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)

Resveratrol (3,4',5-trans-trihydroxystilbene) is a phytoalexin with emerging lines of evidence supporting its beneficial effects on cardiovascular systems and inhibition of carcinogenesis. It has also been reported that certain methylated resveratrol derivatives are more effective than resveratrol in the prevention/treatment of cancer. However, little is known about the impact of resveratrol and its derivatives on the development of Parkinson's disease. In this study, we compared the neuroprotective effects of resveratrol with four methylated (fully or partially) resveratrol derivatives against parkinsonian mimetic 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. Release of lactate dehydrogenase and activity of caspase-3 triggered by 6-OHDA were significantly reduced by resveratrol and one of the methylated derivatives, pinostilbene (3,4'-dihydroxy-5-methoxystilbene), in a dose-dependent manner. In addition, pinostilbene exerted a potent neuroprotective effect with a wider effective concentration range than resveratrol. By using high-performance liquid chromatography, we found that uptake of pinostilbene into SH-SY5Y cells was significantly higher than that of resveratrol. Enhanced bioavailability may thus be a major factor contributing to the neuroprotective activity of pinostilbene. Moreover, Western blot analysis demonstrated that pinostilbene markedly attenuated the phosphorylation of JNK and c-Jun triggered by 6-OHDA. Besides, mammalian target of rapamycin kinase may be an intracellular target accounting for the neuroprotective effects of pinostilbene. Our findings demonstrate the potential of methylated stilbenes in neuroprotection and provide important information for further research in this field.
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PMID:Protective effects of pinostilbene, a resveratrol methylated derivative, against 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells. 1944

Constitutive tyrosine kinase (TK) activity of p210 BCR-ABL fusion protein of chronic myeloid leukemia (CML) usurps physiological functions of normal p145 c-ABL protein. Accordingly, its inhibition by imatinib mesylate (IM) lets p145 c-ABL translocate into the nuclear compartment, which drives cell growth arrest and apoptotic death. Here we show that IM and the mammalian target of rapamycin (mTOR) inhibitor RAD001 (Everolimus) have additive effects on BCR-ABL-expressing cells. Those effects are at least partly conditional upon the enhanced nuclear accumulation of p145 c-ABL through events encompassing post-translational modifications of p145 c-ABL (Thr(735) phosphorylation) precluding its nuclear export and of 14-3-3 sigma (Ser(186) phosphorylation by c-Jun N-terminal kinase [JNK]) promoting p145 c-ABL nuclear re-import.
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PMID:mTOR inhibitor RAD001 (Everolimus) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c-ABL protein. 1964 77

Insulin receptor substrates (IRS) serine phosphorylation is a time-controlled physiological feedback mechanism in insulin signaling that is hijacked by metabolic and inflammatory stresses to promote insulin resistance. Kinases, including IKKbeta, JNK, ERK, mTOR, and S6K, activated by the inducers of insulin resistance induce uncontrolled IRS serine phosphorylation. Studies with genetically modified mice reveal that these kinases integrate signals from metabolic and inflammatory stresses in adipose tissue, liver, and hypothalamus leading to peripheral and central insulin resistance. Moreover, IKKbeta/NF-kappaB and JNK1 pathways in myeloid cells represent a core mechanism involved in inflammation linked to obesity. These kinases are thus potential drug targets against insulin resistance and the targeting of the IKKbeta/NF-kappaB or the JNK pathway may evolve into future diabetes medication.
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PMID:Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. 1968 71

The IGF axis is critical for the regulation of apoptosis in many human cancer cell lines. Recently, potent anti-tumorigenic effects of pomegranate juice and extracts have been reported. Consequently, pomegranate has potential not only as a treatment but also as a preventative measure against certain types of cancer, including prostate. In this study, we investigated the relationship between pomegranate-induced apoptosis in human prostate cancer cells and the IGF/IGFBP system. Treatment of LAPC4 prostate cancer cells with 10microg/ml POMx, a highly potent pomegranate extract prepared from skin and arils minus seeds and standardized to ellagitannin content (37% punicalagins by HPLC), resulted in inhibition of cell proliferation and induction of apoptosis. Interestingly, co-treatment with POMx and IGFBP-3 revealed synergistic stimulation of apoptosis and additive inhibition of cell growth. Western blot analysis revealed that treatment with POMx or POMx/IGFBP-3 combination resulted in increased JNK phosphorylation, and decreased Akt and mTOR activation, consistent with a growth inhibitory, pro-apoptotic function. We also investigated the relationship between IGF-1 and pomegranate-induced apoptosis in 22RV1 prostate cancer cells. Co-treatment with 100ng/ml IGF-1 completely blocked apoptosis induction by POMx. In contrast, IGF-I failed to inhibit POMx-induced apoptosis in R(-) cells, suggesting the importance of IGF-IR. POMx-treatment decreased Igf1 mRNA expression in a dose-dependent manner indicating that its actions also involve tumor-specific suppression of IGF-1. These studies revealed novel interactions between the IGF system and pomegranate-induced apoptosis.
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PMID:Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGF-IGFBP axis. 1985 87

In addition to regulating mast cell homeostasis, the activation of KIT following ligation by stem cell factor promotes a diversity of mast cell responses, including cytokine production and chemotaxis. Although we have previously defined a role for the mammalian target of rapamycin complex 1 in these responses, it is clear that other signals are also required for maximal KIT-dependent cytokine production and chemotaxis. In this study, we provide evidence to support a role for glycogen synthase kinase 3beta (GSK3beta) in such regulation in human mast cells (HuMCs). GSK3beta was observed to be constitutively activated in HuMCs. This activity was inhibited by knockdown of GSK3beta protein following transduction of these cells with GSK3beta-targeted shRNA. This resulted in a marked attenuation in the ability of KIT to promote chemotaxis and, in synergy with FcepsilonRI-mediated signaling, cytokine production. GSK3beta regulated KIT-dependent mast cell responses independently of mammalian target of rapamycin. However, evidence from the knockdown studies suggested that GSK3beta was required for activation of the MAPKs, p38, and JNK and downstream phosphorylation of the transcription factors, Jun and activating transcription factor 2, in addition to activation of the transcription factor NF-kappaB. These studies provide evidence for a novel prerequisite priming mechanism for KIT-dependent responses regulated by GSK3beta in HuMCs.
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PMID:Glycogen synthase kinase 3beta activation is a prerequisite signal for cytokine production and chemotaxis in human mast cells. 2000 84

Interleukin-1 (IL-1)-mediated signaling in T cells is essential for T helper 17 (Th17) cell differentiation. We showed here that SIGIRR, a negative regulator of IL-1 receptor and Toll-like receptor signaling, was induced during Th17 cell lineage commitment and governed Th17 cell differentiation and expansion through its inhibitory effects on IL-1 signaling. The absence of SIGIRR in T cells resulted in increased Th17 cell polarization in vivo upon myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide immunization. Recombinant IL-1 promoted a marked increase in the proliferation of SIGIRR-deficient T cells under an in vitro Th17 cell-polarization condition. Importantly, we detected increased IL-1-induced phosphorylation of JNK and mTOR kinase in SIGIRR-deficient Th17 cells compared to wild-type Th17 cells. IL-1-induced proliferation was abolished in mTOR-deficient Th17 cells, indicating the essential role of mTOR activation. Our results demonstrate an important mechanism by which SIGIRR controls Th17 cell expansion and effector function through the IL-1-induced mTOR signaling pathway.
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PMID:The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation. 2006 Mar 29

The sodium-dependent glucose co-transporter (SGLT1) is regulated by protein kinases. The aim of the present study was to examine the role of protein kinase C (PKC) in the regulation of rabbit (rb) SGLT1 activity as determined by alpha-methyl-D-glucopyranoside (AMG) uptake and to identify the cellular mechanisms involved in this process. For this purpose Chinese hamster ovary cells expressing rbSGLT1 (CHO-G6D3) were treated with PKC activators and inhibitors. PKC activators did not exert any effect on AMG uptake, as corroborated by mutation of the putative phosphorylation sites of PKC. In contrast, the PKC inhibitor bisindolylmaleimide I (BIM) increased AMG uptake. This effect was associated with translocation of rbSGLT1 from the intracellular pool to the plasma membrane demonstrated by pre-treatment of G6D3 cells with cytochalasin D that abolished the effect of BIM. In addition, intracellular signaling pathways (p38/MAPK, ERK/MAPK, JNK/MAPK, and PI3K/Akt/mTOR) were associated with PKC-regulated AMG uptake. Moreover, rbSGLT1 mRNA level was higher in BIM-treated cells than in untreated, control cells. This effect was completely abolished by actinomycin D treatment. The present study demonstrates that PKC regulates rbSGLT1 activity via a complex intracellular mechanism that involves sorting and transcriptional regulation of rbSGLT1. The study findings suggest the involvement of two complementary opposite mechanism of action, in which the balance between two antagonistic effects, namely stimulation and inhibition of the transporter, regulates the activity of rbSGLT1 by PKC.
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PMID:Protein kinase C mediated intracellular signaling pathways are involved in the regulation of sodium-dependent glucose co-transporter SGLT1 activity. 2006 50

We have studied the mechanism by which a previously described primary muscle culture growing on microcarriers predominantly expresses fast myosin heavy chain (MHC) IId/x. We have measured MHC IId/x mRNA and protein levels, mRNA of MHC I and markers of muscle metabolism, insulin-like growth factor (IGF)-1 and mechano-growth factor (MGF) transcripts, indicators of the activation of the Akt-mammalian target of rapamycin (mTOR) axis, the p38-, ERK1/2-, and JNK-mitogen-activated protein kinase (MAP) kinase pathways, and of protein phosphatase PP2A, and we have assessed the involvement of integrin. By placing the culture flasks on a rotary shaker, we induce a continuous motion of the culture medium in which the carrier-myotube aggregates are suspended. This motion exerts passive forces on the myotubes that are decisive for the predominance of MHC II expression. These forces act via integrin, which transduces the mechanical signal into activation of PP2A and of p38 MAP-Kinase. The latter presumably is directly responsible for a drastic upregulation of MHC IId/x, whereas MHC I and metabolic markers remain unaffected. At the same time, despite an elevated level of IGF-1 transcription under passive forces, the IGF-1 receptor-Akt-mTOR axis is switched off as evident from the lack of an effect of inhibition of the IGF-1 receptor and from the PP2A-mediated low degree of phosphorylation of Akt and 4E-BP1. Similarly, the ERK1/2- and JNK-MAP kinase pathways are repressed. We conclude that passive stretch exerted on the myotubes by the rotary fluid motion induces a rather selective upregulation of fast MHC II, which goes along with a mild muscle hypertrophy as judged from the amount of protein per cell and is caused by p38 MAP kinase activity elevated via integrin sensing. The direct link between passive stretch and MHC II expression constitutes a novel mechanism, which is expected to become effective physiologically under passive stretch and eccentric contractions of skeletal muscles.
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PMID:Passive mechanical forces upregulate the fast myosin heavy chain IId/x via integrin and p38 MAP kinase activation in a primary muscle cell culture. 2007 89

Autophagy that is induced by starvation or cellular stress can enable cancer cell survival by sustaining energy homeostasis and eliminating damaged organelles and proteins. In response to stress, cancer cells have been reported to accumulate the protein p62/SQSTM1 (p62), but its role in the regulation of autophagy is controversial. Here, we report that the plant phytoalexin resveratrol (RSV) triggers autophagy in imatinib-sensitive and imatinib-resistant chronic myelogenous leukemia (CML) cells via JNK-dependent accumulation of p62. JNK inhibition or p62 knockdown prevented RSV-mediated autophagy and antileukemic effects. RSV also stimulated AMPK, thereby inhibiting the mTOR pathway. AMPK knockdown or mTOR overexpression impaired RSV-induced autophagy but not JNK activation. Lastly, p62 expression and autophagy in CD34+ progenitors from patients with CML was induced by RSV, and disrupting autophagy protected CD34+ CML cells from RSV-mediated cell death. We concluded that RSV triggered autophagic cell death in CML cells via both JNK-mediated p62 overexpression and AMPK activation. Our findings show that the JNK and AMPK pathways can cooperate to eliminate CML cells via autophagy.
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PMID:Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation. 2010 47

Cadmium (Cd) is a toxic metal that enters the food chain. Following oral ingestion, the intestinal epithelium may in part protect against Cd toxicity but is also a target tissue. Using human enterocytic-like Caco-2 cells, we have previously shown differences in sensitivity to Cd according to the differentiation status. The present study focuses on Cd effects on differentiated cells. Concentration and time-dependent increases in MTT (3-[4,5-dimethyl-2-thiazol-2-yl]-2,5-diphenyltetrazolium bromide assay) activity were observed in post-confluent cultures exclusively, with a twofold maximal stimulation in 21-day-old cells exposed to 10 microM Cd for 24 h. No concomitant increase in [methyl-(3)H] thymidine incorporation was noted and Cd did not modify cell distribution in the cell-cycle phases. However, Cd-induced increase in MTT activity was inhibited by cycloheximine as well as by inhibitors of ERK1/2 and p38, but not by that of JNK. Consistently, Cd increased the levels of ERK1/2 and p38 phosphorylation. Inhibition of Ras-GTP or PI3K enhanced the stimulatory effect of Cd, whereas mTOR inhibition had no effect. Inhibition of G protein-phospholipase and PKC decreased MTT stimulation. These results show a hormesis-like stimulation of Cd on MTT activity in differentiated intestinal cells exclusively. This effect is not related to cell proliferation but more likely to increased protein synthesis which involves ERK1/2 and p38 cascades and possibly PLC-beta signaling pathways. Because growth-related differentiation of intestinal cells is linked to the selective and sequential activation of MAPKs, the impacts that these Cd-induced perturbations in signaling pathways may have on intestinal functions clearly deserve to be investigated.
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PMID:Cadmium-induced hormetic effect in differentiated Caco-2 cells: ERK and p38 activation without cell proliferation stimulation. 2023 14


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