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)

Foxp3, forkhead/winged helix transcription factor 3, is a master transcription factor for the development and function of regulatory T cells. Foxp3 has been proved to be associated with immunoregulation, autoimmune diseases, infections, and tumor immune evasion/escape. Foxp3 regulates other critical gene transcriptions. However, the mechanism how the transcription of Foxp3 itself is regulated remains partly clear. In this article, we provided an overview of the current understanding of the transcriptional regulation of Foxp3 gene, including signaling pathways initiated by TCR, IL-2R/STAT pathway, TGF-beta/Smad pathway, PI3K/Akt/mTOR axis, Notch signal pathway, IFN/IRF and IFN/nitric oxide axis, and epigenetic mechanisms. Some therapeutic agents on Foxp3 regulation were also reviewed. Points for attention in further study of Foxp3 transcription regulation, such as the combinations/cross-talks, the bi-directional functions, and species specificity of these pathways, were discussed as well.
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PMID:Transcriptional regulation of Foxp3 gene: multiple signal pathways on the road. 1926

An appealing therapeutic target in AML is constitutively activated, mutant FLT3, which is expressed in a subpopulation of AML patients and is generally a poor prognostic indicator in patients under the age of 65. There are currently several FLT3 inhibitors that are undergoing clinical investigation. However, the discovery of drug-resistant leukemic blast cells in FLT3 inhibitor-treated AML patients has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to circumvent drug resistance. Here, we provide an overview of FLT3 inhibitors under preclinical and clinical investigation, and we discuss mechanisms whereby AML cells develop resistance to FLT3 inhibitors, and the ways in which combination therapy could potentially be utilized to override drug resistance. We discuss how the cross-talk between major downstream signaling pathways, such as PI3K/PTEN/Akt/mTOR, RAS/Raf/MEK/ERK, and Jak/STAT, can be exploited for therapeutic purposes by targeting key signaling molecules with selective inhibitors, such as mTOR inhibitors, HSP90 inhibitors, or farnesyltransferase inhibitors, and identifying those agents with the ability to positively combine with inhibitors of FLT3, such as PKC412 and sunitinib. With the widespread onset of drug resistance associated with tyrosine kinase inhibitors, due to mechanisms involving development of point mutations or gene amplification of target proteins, the use of a multi-targeted therapeutic approach is of potential clinical benefit.
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PMID:FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML. 1946 16

Autoimmunity affects a substantial fraction of our population. In patients with autoimmune disease, the immune system recognizes self-tissues as foreign. Common autoimmune diseases include rheumatoid arthritis, diabetes mellitus, lupus and multiple sclerosis. Though different target organs may be affected in different autoimmune diseases, aberrations in adaptive or innate immunity underlie all of these diseases. Abnormal functioning, differentiation and/or activation of T-cells, B-cells and myeloid cells have been documented in various autoimmune diseases. More recent studies have also detailed anomalous activation of various signaling axes including various MAPK, AKT, NF-kappaB, Bcl-2 family members, and JAK/STAT molecules in these cells, in the context of systemic autoimmunity. Among these, one molecular pathway that appears to be particularly attractive for therapeutic targeting is the PI3K/AKT/mTOR axis. In this review, we summarize how the AKT axis affects multiple molecular processes in autoimmune diseases and discuss the potential of targeting this axis in these diseases.
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PMID:The AKT axis as a therapeutic target in autoimmune diseases. 1951 64

Effector T cell differentiation requires the simultaneous integration of multiple, and sometimes opposing, cytokine signals. We demonstrated mTOR's role in dictating the outcome of T cell fate. mTOR-deficient T cells displayed normal activation and IL-2 production upon initial stimulation. However, such cells failed to differentiate into T helper 1 (Th1), Th2, or Th17 effector cells. The inability to differentiate was associated with decreased STAT transcription factor activation and failure to upregulate lineage-specific transcription factors. Under normally activating conditions, T cells lacking mTOR differentiated into Foxp3(+) regulatory T cells. This was associated with hyperactive Smad3 activation in the absence of exogenous TGF-beta. Surprisingly, T cells selectively deficient in TORC1 do not divert to a regulatory T cell pathway, implicating both TORC1 and TORC2 in preventing the generation of regulatory T cells. Overall, our studies suggest that mTOR kinase signaling regulates decisions between effector and regulatory T cell lineage commitment.
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PMID:The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. 1953 25

Inflammation often exists in the tumor microenvironment and is induced by inflammatory mediators (cytokines, chemokines, and growth factors) produced by the tumor, stroma, and infiltrating cells. These factors modulate tissue remodeling and angiogenesis and actively promote tumor cell survival and chemoresistance through autocrine and paracrine mechanisms. Head and neck squamous cell carcinomas (HNSCCs) are highly inflammatory and aggressive in nature, and they express a number of cytokines and growth factors involved in inflammation. These cytokines and growth factors activate important signal transduction pathways, including NF-kappaB, JAK/STAT, and PI3K/Akt/mTOR, which regulate the expression of genes controlling growth, survival, and chemosensitivity. This review provides an update on recent advances in the understanding of the mechanisms driving cancer-related inflammation in HNSCC and on molecular targeted therapies under preclinical and clinical investigation.
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PMID:Current and potential inflammation targeted therapies in head and neck cancer. 1957 Jul 15

The anti-epidermal growth factor receptor monoclonal antibodies cetuximab and panitumumab have established efficacy as single agent and in combination with chemotherapy in advanced colorectal cancer. However, only a small percentage of unselected patients (around 10%) are responsive to these costly agents. Mutations in the KRAS gene are associated with resistance to both cetuximab and panitumumab and account for approximately 30% to 40% of resistant patients. Nevertheless, having an intact KRAS is necessary but not sufficient to derive benefit from EGFR inhibition. Further, positive predictive markers that are currently being evaluated include an increase in EGFR gene copy number and additional data suggest that other EGFR downstream pathways such as the PI3K/PTEN/AKT/mTOR and JAK/STAT pathways are also important when considering mechanisms of EGFR antibody resistance. New data seem to support the role of BRAF mutational status. In addition, high mRNA levels of the EGFR-ligands Epiregulin and Amphiregulin have been associated with increased responsiveness to cetuximab. In this article we will review the available clinical and experimental data potentially useful for a better patients' selection.
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PMID:Anti-EGFR therapy in colorectal cancer: how to choose the right patient. 1966 67

Curcumin is a phytochemical isolated from the rhizome of turmeric. Recent reports have shown curcumin to have antioxidant, anti-inflammatory and anti-tumor properties as well as affecting the 5'-AMP activated protein kinase (AMPK), mTOR and STAT-3 signaling pathways. We provide evidence that curcumin acts as an uncoupler. Well-established biochemical techniques were performed on isolated rat liver mitochondria in measuring oxygen consumption, F(0)F(1)-ATPase activity and ATP biosynthesis. Curcumin displays all the characteristics typical of classical uncouplers like fccP and 2,4-dinitrophenol. In addition, at concentrations higher than 50 microM, curcumin was found to inhibit mitochondrial respiration which is a characteristic feature of inhibitory uncouplers. As a protonophoric uncoupler and as an activator of F(0)F(1)-ATPase, curcumin causes a decrease in ATP biosynthesis in rat liver mitochondria. The resulting change in ATP:AMP could disrupt the phosphorylation status of the cell; this provides a possible mechanism for its activation of AMPK and its downstream mTOR and STAT-3 signaling.
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PMID:Uncoupling of oxidative phosphorylation by curcumin: implication of its cellular mechanism of action. 1971 74

The past decade has witnessed a dramatic improvement in the therapeutic options in multiple myeloma (MM). Several novel biologically targeted agents are in clinical use and have resulted in improved outcomes. However, the disease remains incurable, underscoring the need for continued efforts towards understanding MM biology, better risk stratification and exploitation of novel therapeutic approaches. Novel agents that target tumor and stromal compartments can be categorized as those that target protein dynamics (e.g., heat shock protein 90 and the ubiquitin-proteasome system), intracellular signaling kinases (e.g., JAK/STAT, PI3k/Akt/mTOR and MAPK pathways), cell cycle molecular machinery (e.g., cyclin-dependent kinase inhibitor and Aurora kinase inhibitors), membrane-bound receptors (e.g., IGF-1, VEGF and CD40), epigenetic modulators (e.g., DNA methyltransferase and histone deacetylase), tumor vasculature and microenvironment (e.g., angiogenesis and integrins) and agents modulating anti-MM immune responses. This article focuses on a series of new therapeutic targets that have shown promising preclinical results and early evidence of anti-MM activity in clinical studies, either alone or in combination with other conventional or novel anti-MM treatments.
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PMID:Novel therapeutic targets for multiple myeloma. 2022 97

Diabetic nephropathy (DN) is characterized by a plethora of signaling abnormalities that together ultimately result in the clinical and pathologic hallmarks of DN, namely progressive albuminuria followed by a gradual decline in glomerular filtration rate leading to kidney failure, and accompanied by podocyte loss, progressive glomerular sclerosis and, ultimately, progressive tubulointerstitial fibrosis. Over the past few years, the general understanding of the abnormalities in signaling pathways that lead to DN has expanded considerably. In this review, some of the important pathways that appear to be involved in driving this process are discussed, with special emphasis on newer findings and insights. Newer concepts regarding signaling changes in bradykinin, mTOR, JAK/STAT, MCP-1, VEGF, endothelial nitric oxide synthase, activated protein C and other pathways are discussed.
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PMID:Abnormalities in signaling pathways in diabetic nephropathy. 2022 2

Most aspects of leukocyte physiology are under the control of reversible tyrosine phosphorylation. It is clear that excessive phosphorylation of signal transduction elements is a pivotal element of many different pathologies including haematological malignancies and accordingly, strategies that target such phosphorylation have clinically been proven highly successful for treatment of multiple types of leukemias and lymphomas. Cellular phosphorylation status is dependent on the resultant activity of kinases and phosphatases. The cell biology of the former is now well understood; for most cellular phosphoproteins we now know the kinases responsible for their phosphorylation and we understand the principles of their aberrant activity in disease. With respect to phosphatases, however, our knowledge is much patchier. Although the sequences of whole genomes allow us to identify phosphatases using in silico methodology, whereas transcription profiling allows us to understand how phosphatase expression is regulated during disease, most functional questions as to substrate specificity, dynamic regulation of phosphatase activity and potential for therapeutic intervention are still to a large degree open. Nevertheless, recent studies have allowed us to make meaningful statements on the role of tyrosine phosphatase activity in the three major signaling pathways that are commonly affected in leukemias, i.e. the Ras-Raf-ERK1/2, the Jak-STAT and the PI3K-PKB-mTOR pathways. Lessons learned from these pathways may well be applicable elsewhere in leukocyte biology as well.
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PMID:Reversible phosphorylation in haematological malignancies: potential role for protein tyrosine phosphatases in treatment? 2065 29


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