as the wild-type FGFR1. Furthermore, we show that FOP-FGFR1 phosphorylates phosphatidylinositol 3 (PI3)-kinase and AKT and that specific inhibitors of PI3-kinase impair its ability to promote cell survival. In addition, FOP-FGFR1-expressing cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase; this phosphorylation is inhibited by PI3-kinase and mTOR (mammalian target of rapamycin) inhibitors. These results indicate that translation control is important to mediate the cell survival effect induced by FOP-FGFR1. Finally, FOP-FGFR1 protects cells from apoptosis by survival signals including BCL2 overexpression and inactivation of caspase-9 activity. Elucidation of signaling events downstream of FOP-FGFR1 constitutive activation provides insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.
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PMID:8p12 stem cell myeloproliferative disorder: the FOP-fibroblast growth factor receptor 1 fusion protein of the t(6;8) translocation induces cell survival mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt/mTOR pathways. 1168 2

Interleukin-6 (IL-6) is a prominent tumor growth factor for malignant multiple myeloma cells. In addition to its known activation of the Janus tyrosine kinase-STAT and RAS-MEK-ERK pathways, recent work suggests that IL-6 can also activate the phosphatidylinositol 3-kinase (PI3-K)/AKT kinase pathway in myeloma cells. Because activation of the PI3-K/AKT as well as RAS-MEK-ERK pathways may result in downstream stimulation of the p70(S6K) (p70) and phosphorylation of the 4E-BP1 translational repressor, we assessed these potential molecular targets in IL-6-treated myeloma cells. IL-6 rapidly activated p70 kinase activity and p70 phosphorylation. Activation was inhibited by wortmannin, rapamycin, and the ERK inhibitors PD98059 and UO126, as well as by a dominant negative mutant of AKT. The concurrent requirements for both ERK and PI3-K/AKT appeared to be a result of their ability to phosphorylate p70 on different residues. In contrast, IL-6-induced phosphorylation of 4E-BP1 was inhibited by rapamycin, wortmannin, and dominant negative AKT but ERK inhibitors had no effect, indicating ERK function was dispensable. In keeping with these data, a dominant active AKT mutant was sufficient to induce 4E-BP1 phosphorylation but could not by itself activate p70 kinase activity. Prevention of IL-6-induced p70 activation and 4E-BP1 phosphorylation by the mammalian target of rapamycin inhibitors rapamycin and CCI-779 resulted in inhibition of IL-6-induced myeloma cell growth. These results indicate that both ERK and PI3-K/AKT pathways are required for optimal IL-6-induced p70 activity, but PI3-K/AKT is sufficient for 4E-BP1 phosphorylation. Both effects are mediated via mammalian target of rapamycin function, and, furthermore, these effects are critical for IL-6-induced tumor cell growth.
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PMID:Signal pathways involved in activation of p70S6K and phosphorylation of 4E-BP1 following exposure of multiple myeloma tumor cells to interleukin-6. 1187 47

Recent work identifies the AKT kinase as a potential mediator of tumor expansion in multiple myeloma. The finding of PTEN mutations in several myeloma cell lines suggests that loss of PTEN function may be one mechanism by which AKT activity is increased in this disease. Because PTEN-deficient myeloma cells may have up-regulated activity of the mammalian target of rapamycin (mTOR), downstream of AKT, they may be particularly sensitive to mTOR inhibition. To test this hypothesis, we challenged myeloma cell lines with CCI-779, a newly developed analogue of rapamycin and an efficient inhibitor of mTOR. Three of four PTEN-deficient cell lines with constitutively active AKT were remarkably sensitive to cytoreduction and G(1) arrest induced by CCI-779 with ID(50) concentrations of <1 nM. In contrast, myeloma cells expressing wild-type PTEN were >1000-fold more resistant. Acute expression of a constitutively active AKT gene in CCI-779-resistant myeloma cells containing wild-type PTEN and quiescent AKT did not convert them to the CCI-779-sensitive phenotype. Conversely, expression of wild-type PTEN in CCI-779-sensitive, PTEN-deficient myeloma cells did not induce resistance. Differential sensitivity did not appear to be due to differences in the ability of CCI-779 to inhibit mTOR and induce dephosphorylation of p70S6kinase or 4E-BP1. However, CCI-779 inhibited expression of c-myc in CCI-sensitive PTEN-null myeloma cells but had no effect on expression in CCI-resistant cells. In contrast, cyclin D1 expression was not altered in either sensitive or resistant cells. These results indicate that PTEN-deficient myeloma cells are remarkably sensitive to mTOR inhibition. Although the results of transfection studies suggest that the level of PTEN and AKT function per se does not regulate sensitivity, PTEN/AKT status may be a good predictive marker of sensitivity.
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PMID:Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. 1220 57

Ectopic expression of mutated K-ras or N-ras in the interleukin 6 (IL-6)-dependent ANBL6 multiple myeloma cell line induces cytokine-independent growth. To investigate the signaling pathways activated by oncogenic ras that may stimulate IL-6-independent growth, we compared ANBL6 cells stably transfected with mutated K or N-ras genes with wild-type ras-expressing control cells identically transfected with an empty vector. Upon depletion of IL-6, both mutated ras-containing myeloma lines demonstrated constitutive activation of mitogen-activated extracellular kinase 2(MEK)/extracellular signal-regulated kinase (ERK), phosphatidylinositol-3 kinase (PI3-kinase)/AKT, mammalian target of rapamycin (mTOR)/p70S6-kinase, and nuclear factor kappa B (NF-kappa B) pathways. In contrast, signal transducer and activator of transcription-3 (STAT-3) was not constitutively tyrosine phosphorylated in mutant ras-expressing cells. We used several maneuvers in attempts to selectively target these constitutively active pathways. The mTOR inhibitors rapamycin and CCI-779, the PI3-kinase inhibitor LY294002, and the MEK inhibitor PD98059 all significantly curtailed growth of mutant ras-containing cells. Farnesyl transferase inhibitors, used to target ras itself, had modest effects only against mutant N-ras-containing cells. Growth of mutant N-ras-containing myeloma cells was also inhibited by acute expression of the IKB superrepressor gene, which abrogated NF-kappa B activation. These results indicate that several pathways contributing to stimulation of cytokine-independent growth are activated downstream of oncogenic ras in myeloma cells. They also suggest that therapeutic strategies that target these pathways may be particularly efficacious in patients whose myeloma clones contain ras mutations.
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PMID:Downstream effectors of oncogenic ras in multiple myeloma cells. 1251 20

Chronic lymphocytic leukemia therapy has changed dramatically over the past decade, with recent studies supporting the use of fludarabine as the initial therapy for symptomatic disease. New findings relative to the use of fludarabine and complications arising from this therapy are reviewed. Exciting combination approaches using monoclonal antibodies such as rituximab or Campath-1H in combination with fludarabine offer the opportunity to improve the complete response rate further in chronic lymphocytic leukemia. Furthermore, the field of experimental therapeutics for chronic lymphocytic leukemia was advanced by the description of a new mouse model of human chronic lymphocytic leukemia and identification of several disrupted signal transduction pathways in this disease. The description of therapies that target AKT, protein kinase C, phosphodiesterase 4, mammalian target of rapamycin, histone deacetylase, and methyltransferase offer the opportunity to utilize molecularly targeted therapy for this disease. Such targeted approaches offer hope that we might be on the threshold to changing the natural history of chronic lymphocytic leukemia.
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PMID:Advances in the therapy of chronic lymphocytic leukemia. 1279 36

Growing evidence indicates that inflammation is a contributing factor leading to cancer development. However, pathways involved in this progression are not well understood. To examine whether HIF-1alpha is a factor linking inflammation and tumorigenesis, we investigated whether the HIF-1 signaling pathway was stimulated by the pro-inflammatory cytokine interleukin-1beta (IL-1beta) in A549 cells. We find that IL-1beta up-regulated HIF-1alpha protein under normoxia and activated the HIF-1-responsive gene vascular endothelial growth factor (VEGF) via a pathway dependent on nuclear factor kappaB (NFkB). Interestingly, although this pathway is stimulated by upstream signaling via AKT and mTOR and requires new transcription, IL-1 mediated HIF-1alpha induction also utilizes a post-transcriptional mechanism that involves antagonism of VHL-dependent HIF-1alpha degradation, which results in increased HIF-1alpha protein stability. IL-1 mediated NFkB-dependent cyclooxygenases-2 (COX-2) expression served as a positive effector for HIF-1alpha induction. Although COX-2 inhibitors attenuated IL-1 mediated HIF-1alpha induction, prostaglandin E2 (PGE2), a physiological product of COX-2, induced HIF-1alpha protein in a dose-dependent manner. Our data, therefore, demonstrate that IL-1beta up-regulates functional HIF-1alpha protein through a classical inflammatory signaling pathway involving NFkB and COX-2, culminating in up-regulation of VEGF, a potent angiogenic factor required for tumor growth and metastasis. Thus, HIF-1 is identified as a pivotal transcription factor linking the inflammatory and oncogenic pathways.
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PMID:IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. 1295 48


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