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

Insulin-increased prolactin gene transcription in GH4 cells was enhanced by binding on fibronectin. This was mediated by receptor-like protein tyrosine phosphatase alpha, which activated Src, Rho, and phosphatidylinositol 3-kinase. It suggested that insulin signaling to gene transcription was partly dependent on actin rearrangement. This was confirmed through studies using inhibitors of actin treadmilling. Cytochalasin D, jasplakinolide, latrunculin B, and swinholide A altered the actin cytoskeleton of GH4 cells, as assessed by Alexa Fluor phalloidin staining, and inhibited insulin-increased prolactin gene transcription. These reagents did not affect the controls. Nor was it due to a gross defect of insulin signaling because activation/translocation of glycogen synthase kinase 3beta and mammalian target of rapamycin were not affected. Expression of wild-type and mutant actin treadmilling agents, Cdc42, TC10, neuronal Wiskott-Aldrich syndrome protein, and Nck, indicated that they were essential to insulin-increased prolactin gene expression, and suggested that activation of p21 associated kinase (PAK) might also be essential to this process. PAK expression also increased and PAK mutants decreased prolactin promoter activity in insulin-treated cells. The activation of PAK in the presence of inhibitors was also consistent with a role in activation of insulin-increased prolactin gene expression. Finally, small interfering RNA-mediated reduction of PAK decreased the effect of insulin on prolactin gene expression. Thus, it is likely that insulin activation of actin treadmilling through Cdc42/TC10 and neuronal Wiskott-Aldrich syndrome protein activates PAK and prolactin gene transcription.
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PMID:Insulin-increased prolactin gene expression requires actin treadmilling: potential role for p21 activated kinase. 1788 42

The mechanisms by which retinoids regulate initiation of mRNA translation for proteins that mediate their biological effects are not known. We have previously shown that all-trans-retinoic acid (ATRA) induces mTOR-mediated activation of the p70 S6 kinase, suggesting the existence of a mechanism by which retinoids may regulate mRNA translation. We now demonstrate that treatment of acute promyelocytic leukemia (APL)-derived NB4 cells with ATRA results in dissociation of the translational repressor 4E-BP1 from the eukaryotic initiation factor eIF4E, and subsequent formation of eIF4G-eIF4E complexes. We also show that siRNA-mediated inhibition of 4E-BP1 expression enhances ATRA-dependent upregulation of p21(Waf1/Cip1), a protein that plays a key role in the induction of retinoid-dependent responses. Our data also establish that ATRA- or cis-RA-dependent p21(Waf1/Cip1) protein expression is enhanced in mouse embryonic fibroblasts with targeted disruption of the 4e-bp1 gene, in the absence of any effects on the transcriptional regulation of the p21(Waf1/Cip1) gene. Moreover, generation of ATRA- or cis-retinoic acid (cis-RA)-antiproliferative responses is enhanced in 4E-BP1 knockout cells. Altogether, these findings strongly suggest a key regulatory role for the translational repressor 4E-BP1 in the generation of retinoid-dependent functional responses.
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PMID:Role of the translational repressor 4E-BP1 in the regulation of p21(Waf1/Cip1) expression by retinoids. 1828 Aug 4

Hypoxia plays important roles in some early stages of mammalian embryonic development and in various physiological functions. This study examined the effect of arachidonic acid on short-period hypoxia-induced regulation of G(1) phase cell-cycle progression and inter-relationships among possible signalling molecules in mouse embryonic stem cells. Hypoxia increased the level of hypoxia-inducible factor-1alpha (HIF-1alpha) expression and H2O2 generation in a time-dependent manner. In addition, hypoxia increased the levels of cell-cycle regulatory proteins (cyclin D(1), cyclin E, cyclin-dependent kinase 2 (CDK2) and CDK4). Maximum increases in the level of these proteins and retinoblastoma phosphorylation were observed after 12-24 h of exposure to hypoxic conditions, and then decreased. Alternatively, the level of the CDK inhibitors, p21(Cip1) and p27(Kip1) were decreased. These results were consistent with the results of [3H]-thymidine incorporation and cell counting. Hypoxia also increased the level of [3H]-arachidonic acid release and inhibition of cPLA(2) reduced hypoxia-induced increase in levels of the cell-cycle regulatory proteins and [3H]-thymidine incorporation. The level of cyclooxygenase-2 (COX-2) was also increased by hypoxia and inhibition of COX-2 decreased the levels of cell-cycle regulatory proteins and [3H]-thymidine incorporation. Indeed, the percentage of cells in S phase, levels of cell cycle regulatory proteins, and [3H]-thymidine incorporation were further increased in hypoxic conditions with arachidonic acid treatment compared to normoxic conditions. Hypoxia-induced Akt and mitogen-activated protein kinase (MAPK) phosphorylation was inhibited by vitamin C (antioxidant, 10(-3) M). In addition, hypoxia-induced increase of cell-cycle regulatory protein expression and [(3)H]-thymidine incorporation were attenuated by LY294002 (PI3K inhibitor, 10(-6) M), Akt inhibitor (10(-6) M), rapamycin (mTOR inhibitor, 10(-9) M), PD98059 (p44/42 inhibitor, 10(-5) M), and SB203580 (p38 MAPK inhibitor, 10(-6) M). Furthermore, hypoxia-induced increase of [(3)H]-arachidonic acid release was blocked by PD98059 or SB203580, but not by LY294002 or Akt inhibitor. In conclusion, arachidonic acid up-regulates short time-period hypoxia-induced G(1) phase cyclins D(1) and E, and CDK 2 and 4, in mouse embryonic stem cells through the cooperation of PI3K/Akt/mTOR, MAPK and cPLA(2)-mediated signal pathways.
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PMID:Short-period hypoxia increases mouse embryonic stem cell proliferation through cooperation of arachidonic acid and PI3K/Akt signalling pathways. 1833 69

In mice fed trypsin inhibitor (camostat) to elevate endogenous CCK, pancreatic growth plateaus by 7 days. It is unknown whether this represents the maximum growth capacity of the pancreas. To test the ability of CCK to drive further growth, mice were fed chow containing camostat (0.1%) for 1 wk, then fed standard chow for 1 wk, and finally returned to the camostat diet for a week. Pancreatic mass increased to 245% of initial value (iv) following 1 wk of camostat feeding, decreased to 147% iv following a 1 wk return to normal chow, and increased to 257% iv with subsequent camostat feeding. Camostat feeding was associated with significant increases in circulating CCK and changes in pancreatic mass were paralleled by changes in protein and DNA content. Moreover, regression of the pancreas following camostat feeding was associated with changes in the expression of the autophagosome marker LC3. Pancreatic protein synthetic rates were 130% of control after 2 days on camostat but were equivalent to control after 7 days. Changes in the phosphorylation of 4E-BP1 and S6, downstream effectors of mammalian target of rapamycin (mTOR), paralleled changes in protein synthetic rates. Cellular content of Akt, an upstream activating kinase of mTOR, decreased after 7 days of camostat feeding whereas expression of the E3 ubiquitin-ligases and the cell cycle inhibitor p21 increased after 2 days. These results indicate that CCK-stimulated growth of the pancreas is not limited by acinar cell mitogenic capacity but is due, at least in part, to inhibition of promitogenic Akt signaling.
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PMID:CCK-induced pancreatic growth is not limited by mitogenic capacity in mice. 1835 33

The mammalian target of rapamycin (mTOR) pathway plays a central role in regulating protein synthesis, ribosomal protein translation, and cap-dependent translation. Deregulations in mTOR signaling are frequently associated with tumorigenesis, angiogenesis, tumor growth and metastasis. This review highlights the role of the mTOR in anticancer drug resistance. We discuss the network of signaling pathways in which the mTOR kinase is involved, including the structure and activation of the mTOR complex and the pathways upstream and downstream of mTOR as well as other molecular interactions of mTOR. Major upstream signaling components in control of mTOR activity are PI3K/PTEN/AKT and Ras/Raf/MEK/ERK pathways. We discuss the central role of mTOR in mediating the translation of mRNAs of proteins related to cell cycle progression, those involved in cell survival such as c-myc, hypoxia inducible factor 1* (HIF-1*) and vascular endothelial growth factor (VEGF), cyclin A, cyclin dependent kinases (cdk1/2), cdk inhibitors (p21(Cip1) and p27(Kip1)), retinoblastoma (Rb) protein, and RNA polymerases I and III. We then discuss the potential therapeutic opportunities for using mTOR inhibitors rapamycin, CCI-779, RAD001, and AP-23573 in cancer therapy as single agents or in combinations to reverse drug resistance.
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PMID:Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment. 1844 Aug 54

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and highly resistant to available chemotherapies. Mammalian target of rapamycin (mTOR) functions to regulate protein translation, angiogenesis and cell cycle progression in many cancers including HCC. In the present study, subcutaneous patient-derived HCC xenografts were used to study the effects of an mTOR inhibitor, RAD001 (everolimus), on tumour growth, apoptosis and angiogenesis. We report that oral administration of RAD001 to mice bearing patient-derived HCC xenografts resulted in a dose-dependent inhibition of tumour growth. RAD001-induced growth suppression was associated with inactivation of downstream targets of mTOR, reduction in VEGF expression and microvessel density, inhibition of cell proliferation, up-regulation of p27(Kip1) and down-regulation of p21(Cip1/Waf1), Cdk-6, Cdk-2, Cdk-4, cdc-25C, cyclin B1 and c-Myc. Our data indicate that the mTOR pathway plays an important role in angiogenesis, cell cycle progression and proliferation of liver cancer cells. Our study provides a strong rationale for clinical investigation of mTOR inhibitor RAD001 in patients with HCC.
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PMID:RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma. 1846 52

Activation of the phosphatidylinositol-3 kinase/Akt/mammalian target of the rapamycin (PI3K/Akt/mTOR) pathway and inactivation of wild-type p53 by murine double minute 2 homologue (Mdm2) overexpression are frequent molecular events in acute myeloid leukemia (AML). We investigated the interaction of PI3K/Akt/mTOR and p53 pathways after their simultaneous blockade using the dual PI3K/mTOR inhibitor PI-103 and the Mdm2 inhibitor Nutlin-3. We found that PI-103, which itself has modest apoptogenic activity, acts synergistically with Nutlin-3 to induce apoptosis in a wild-type p53-dependent fashion. PI-103 synergized with Nutlin-3 to induce Bax conformational change and caspase-3 activation, despite its inhibitory effect on p53 induction. The PI-103/Nutlin-3 combination caused profound dephosphorylation of 4E-BP1 and decreased expression of many proteins including Mdm2, p21, Noxa, Bcl-2 and survivin, which can affect mitochondrial stability. We suggest that PI-103 actively enhances downstream p53 signaling and that a combination strategy aimed at inhibiting PI3K/Akt/mTOR signaling and activating p53 signaling is potentially effective in AML, where TP53 mutations are rare and downstream p53 signaling is intact.
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PMID:The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. 1854 93

Classically, the development of emphysema in chronic obstructive pulmonary disease is believed to involve inflammation induced by cigarette smoke and leukocyte activation, including oxidant-antioxidant and protease-antiprotease imbalances. While there is substantial evidence for this, additional aspects have been suggested by a number of clinical and experimental observations. Smokers exhibit signs of premature aging, particularly obvious in the skin. The link between aging and chronic disease is well-known, e.g., for the brain and musculoskeletal or cardiovascular system, as well as the clinical link between malnutrition and emphysema, and the experimental link to caloric restriction. Interestingly, this intervention also increases lifespan, in parallel with alterations in metabolism, oxidant burden and endocrine signaling. Of special interest is the observation that, even in the absence of an inflammatory environment, lung fibroblasts from patients with emphysema show persistent alterations, possibly based on epigenetic mechanisms. The importance of these mechanisms for cellular reprogramming and response patterns, individual risk profile and therapeutic options is becoming increasingly recognized. The same applies to cellular senescence. Recent findings from patients and experimental models open novel views into the arena of gene-environment interactions, including the role of systemic alterations, cellular stress, telomeres, CDK inhibitors such as p16, p21, pRb, PI3K, mTOR, FOXO transcription factors, histone modifications, and sirtuins. This article aims to outline this emerging picture and to stimulate the identification of challenging questions. Such insights also bear implications for the long-term course of the disease in relation to existing or future therapies and the exploration of potential lung regeneration.
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PMID:Aging and induced senescence as factors in the pathogenesis of lung emphysema. 1861 81

Less information is available concerning the molecular mechanisms of cell survival after hypoxia in hepatocytes. Therefore, this study examined the effect of hypoxia on DNA synthesis and its related signal cascades in primary cultured chicken hepatocytes. Hypoxia increased [3H] thymidine incorporation, which was increased significantly after 0-24 h of hypoxic exposure. Indeed, the percentage of cell population in the S phase was increased in hypoxia condition. However, the release of LDH indicating cellular injury was not changed under hypoxic conditions. Hypoxia increased Ca2+ uptake and PKC translocation from the cytosol to the membrane fraction. Among the PKC isoforms, hypoxia stimulated the translocation of PKC alpha and epsilon. Hypoxia also phosphorylated the p38 and p44/42 mitogen-activated protein kinases (MAPKs), which were blocked by the inhibition of PKC. On the other hand, hypoxia increased Akt and mTOR phosphorylation, which was blocked in the absence of intra/extracellular Ca2+. The inhibition of PKC/MAPKs or PI3K/Akt pathway blocked the hypoxia-induced [3H] thymidine incorporation. However, hypoxia-induced Ca2+ uptake and PKC translocation was not influenced by LY 294002 or Akt inhibitor and hypoxia-induced MAPKs phosphorylation was not changed by rapamycin. In addition, LY 294002 or Akt inhibitor has no effect on the phosphorylation of MAPKs. It suggests that there is no direct interaction between the two pathways, which cooperatively mediated cell cycle progression to hypoxia in chicken hepatocytes. Hypoxia also increased the level of the cell cycle regulatory proteins [cyclin D(1), cyclin E, cyclin-dependent kinase (CDK) 2, and CDK 4] and p-RB protein but decreased the p21 and p27 expression levels, which were blocked by inhibitors of upstream signal molecules. In conclusion, short time exposure to hypoxia increases DNA synthesis in primary cultured chicken hepatocytes through cooperation of Ca2+/PKC, p38 MAPK, p44/42 MAPKs, and PI3K/Akt pathways.
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PMID:A potential mechanism for short time exposure to hypoxia-induced DNA synthesis in primary cultured chicken hepatocytes: Correlation between Ca(2+)/PKC/MAPKs and PI3K/Akt/mTOR. 1864 54

Malignant tumors are exposed to various levels of hypoxic condition in vivo. It has been known that tumor cells under hypoxia are resistant to chemotherapies. To clarify the mechanism of the hypoxia-induced chemoresistance, we evaluated the effects of hypoxia on the resistance of oral squamous cell carcinoma (OSCC) cell lines to 5-fluorouracil (5-FU). OSCC cells were divided to two groups by the proliferation activity under hypoxic condition; hypoxia-resistant (HR) and hypoxia-sensitive (HS) cells. Growth of HS cells were inhibited by hypoxia and introduced to G(1) arrest in cell cycle. 5-FU effect on HS cell viability was markedly reduced in hypoxic condition without an induction of chemoresistant related protein, P-glycoprotein. However, proliferation, cell cycle, and 5-FU sensitivity of HR cells were not affected by hypoxia. Hypoxia-inducible factor (HIF)-1alpha was induced by hypoxia in all OSCC cell lines, but diminished in HS cells within 48h. Expression of p21 and p27 was strongly augmented and CyclinD expression was reduced by hypoxia in HS cells. However, the expression of these proteins was constitutive in HR cells during 48h hypoxic culture. Phosphorylation of mammalian target of rapamycin (mTOR) was reduced by hypoxia in HS cells. From these findings, we concluded that HS OSCC cells acquire 5-FU resistance under hypoxia by G(1)/S transition through an upregulation of cell cycle inhibitors.
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PMID:Hypoxia induces resistance to 5-fluorouracil in oral cancer cells via G(1) phase cell cycle arrest. 1871 Aug 19


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