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)

Mammary gland growth and involution are based on a dynamic equilibrium between proliferation and apoptosis of mammary epithelial cells (MEC). The main type of cell death responsible for bovine mammary gland involution is apoptosis, but MEC also exhibit morphological features of autophagy. The present study has been undertaken in order to examine factors, which are responsible for the regulation of autophagy in bovine MEC. We used a model of in vitro mammary gland involution known to be dependent on fetal bovine serum (FBS) deficiency in the culture of bovine BME-UV1 cells. We investigated the effects of insulin-like growth factor-1 (IGF-I) and epidermal growth factor (EGF) signaling, as well as sex steroids and rapamycin (a specific inhibitor of mammalian target of rapamycin, mTOR, kinase) on autophagy in the MEC line BME-UV1. Our main focus was on the role of mTOR in the regulation of autophagy by growth factors and hormones. Laser scanning cytometry, electron microscopy, Western-blot analysis, GFP-LC3 reporter-based expression analysis, and LysoTracker Green-related fluorescence were used to determine the activity of autophagy in BME-UV1 cells. We found that FBS deficiency induced both autophagy and apoptosis with the highest intensity of both processes after 48h of MEC exposure to the deficient medium (0.5% FBS). Addition of IGF-I or/and EGF to the FBS-deficient medium clearly diminished autophagy. We also show that IGF-I and EGF are involved in the activation of mTOR in bovine MEC, whereas inhibition of mTOR by rapamycin abrogated the suppressive effects of IGF-I and EGF on autophagy. This suggests that mTOR links IGF-I and EGF signaling in inhibiting the autophagy pathways. Contrary to IGF-I and EGF, 17beta-estradiol and progesterone exerted stimulatory effects on autophagy in bovine MEC. At the same time we observed a suppressive effect of both steroids on mTOR activation/phosphorylation. In conclusion, autophagy in bovine MEC undergoes complex regulation, where its activity is controlled by survival pathways dependent on IGF-I and EGF, which are involved in suppression of autophagy, and by pregnancy steroids, which act as inducers of the process.
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PMID:IGF-I, EGF, and sex steroids regulate autophagy in bovine mammary epithelial cells via the mTOR pathway. 1901 62

Tumor hypoxia is an obstacle to radiotherapy. Radiosensitivity under hypoxic conditions is determined by molecular oxygen levels, as well as by various biological cellular responses. The insulin-like growth factor (IGF) signaling pathway is a widely recognized survival signal that confers radioresistance. However, under hypoxic conditions the role of IGF signaling in radiosensitivity is still poorly understood. Here, we demonstrate that IGF-II stimulation decreases clonogenic survival under hypoxic conditions in the pancreatic cancer cell lines AsPC-1 and Panc-1, and in the human breast cancer cell line MCF-7. IGF treatment under hypoxic conditions suppressed increased radiation sensitivity in these cell lines by pharmacologically inhibiting the phosphoinositide 3-kinase-mammalian target of rapamycin pathway, a major IGF signal-transduction pathway. Meanwhile, IGF-II induced the endoplasmic reticulum stress response under hypoxia, including increased protein levels of CHOP and ATF4, mRNA levels of CHOP, GADD34, and BiP, as well as splicing levels of XBP-1. The response was suppressed by inhibiting phosphoinositide 3-kinase and mammalian target of rapamycin activity. Overexpression of CHOP in AsPC-1 cells increased radiation sensitivity by IGF-II simulation under hypoxic conditions, whereas suppression of CHOP expression levels with small hairpin RNA or a dominant negative form of a proline-rich extensin-like receptor protein kinase in hypoxia decreased IGF-induced radiosensitivity. IGF-induced endoplasmic reticulum stress contributed to radiosensitization independent of cell cycle status. Taken together, IGF stimulation increased radiosensitivity through the endoplasmic reticulum stress response under hypoxic conditions.
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PMID:Insulin-like growth factor stimulation increases radiosensitivity of a pancreatic cancer cell line through endoplasmic reticulum stress under hypoxic conditions. 1901 73

Anti-inflammatory strategies are often used to reduce muscle pain and soreness that can result from high-intensity muscular activity. However, studies indicate that components of the acute inflammatory response may be required for muscle repair and growth. The hypothesis of this study was that cyclooxygenase (COX)-2 activity is required for compensatory hypertrophy of skeletal muscle. We used the synergist ablation model of skeletal muscle hypertrophy, along with the specific COX-2 inhibitor NS-398, to investigate the role of COX-2 in overload-induced muscle growth in mice. COX-2 was expressed in plantaris muscles during compensatory hypertrophy and was localized mainly in or near muscle cell nuclei. Treatment with NS-398 blunted the increases in mass and protein content in overloaded muscles compared with vehicle-treated controls. Additionally, the COX-2 inhibitor decreased activity of the urokinase type plasminogen activator, macrophage accumulation, and cell proliferation, all of which are required for hypertrophy after synergist ablation. Expression of insulin-like growth factor-1 and phosphorylation of Akt, mammalian target of rapamycin, and p70S6K were increased following synergist ablation, but were not affected by NS-398. Additionally, expression of atrogin-1 was reduced during hypertrophy, but was also not affected by NS-398. These results demonstrate that COX-2 activity is required for skeletal muscle hypertrophy, possibly through facilitation of extracellular protease activity, macrophage accumulation, and cell proliferation.
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PMID:COX-2 inhibitor reduces skeletal muscle hypertrophy in mice. 1917 87

Multiple myeloma is still incurable. Myeloma cells become resistant to common drugs and patients eventually die of tumour progression. Therefore, new targets and drugs are needed immediately. NVP-AEW541 is a new, orally bioavailable small molecule inhibitor of the insulin-like growth factor-1 receptor (IGF-1R). Here, we show that NVP-AEW541 inhibits cell growth in myeloma cells at low concentrations in a time-dependent and a dose-dependent manner. Further experiments using the annexin-V-fluorescein isothiocyanate/propidium iodide assay revealed induction of apoptosis in common myeloma cell lines, but not in peripheral blood mononuclear cell from healthy donors. Stimulation of myeloma cells with IGF-1 led to a vast increase of cell growth and this was blocked by low doses of NVP-AEW541. Stimulation of myeloma cells with conditioned medium obtained from a 48-h-old HS-5 stromal cell culture was only partly blocked by NVP-AEW541. Western blotting experiments revealed that NVP-AEW541 decreased the phosphorylation status of P70S6 kinase and 4E-BP-1 but not of mammalian target of rapamycin (mTOR). Combined inhibition of IGF-1R and mTOR using the novel mTOR inhibitor Rad001 led to additive/synergistic increase of cell growth inhibition in multiple myeloma cells, which was accompanied by a stronger dephosphorylation of P70S6 kinase and 4E-BP-1. Taken together, we show that the combined inhibition of IGF-1R and mTOR by combining NVP-AEW541 and Rad001 is highly effective in multiple myeloma and might represent a potential new treatment strategy.
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PMID:Myeloma cell growth inhibition is augmented by synchronous inhibition of the insulin-like growth factor-1 receptor by NVP-AEW541 and inhibition of mammalian target of rapamycin by Rad001. 1924 Jun 43

Gastric cancer is the second most common cause of cancer death worldwide with approximately one million cases diagnosed annually. Despite considerable improvements in surgical techniques, innovations in clinical diagnostics and the development of new chemotherapy regimens, the clinical outcome for patients with advanced gastric cancer and cancer of the GEJ is generally poor with 5-year survival rates ranging between 5 and 15%. The understanding of cancer relevant events has resulted in new therapeutic strategies, particularly in developing of new molecular targeted agents. These agents have the ability to target a variety of cancer relevant receptors and downstream pathways including the epidermal growth factor receptor (EGFR), the vascular endothelial growth factor receptor (VEGFR), the insulin-like growth factor receptor (IGFR), the c-Met pathway, cell-cycle pathways, and down-stream signalling pathways such as the Akt-PI3k-mTOR pathway. In the era of new molecularly targeted agents this review focuses on recent developments of targeting relevant pathways involved in gastric cancer and cancer of the GEJ.
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PMID:Gastric cancer in the era of molecularly targeted agents: current drug development strategies. 1936 21

The precise mechanism whereby epidermal growth factor (EGF) activates the serine-threonine kinase Akt and the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) remains elusive. Here, we report that the alpha subunits of the heterotrimeric guanine nucleotide-binding proteins (G proteins) Galpha(i1) and Galpha(i3) are critical for this activation process. Both Galpha(i1) and Galpha(i3) formed complexes with growth factor receptor binding 2 (Grb2)-associated binding protein 1 (Gab1) and the EGF receptor (EGFR) and were required for the phosphorylation of Gab1 and its subsequent interaction with the p85 subunit of phosphatidylinositol 3-kinase in response to EGF. Loss of Galpha(i1) and Galpha(i3) severely impaired the activation of Akt and of p70 S6 kinase and 4E-BP1, downstream targets of mTORC1, in response to EGF, heparin-binding EGF-like growth factor, and transforming growth factor alpha, but not insulin, insulin-like growth factor, or platelet-derived growth factor. In addition, ablation of Galpha(i1) and Galpha(i3) largely inhibited EGF-induced cell growth, migration, and survival and the accumulation of cyclin D1. Overall, this study suggests that Galpha(i1) and Galpha(i3) lie downstream of EGFR, but upstream of Gab1-mediated activation of Akt and mTORC1, thus revealing a role for Galpha(i) proteins in mediating EGFR signaling.
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PMID:Galpha(i1) and Galpha(i3) are required for epidermal growth factor-mediated activation of the Akt-mTORC1 pathway. 1940 91

The reduced incidence of breast cancer in certain Eastern countries has been attributed to high soy diets although this evidence is simply epidemiological. One of the major constituents of soy is genistein, but paradoxically this phytoestrogen binds to oestrogen receptors and stimulates growth at concentrations that would be achieved by a high soy diet, but inhibits growth at high experimental concentrations. To determine the effects of low-dose, long-term genistein exposure we have cultured MCF-7 breast cancer cells in 10 nM genistein for 10-12 weeks and investigated whether or not this long-term genistein treatment (LTGT) altered the expression of oestrogen receptor alpha (ERalpha) and the activity of the PI3-K/Akt signalling pathway. This is known to be pivotal in the signalling of mitogens such as oestradiol (E(2)), insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF). LTGT significantly reduced the growth promoting effects of E(2) and increased the dose-dependent growth-inhibitory effect of the PI3-K inhibitor, LY 294002, compared to untreated control MCF-7 cells. This was associated with a significant decreased protein expression of total Akt and phosphorylated Akt but not ERalpha. Rapamycin, an inhibitor of one of the down-stream targets of Akt, mammalian target of rapamycin (mTOR), also dose-dependently inhibited growth but the response to this drug was similar in LTGT and control MCF-7 cells. The protein expression of liver receptor homologue-1 (LRH1), an orphan nuclear receptor implicated in tumourigenesis was not affected by LTGT. The results show that LTGT results in a down-regulation of the PI3-K/Akt signalling pathway and may be a mechanism through which genistein could offer protection against breast cancer.
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PMID:Evidence that low-dose, long-term genistein treatment inhibits oestradiol-stimulated growth in MCF-7 cells by down-regulation of the PI3-kinase/Akt signalling pathway. 1940 42

Chronic complete spinal cord injury (SCI) is associated with severe skeletal muscle atrophy as well several atrophy and physical-inactivity-related comorbidity factors such as diabetes, obesity, lipid disorders, and cardiovascular diseases. Intracellular mechanisms associated with chronic complete SCI-related muscle atrophy are not well understood, and thus their characterization may assist with developing strategies to reduce the risk of comorbidity factors. Therefore, the aim of this study was to determine whether there was an increase in catabolic signaling targets, such as atrogin-1, muscle ring finger-1 (MuRF1), forkhead transcription factor (FoXO), and myostatin, and decreases in anabolic signaling targets, such as insulin-like growth factor (IGF), v-akt murine thymoma viral oncogene (Akt), glycogen synthase kinase-beta (GSK-3beta), mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E binding protein 1 (4E-BP1), and p70(s6kinase) in chronic complete SCI patients. In SCI patients, when compared with controls, there was a significant reduction in mRNA levels of atrogin-1 (59%; P < 0.05), MuRF1 (55%; P < 0.05), and myostatin (46%; P < 0.01), and in protein levels of FoXO1 (72%; P < 0.05), FoXO3a (60%; P < 0.05), and atrogin-1 (36%; P < 0.05). Decreases in the protein levels of IGF-1 (48%; P < 0.001) and phosphorylated GSK-3beta (54%; P < 0.05), 4E-BP1 (48%; P < 0.05), and p70(s6kinase) (60%; P = 0.1) were also observed, the latter three in an Akt- and mTOR-independent manner. Reductions in atrogin-1, MuRF1, FoXO, and myostatin suggest the existence of an internal mechanism aimed at reducing further loss of muscle proteins during chronic SCI. The downregulation of signaling proteins that regulate anabolism, such as IGF, GSK-3beta, and 4E-BP1, would reduce the ability to increase protein synthesis rates.
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PMID:Atrogin-1, MuRF1, and FoXO, as well as phosphorylated GSK-3beta and 4E-BP1 are reduced in skeletal muscle of chronic spinal cord-injured patients. 1953 53

Adjunctive chemotherapy with bisphosphonates has been reported to delay bone metastasis and improve overall survival in breast cancer. Aside from its antiresorptive effect, bisphosphonates exhibit antitumor activities, in vitro and in vivo, via several mechanisms, including antiangiogenesis. In this study, we investigated the potential molecular mechanisms underlying the antiangiogenic effect of non-nitrogen-containing and nitrogen-containing bisphosphonates, clodronate and pamidronate, respectively, in insulin-like growth factor (IGF)-1 responsive human breast cancer cells. We tested whether bisphosphonates had any effects on hypoxia-inducible factor (HIF)-1alpha/vascular endothelial growth factor (VEGF) axis that plays a pivotal role in tumor angiogenesis, and our results showed that both pamidronate and clodronate significantly suppressed IGF-1-induced HIF-1alpha protein accumulation and VEGF expression in MCF-7 cells. Mechanistically, we found that either pamidronate or clodronate did not affect mRNA expression of HIF-1alpha, but they apparently promoted the degradation of IGF-1-induced HIF-1alpha protein. Meanwhile, we found that the presence of pamidronate and clodronate led to a dose-dependent decease in the newly-synthesized HIF-1alpha protein induced by IGF-1 in breast cancer cells after proteasomal inhibition, thus, indirectly reflecting the inhibition of protein synthesis. In addition, our results indicated that the inhibitory effects of bisphosphonates on the HIF-1alpha/VEGF axis are associated with the inhibition of the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathways. Consistently, we demonstrated that pamidronate and clodronate functionally abrogated both in vitro and in vivo tumor angiogenesis induced by IGF-1-stimulated MCF-7 cells. These findings have highlighted an important mechanism of the pharmacological action of bisphosphonates in the inhibition of tumor angiogenesis in breast cancer cells.
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PMID:Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha/VEGF signaling pathways in human breast cancer cells. 1956 75

Hyperinsulinemia and type II diabetes are associated with an increased risk of developing colorectal tumors. We found previously that in intestinal cells, insulin or insulin-like growth factor-1 stimulates c-Myc and cyclin D1 protein expression through both Akt-dependent and Akt-independent mechanisms. The effect of Akt is attributed to the stimulation of c-Myc translation by mammalian target of rapamycin. However, Akt-independent stimulation was, associated with an increase in beta-catenin (beta-cat) in the nucleus and an increased association between beta-cat and T-cell factor binding sites on the c-Myc promoter, detected by chromatin immunoprecipitation. In this study, we show that insulin stimulated the phosphorylation/activation of p-21-activated protein kinase-1 (PAK-1) in an Akt-independent manner in vitro and in an in vivo hyperinsulinemic mouse model. Significantly, shRNA (small hairpin RNA)-mediated PAK-1 knockdown attenuated both basal and insulin-stimulated c-Myc and cyclin D1 expression, associated with a marked reduction in extracellular signal-regulated kinase activation and beta-cat phosphorylation at Ser675. Furthermore, PAK-1 silencing led to a complete blockade of insulin-stimulated beta-cat binding to the c-Myc promoter and cellular growth. Finally, inhibition of MEK, a downstream target of PAK-1, blocked insulin-stimulated nuclear beta-cat accumulation and c-Myc expression. Our observations suggest that PAK-1 serves as an important linker between insulin and Wnt signaling pathways.
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PMID:P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine. 1958 24


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