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)

The insulin-like growth factor 1 (IGF-1)-AKT-mTOR pathways sense the availability of nutrients and mitogens and respond by signaling for cell growth and division. The p53 pathway senses a variety of stress signals which will reduce the fidelity of cell growth and division, and responds by initiating cell cycle arrest, senescence, or apoptosis. This study explores four p53-regulated gene products, the beta1 and beta2 subunits of the AMPK, which are shown for the first time to be regulated by the p53 protein, TSC2, PTEN, and IGF-BP3, each of which negatively regulates the IGF-1-AKT-mTOR pathways after stress. These gene products are shown to be expressed under p53 control in a cell type and tissue-specific fashion with the TSC2 and PTEN proteins being coordinately regulated in those tissues that use insulin-dependent energy metabolism (skeletal muscle, heart, white fat, liver, and kidney). In addition, these genes are regulated by p53 in a stress signal-specific fashion. The mTOR pathway also communicates with the p53 pathway. After glucose starvation of mouse embryo fibroblasts, AMPK phosphorylates the p53 protein but does not activate any of the p53 responses. Upon glucose starvation of E1A-transformed mouse embryo fibroblasts, a p53-mediated apoptosis ensues. Thus, there is a great deal of communication between the p53 pathway and the IGF-1-AKT and mTOR pathways.
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PMID:The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. 1740 11

N-BP, rapamycin and its derivatives have been originally developed respectively as anti-resorptive and anti-fungal agents. In fact, in vitro and in vivo experiments demonstrated that these compounds are multi-functional molecules exerting their effects on tumour cell growth and bone remodelling. The major challenge in treating cancer relates to mutations in key genes such as p53, Rb or proteins affecting caspase signalling carried by many tumour cells. Whether nitrogen containing bisphosphonates (N-BP) are potent bone inhibitors, they also inhibit tumour cell proliferation and increase atypical apoptosis of bone tumour cells regardless of the p53 and Rb status. N-BP may be then considered as effective therapeutic agents in clinical trials of bone tumours. Rapamycin and its derivatives inhibit mTOR dependent mRNA translation both in osteoclasts and tumour cells. Cellular physiological mechanisms regulated by mTOR integrate many environmental parameters including growth factors, hormones, cytokines, amino acids, energy availability and cellular stresses that are coupled with cell cycle progression and cell growth. Rapamycin and its derivatives as well as N-BP must be considered as bi-(multi) functional molecules affecting simultaneously bone and tumour metabolisms. The present survey describes these two molecular families and discusses their therapeutic interests for primary bone tumours and bone metastases.
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PMID:mTOR inhibitors (rapamycin and its derivatives) and nitrogen containing bisphosphonates: bi-functional compounds for the treatment of bone tumours. 1758 50

Cellular responses to gamma-irradiation exposure are controlled by phosphatidylinositol 3-kinase-related kinases (PIKK) in the nucleus, and in addition, cytosolic PIKKs may have a role in such responses. Here, we show that the expression of tripeptidyl-peptidase II (TPPII), a high molecular weight cytosolic peptidase, required PIKK signaling and that TPPII was rapidly translocated into the nucleus of gamma-irradiated cells. These events were dependent on mammalian target of rapamycin, a cytosolic/mitochondrial PIKK that is activated by gamma-irradiation. Lymphoma cells with inhibited expression of TPPII failed to efficiently stabilize p53 and had reduced ability to arrest proliferation in response to gamma-irradiation. We observed that TPPII contains a BRCA COOH-terminal-like motif, contained within sequences of several proteins involved in DNA damage signaling pathways, and this motif was important for nuclear translocation of TPPII and stabilization of p53. Novel tripeptide-based inhibitors of TPPII caused complete in vivo tumor regression in mice in response to relatively low doses of gamma-irradiation (3-4 Gy/wk). This was observed with established mouse and human tumors of diverse tissue backgrounds, with no tumor regrowth after cancellation of treatment. These TPPII inhibitors had minor effects on tumor growth as single agent and had low cellular toxicity. Our data indicated that TPPII connects signaling by cytosolic/mitochondrial and nuclear PIKK-dependent pathways and that TPPII can be targeted for inhibition of tumor therapy resistance.
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PMID:Tripeptidyl-peptidase II controls DNA damage responses and in vivo gamma-irradiation resistance of tumors. 2115 58

In this chapter, we will review how signal transduction pathways have been assembled in the past, bringing us to our present understanding of this area of research. The methods employed have relied heavily upon the genetics of yeast, worms, flies, mice, and humans. The use of second site suppressors and epistasis has permitted the detection of interacting elements and the sequence of genetic activities. Biochemistry has been employed to elucidate metabolic pathways, demonstrate protein complexes, and identify functions of gene products. The tools of molecular biology-knocking concentration of protein products down or up-have been helpful to trace the function of pathways in vivo. The study of disease states has led to the identification of a set of altered genes and helped define a network that is altered and gives rise to the disease. We will also discuss some serious limitations in these approaches. After reviewing how signal transduction pathways are constructed and investigated, we will turn our attention to an example that demonstrates the inter-relationships between pathways and the regulation of a specific set of pathways. We will examine how the p53 pathway in responding to stress shuts down the AKT-1 and mTOR pathways so as to limit the error frequency of cell growth and division during a stressful time where homeostatic mechanisms are required to respond and increase the fidelity of these processes.
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PMID:Reconstructing signal transduction pathways: challenges and opportunities. 1793 60

The circuitous cell signalling pathways of hepatocytes comprise several factors that operate to downgrade or even interrupt the transmission of a given signal. These down-regulating influences are essential to keep cell proliferation and cell survival in check and if impaired, can alter a delicate balance in favour of cell proliferation. Each signalling pathway that has been implicated in carcinogenesis is influenced by both oncogenic factors that promote tumour growth when activated as well as tumour suppressor proteins that have to be impaired to favour tumour growth. This summary of the Tumour Suppressors in Liver Carcinogenesis Symposium held at the 2007 EASL Annual Meeting discusses four pathways with pre-eminent tumour suppressor activity, each involved in hepatocarcinogenesis: p53, mTOR, beta-catenin and hedgehog.
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PMID:Tumour suppressors in liver carcinogenesis. 1793 20

Miscoordination of growth and proliferation with the cellular stress response can lead to tumorigenesis. Mammalian target of rapamycin (mTOR), a central cell growth controller, is highly activated in some malignant neoplasms, and its clinical implications are under extensive investigation. We show that constitutive mTOR activity amplifies p53 activation, in vitro and in vivo, by stimulating p53 translation. Thus, loss of TSC1 or TSC2, the negative regulators of mTOR, results in dramatic accumulation of p53 and apoptosis in response to stress conditions. In other words, the inactivation of mTOR prevents cell death by nutrient stress and genomic damage via p53. Consistently, we also show that p53 is elevated in TSC tumors, which rarely become malignant. The coordinated relationship between mTOR and p53 during cellular stress provides a possible explanation for the benign nature of hamartoma syndromes, including TSC. Clinically, this also suggests that the efficacy of mTOR inhibitors in anti-neoplastic therapy may also depend on p53 status, and mTOR inhibitors may antagonize the effects of genotoxic chemotherapeutics.
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PMID:Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53. 1796 6

The development of novel therapies for multiple myeloma depends on a comprehensive understanding of the events leading to cellular proliferation and survival. Controlling pathways that regulate growth signals is an emerging and complementary approach to myeloma treatment. The PI3K/Akt pathway is a central gatekeeper for crucial cellular functions including adhesion, angiogenesis, migration and development of drug resistance. Established proteins and genes such as mTOR, p53, NF-kappaB and BAD are all regulated through PI3K and Akt activation, making them attractive targets for broad downstream effects. Direct PI3K inhibition has demonstrated impressive tumor inhibition and regression in cell-line and animal models, and multiple agents including SF1126 are currently in clinical trials. Drugs such as perifosine that are specific for Akt are also in development. Combinations of these agents with existing therapies are rational approaches on the path to improving myeloma treatment.
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PMID:PI3 kinase/AKT pathway as a therapeutic target in multiple myeloma. 1804 16

Hepatocellular carcinoma (HCC) is a frequent neoplasia which still misses a therapeutical gold standard. Recently, new acquisitions in cancerogenesis process evidenced the genetic and epigenetic alterations of genes involved in the different metabolic pathways of liver cancer suggesting that antibodies, small molecules, demethylating agents, etc. specifically acting against molecular target can be utilized alone or in combination in clinical practice. The main altered targets are: cell membrane receptors, in particular tyrosine kinase receptors, factors involved in cell signalling, specifically Wnt/beta-catenin, Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathways, proteins linked to cell cycle regulation pathway (i.e. p53, p16/INK4, cyclin/cdk complex) or in invasiveness (EMT, TGFbeta) and proteins involved in DNA metabolism. Genetic or epigenetic changes in these molecules have been used in preclinical settings and, some of them also in clinical trials of phase II and III. This scenario opens new avenues for the prevention and the treatment of HCC. In the present review the main metabolic pathways and molecular alterations have been described together with recent advances in molecular and gene therapy.
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PMID:Molecular pathways and related target therapies in liver carcinoma. 1804 79

Accumulating evidences suggest that many molecules are working as inhibitors of proliferation in myeloma cells e.g., PTEN, mTOR(PI3-kinase signal molecules), p53, RB1, INK4 family and KIP/CIP family (cell cycle check point molecules), PF4 (inhibitor of angiogenesis). In this review, significance of these molecules in myeloma is summarized. Additionally, our finding of growth inhibitory effect by PU.1 is explained.
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PMID:[Molecular mechanisms inhibiting proliferation of myeloma cells]. 1806 60

Lkb1 is a central regulator of cell polarity and energy metabolism through its capacity to activate the AMP-activated protein kinase (AMPK)-related family of protein kinases. Germ line-inactivating mutation of Lkb1 leads to Peutz-Jeghers syndrome, which is characterized by benign hamartomas and a susceptibility to malignant epithelial tumors. Mutations in Lkb1 are also found in sporadic carcinomas, most frequently in lung cancers associated with tobacco carcinogen exposure. The basis for Lkb1-dependent tumor suppression is not defined. Here, we uncover a marked sensitivity of Lkb1 mutant mice to the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Lkb1(+/-) mice are highly prone to DMBA-induced squamous cell carcinoma (SCC) of the skin and lung. Confirming a cell autonomous tumor suppressor role of Lkb1, mice with epidermal-specific Lkb1 deletion are also susceptible to DMBA-induced SCC and develop spontaneous SCC with long latency. Restoration of wild-type Lkb1 causes senescence in tumor-derived cell lines, a process that can be partially bypassed by inactivation of the Rb pathway, but not by inactivation of p53 or AMPK. Our data indicate that Lkb1 is a potent suppressor of carcinogen-induced skin and lung cancers and that downstream targets beyond the AMPK-mTOR pathway are likely mediators of Lkb1-dependent tumor suppression.
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PMID:LKB1 deficiency sensitizes mice to carcinogen-induced tumorigenesis. 1817 96


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