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)

LKB1, a tumor-suppressor gene that codifies for a serine/threonine kinase, is mutated in the germ-line of patients affected with the Peutz-Jeghers syndrome (PJS), which have an increased incidence of several cancers including gastrointestinal, pancreatic and lung carcinomas. Regarding tumors arising in non-PJS patients, we recently observed that at least one-third of lung adenocarcinomas (LADs) harbor somatic LKB1 gene mutations, supporting a role for LKB1 in the origin of some sporadic tumors. To characterize the pattern of LKB1 mutations in LADs further, we first screened for LKB1 gene alterations (gene mutations, promoter hypermethylation and homozygous deletions) in 19 LADs and, in agreement with our previous data, five of them (26%) were shown to harbor mutations, all of which gave rise to a truncated protein. Recent reports demonstrate that LKB1 is able to suppress cell growth, but little is known about the specific mechanism by which it functions. To further our understanding of LKB1 function, we analysed global expression in lung primary tumors using cDNA microarrays to identify LKB1-specific variations in gene expression. In all, 34 transcripts, 24 of which corresponded to known genes, differed significantly between tumors with and without LKB1 gene alterations. Among the most remarkable findings was deregulation of transcripts involved in signal transduction (e.g. FRAP1/mTOR, ARAF1 and ROCK2), cytoskeleton (e.g. MPP1), transcription factors (e.g. MEIS2, ATF5), metabolism of AMP (AMPD3 and APRT) and ubiquitinization (e.g. USP16 and UBE2L3). Real-time quantitative RT-PCR on 15 tumors confirmed the upregulation of the homeobox MEIS2 and of the AMP-metabolism AMPD3 transcripts in LKB1-mutant tumors. In addition, immunohistochemistry in 10 of the lung tumors showed the absence of phosphorylated FRAP1/mTOR protein in LKB1-mutant tumors, indicating that LKB1 mutations do not lead to FRAP1/mTOR protein kinase activation. In conclusion, our results reveal that several important factors contribute to LKB1-mediated carcinogenesis in LADs, confirming previous observations and identifying new putative pathways that should help to elucidate the biological role of LKB1.
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PMID:Distinctive gene expression of human lung adenocarcinomas carrying LKB1 mutations. 1507 68

Insulin and moderate oxidative stress stimulate proliferation of ovarian theca-interstitial cells. The effects of these agents on selected signal transduction pathways were examined. PD98059 (inhibitor of MAP2K1, also known as MEK-1, upstream of extracellular signal-regulated protein kinases MAPK3/1, also known as ERK1/2), wortmannin (inhibitor of PIK3C2A, also known as PI3K), and rapamycin (inhibitor of FRAP1, also known as mTOR, upstream of RPS6KB1) each significantly decreased insulin and oxidative stress-induced proliferation of theca-interstitial cells. The greatest inhibition was observed in the presence of rapamycin; this effect occurred without a significant change in cell viability. Phosphorylation of AKT was stimulated by insulin only, while phosphorylation of MAPK3/1 and RPS6KB1 was increased by insulin and oxidative stress. Insulin-induced and oxidative stress-induced phosphorylation of RPS6KB1 was partly inhibited by wortmannin and partly by PD98059; the greatest inhibition was observed in the presence of a combination of wortmannin plus PD98059. Effects of insulin and oxidative stress on phosphorylation of RPS6KB1 were confirmed by kinase activity assays. These findings indicate that actions of insulin and oxidative stress converge on MAPK3/1 and RPS6KB1. Furthermore, we speculate that activation of RPS6KB1 may be in part induced via the MAPK3/1 pathway.
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PMID:Insulin and oxidative stress modulate proliferation of rat ovarian theca-interstitial cells through diverse signal transduction pathways. 1648 89

Angiopoietin-1 (ANGPT1), Angiopoietin-4 (ANGPT4), VEGF, FGF2, FGF4, HGF, Ephrin, IL8 and CXCL12 (SFD1) are pro-angiogenic factors (angiogenic activators), while Angiopoietin-2 (ANGPT2), Angiostatin, Endostatin, Tumstatin, Canstatin, THBS1, THBS2, TNFSF15 (VEGI) and Vasohibin (VASH1) are anti-angiogenic factors (angiogenic inhibitors). ANGPT1 and ANGPT2 are ligands for TIE family receptor tyrosine kinases, TIE1 and TIE2 (TEK). Angiopoietin family consists of ANGPT1, ANGPT2, ANGPT4, ANGPTL1 (ANGPT3), ANGPTL2, ANGPTL3 (ANGPT5), ANGPTL4, ANGPTL5, ANGPTL6 and ANGPTL7. TCF/LEF binding sites within the promoter region of human Angiopoietin family members were searched for by using bioinformatics and human intelligence (Humint). Because four TCF/LEF-binding sites were identified within the human ANGPTL7 promoter, comparative genomics analyses on ANGPTL7 orthologs were further performed. ANGPTL7 gene at human chromosome 1p36.22 was located within intron 28 of FRAP1 gene encoding mTOR protein. Chimpanzee ANGPTL7 gene, consisting of five exons, was located within NW_101546.1 genome sequence. Chimpanzee ANGPTL7 showed 99.4% and 86.1% total-amino-acid identity with human ANGPTL7 and mouse Angptl7, respectively. Human ANGPTL7 mRNA was expressed in neural tissues, keratoconus cornea, trabecular meshwork, melanotic melanoma and uterus endometrial cancer, while mouse Angptl7 mRNA was expressed in four-cell embryo, synovial fibroblasts, thymus, uterus and testis. Four TCF/LEF-binding sites within human ANGPTL7 promoter were conserved in chimpanzee ANGPTL7 promoter; however, only an unrelated TCF/LEF-binding site occurred in mouse and rat Angptl7 promoters. Human ANGPTL7, characterized as potent target gene of WNT/ beta-catenin signaling pathway, is a pharmacogenomics target in the fields of oncology and regenerative medicine.
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PMID:Comparative integromics on Angiopoietin family members. 1668 28

There is no report on the gene expression profile of retinoblastoma (Rb). We analyzed the gene expression profile of Rb by the microarray technique. One thousand four genes were upregulated and 481 genes were downregulated. Microarray data were confirmed by semiquantitative RT-PCR for 5 genes in Rb samples: CDC25A, C17orf75, ERBB3, LATS2, and CHFR. Clusters of differentially expressed genes were identified on chromosomes 1, 16, and 17. Based on the expression profile, we hypothesized that the PI3K/AKT/mTOR (insulin signaling) pathway might be dysregulated in Rb. Our semiquantitative RT-PCR analysis of the PIK3CA, AKT1, FRAP1, and RPS6KB1 genes in Rb samples supported this hypothesis. We suggest that known inhibitors of this pathway could be evaluated for the treatment of Rb.
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PMID:Identification of genes associated with tumorigenesis of retinoblastoma by microarray analysis. 1760 97

Ca(2+)-release-activated Ca(2+) (CRAC) channels generate sustained Ca(2+) signals that are essential for a range of cell functions, including antigen-stimulated T lymphocyte activation and proliferation. Recent studies have revealed that the depletion of Ca(2+) from the endoplasmic reticulum (ER) triggers the oligomerization of stromal interaction molecule 1 (STIM1), the ER Ca(2+) sensor, and its redistribution to ER-plasma membrane (ER-PM) junctions where the CRAC channel subunit ORAI1 accumulates in the plasma membrane and CRAC channels open. However, how the loss of ER Ca(2+) sets into motion these coordinated molecular rearrangements remains unclear. Here we define the relationships among [Ca(2+)](ER), STIM1 redistribution and CRAC channel activation and identify STIM1 oligomerization as the critical [Ca(2+)](ER)-dependent event that drives store-operated Ca(2+) entry. In human Jurkat leukaemic T cells expressing an ER-targeted Ca(2+) indicator, CRAC channel activation and STIM1 redistribution follow the same function of [Ca(2+)](ER), reaching half-maximum at approximately 200 microM with a Hill coefficient of approximately 4. Because STIM1 binds only a single Ca(2+) ion, the high apparent cooperativity suggests that STIM1 must first oligomerize to enable its accumulation at ER-PM junctions. To assess directly the causal role of STIM1 oligomerization in store-operated Ca(2+) entry, we replaced the luminal Ca(2+)-sensing domain of STIM1 with the 12-kDa FK506- and rapamycin-binding protein (FKBP12, also known as FKBP1A) or the FKBP-rapamycin binding (FRB) domain of the mammalian target of rapamycin (mTOR, also known as FRAP1). A rapamycin analogue oligomerizes the fusion proteins and causes them to accumulate at ER-PM junctions and activate CRAC channels without depleting Ca(2+) from the ER. Thus, STIM1 oligomerization is the critical transduction event through which Ca(2+) store depletion controls store-operated Ca(2+) entry, acting as a switch that triggers the self-organization and activation of STIM1-ORAI1 clusters at ER-PM junctions.
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PMID:Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. 1859 93

FRAP1 (FK506-binding protein 12-rapamycin complex-associated protein 1), a component of the nutrient-sensing cell signaling pathway, is critical for cell growth and metabolism. The present study determined expression of FRAP1 and associated members of the mTORC1 and mTORC2 cell signaling pathways in uteri of cyclic and pregnant ewes and conceptuses, as well as effects of pregnancy, progesterone (P4), and interferon tau (IFNT) on their expression. The mRNAs for FRAP1, LST8, MAPKAP1, RAPTOR, RICTOR, TSC1, TSC2, RHEB, and EIF4EBP1 were localized to luminal, superficial glandular, and glandular epithelia and stromal cells of uteri from cyclic and pregnant ewes, as well as trophectoderm and endoderm of conceptuses between Days 13 and 18 of pregnancy. The abundance of FRAP1, RAPTOR, RICTOR, TSC1, and TSC2 mRNAs in endometria was unaffected by pregnancy status or by day of the estrous cycle or pregnancy; however, levels of LST8, MAPKAP1, RHEB, and EIF4EBP1 mRNA increased in endometria during early pregnancy. In ovariectomized ewes, P4 and IFNT stimulated expression of RHEB and EIF4EBP1 in uterine endometria. Total endometrial FRAP1 protein and phosphorylated FRAP1 protein levels were affected by pregnancy status and by day after onset of estrus, and phosphorylated FRAP1 protein was detected in nuclei of uterine epithelia and conceptuses. In endometria of pregnant ewes, increases in abundance of mRNAs for RICTOR, RHEB, and EIF4EBP1, as well as RHEB protein, correlated with rapid conceptus growth and development during the peri-implantation period. These results suggest that the FRAP1 cell signaling pathway mediates interactions between the maternal uterus and peri-implantation conceptuses and that P4 and IFNT affect this pathway by regulating expression of RHEB and EIF4EBP1.
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PMID:Select nutrients in the ovine uterine lumen. VI. Expression of FK506-binding protein 12-rapamycin complex-associated protein 1 (FRAP1) and regulators and effectors of mTORC1 and mTORC2 complexes in ovine uteri and conceptuses. 1929 12

Memory CD8 T cells are a critical component of protective immunity, and inducing effective memory T-cell responses is a major goal of vaccines against chronic infections and tumours. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response, but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells. Here we show that mTOR (mammalian target of rapamycin, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what we expected, the immunosuppressive drug rapamycin has immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced not only the quantity but also the quality of virus-specific CD8 T cells. Similar effects were seen after immunization of mice with a vaccine based on non-replicating virus-like particles. In addition, rapamycin treatment also enhanced memory T-cell responses in non-human primates following vaccination with modified vaccinia virus Ankara. Rapamycin was effective during both the expansion and contraction phases of the T-cell response; during the expansion phase it increased the number of memory precursors, and during the contraction phase (effector to memory transition) it accelerated the memory T-cell differentiation program. Experiments using RNA interference to inhibit expression of mTOR, raptor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 (mTOR complex 1) pathway to regulate memory T-cell differentiation. Thus these studies identify a molecular pathway regulating memory formation and provide an effective strategy for improving the functional qualities of vaccine- or infection-induced memory T cells.
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PMID:mTOR regulates memory CD8 T-cell differentiation. 1986 45

Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in several solid tumour types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Here, using integrative analysis of a genomic profile of the region, we identify a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the trans-Golgi network and interacts with components of the retromer complex, which in yeast has been linked to target of rapamycin (TOR) signalling. Mechanistically, GOLPH3 regulates cell size, enhances growth-factor-induced mTOR (also known as FRAP1) signalling in human cancer cells, and alters the response to an mTOR inhibitor in vivo. Thus, genomic and genetic, biological, functional and biochemical data in yeast and humans establishes GOLPH3 as a new oncogene that is commonly targeted for amplification in human cancer, and is capable of modulating the response to rapamycin, a cancer drug in clinical use.
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PMID:GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer. 1955 91

Hormonal, targeted and chemotherapeutic strategies largely depend on the expression of their cognate receptors and are often accompanied by intolerable toxicities. Effective and less toxic therapies for estrogen receptor negative (ER-) breast cancers are urgently needed. Here, we present the potential molecular mechanisms mediating the selective pro-apoptotic effect induced by BN107 and its principle terpene, oleanolic acid (OA), on ER- breast cancer cells. A panel of breast cancer cell lines was examined and the most significant cytotoxic effect was observed in ER- breast lines. Apoptosis was the major cellular pathway mediating the cytotoxicity of BN107. We demonstrated that sensitivity to BN107 was correlated to the status of ERalpha. Specifically, the presence of functional ERalpha protected cells from BN107-induced apoptosis and absence of ERalpha increased the sensitivity. BN107, an extract rich in OA derivatives, caused rapid alterations in cholesterol homeostasis, presumably by depleting cholesterol in lipid rafts (LRs), which subsequently interfered with signaling mediated by LRs. We showed that BN107 or OA treatment in ER- breast cancer cells resulted in rapid and specific inhibition of LR-mediated survival signaling, namely mTORC1 and mTORC2 activities, by decreasing the levels of the mTOR/FRAP1, RAPTOR and RICTOR. Cotreatment with cholesterol abolished the proapoptotic effect and restored the disrupted mTOR activities. This is the first report demonstrating possible concomitant inhibition of both mTORC1 and mTORC2 activities by modulating the levels of protein constituents present in these signaling complexes, and thus provides a basis for future development of OA-based mTOR inhibitors.
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PMID:Selective concomitant inhibition of mTORC1 and mTORC2 activity in estrogen receptor negative breast cancer cells by BN107 and oleanolic acid. 2002 31

MicroRNAs (miRNAs) are small noncoding RNAs that direct gene regulation through translational repression and degradation of complementary mRNA. Although miRNAs have been implicated as oncogenes and tumor suppressors in a variety of human cancers, functional roles for individual miRNAs have not been described in clear cell ovarian carcinoma, an aggressive and chemoresistant subtype of ovarian cancer. We performed deep sequencing to comprehensively profile miRNA expression in 10 human clear cell ovarian cancer cell lines compared with normal ovarian surface epithelial cultures and discovered 54 miRNAs that were aberrantly expressed. Because of the critical roles of the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin (mTOR) pathway in clear cell ovarian cancer, we focused on mir-100, a putative tumor suppressor that was the most down-regulated miRNA in our cancer cell lines, and its up-regulated target, FRAP1/mTOR. Overexpression of mir-100 inhibited mTOR signaling and enhanced sensitivity to the rapamycin analog RAD001 (everolimus), confirming the key relationship between mir-100 and the mTOR pathway. Furthermore, overexpression of the putative tumor suppressor mir-22 repressed the EVI1 oncogene, which is known to suppress apoptosis by stimulating phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1 signaling. In addition to these specific effects, reversing the expression of mir-22 and the putative oncogene mir-182 had widespread effects on target and nontarget gene populations that ultimately caused a global shift in the cancer gene signature toward a more normal state. Our experiments have revealed strong candidate miRNAs and their target genes that may contribute to the pathogenesis of clear cell ovarian cancer, thereby highlighting alternative therapeutic strategies for the treatment of this deadly cancer.
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PMID:A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer. 2008 Nov 5


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