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)

Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the expansion of the polyglutamine repeat region within the ataxin-3 protein. The mutant protein forms intracellular aggregates in the brain. However, the cellular mechanisms causing toxicity are still poorly understood and there are currently no effective treatments. In this study we show that administration of a rapamycin ester (cell cycle inhibitor-779, temsirolimus) improves motor performance in a transgenic mouse model of spinocerebellar ataxia type 3. Temsirolimus inhibits mammalian target of rapamycin and hence upregulates protein degradation by autophagy. Temsirolimus reduces the number of aggregates seen in the brains of transgenic mice and decreases levels of cytosolic soluble mutant ataxin-3, while endogenous wild-type protein levels remain unaffected. Temsirolimus is designed for long-term use in patients and therefore represents a possible therapeutic strategy for the treatment of spinocerebellar ataxia type 3. Using this disease model and treatment paradigm, we employed a microarray approach to investigate transcriptional changes that might be important in the pathogenesis of spinocerebellar ataxia type 3. This identified ubiquitin specific peptidase-15, which showed expression changes at both the messenger ribonucleic acid and protein level. Ubiquitin specific peptidase-15 levels were also changed in mice expressing another mutant polyglutamine protein, huntingtin. In total we identified 16 transcripts that were decreased in transgenic ataxin-3 mice that were normalized following temsirolimus treatment. In this mouse model with relatively mild disease progression, the number of transcripts changed was low and the magnitude of these changes was small. However, the importance of these transcriptional alterations in the pathogenesis of spinocerebellar ataxia type 3 remains unclear.
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PMID:Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. 2000 18

Although multiple myeloma (MM) remains an incurable bone marrow cancer, survival rates have dramatically improved over the past decade, most notably in the younger patient population. An understanding of MM biology and improvement in stem-cell transplantation, better supportive care, and novel therapies with higher efficacy and lower toxicity are all responsible for this improvement. Despite these trends, improvements among older patients remain modest, underscoring the need for innovative approaches. The availability of a rich pipeline of novel agents undergoing early-phase clinical trials in MM is an exciting and active area of research. Current novel agents targeting tumor and stromal compartments can be conceptualized as those that target membrane-bound receptors (insulin-like growth factor-1, vascular endothelial growth factor, CD40, etc.), intracellular signaling kinases (Janus kinase/signal transducers and activators of transcription, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin, mitogen-activated protein kinase pathways), cell cycle molecular machinery (cyclin-dependent kinases inhibitors), epigenetic abnormalities (DNA methyltransferase and histyone deacetylase), protein dynamics (heat-shock protein 90, ubiquitin-proteasome system), and tumor vasculature and microenvironment (angiogenesis, integrins). This review highlights some of these novel agents tested either alone or in combination for the treatment of MM.
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PMID:Future novel single agent and combination therapies. 2001 Jan 71

The HERC gene family encodes proteins with two characteristic domains: HECT and RCC1-like. Proteins with HECT domains have been described to function as ubiquitin ligases, and those that contain RCC1-like domains have been reported to function as GTPases regulators. These two activities are essential in a number of important cellular processes such as cell cycle, cell signaling, and membrane trafficking. Mutations affecting these domains have been found associated with retinitis pigmentosa, amyotrophic lateral sclerosis, and cancer. In humans, six HERC genes have been reported which encode two subgroups of HERC proteins: large (HERC1-2) and small (HERC3-6). The giant HERC1 protein was the first to be identified. It has been involved in membrane trafficking and cell proliferation/growth through its interactions with clathrin, M2-pyruvate kinase, and TSC2 proteins. Mutations affecting other members of the HERC family have been found to be associated with sterility and growth retardation. Here, we report the characterization of a recessive mutation named tambaleante, which causes progressive Purkinje cell degeneration leading to severe ataxia with reduced growth and lifespan in homozygous mice aged over two months. We mapped this mutation in mouse chromosome 9 and then performed positional cloning. We found a G<-->A transition at position 1448, causing a Gly to Glu substitution (Gly483Glu) in the highly conserved N-terminal RCC1-like domain of the HERC1 protein. Successful transgenic rescue, with either a mouse BAC containing the normal copy of Herc1 or with the human HERC1 cDNA, validated our findings. Histological and biochemical studies revealed extensive autophagy associated with an increase of the mutant protein level and a decrease of mTOR activity. Our observations concerning this first mutation in the Herc1 gene contribute to the functional annotation of the encoded E3 ubiquitin ligase and underline the crucial and unexpected role of this protein in Purkinje cell physiology.
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PMID:Progressive Purkinje cell degeneration in tambaleante mutant mice is a consequence of a missense mutation in HERC1 E3 ubiquitin ligase. 2004 Dec 18

Autophagy is a cellular process that nonspecifically degrades cytosolic components and is involved in many cellular responses. We found that amino sugars with a free amino group such as glucosamine, galactosamine and mannosamine induced autophagy via an mTOR-independent pathway. Glucosamine-induced autophagy at concentrations of at least 500 microM to over 40 mM. In the presence of 40 mM glucosamine, autophagy induction was initiated at 6h and reached a plateau at 36 h. Glucosamine-induced autophagy could remove accumulated ubiquitin-conjugated proteins as well as 79-glutamine repeats. Therefore, orally administered glucosamine could contribute to the prevention of neurodegenerative diseases and promotion of antiaging effects.
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PMID:Glucosamine induces autophagy via an mTOR-independent pathway. 2004 74

Kidney cancer is not a single disease; it is made up of a number of cancers that occur in the kidney, each having a different histology, following a different clinical course, responding differently to therapy, and caused by a different gene. Study of the genes underlying kidney cancer has revealed that it is fundamentally a metabolic disorder. Understanding the genetic basis of cancer of the kidney has significant implications for diagnosis and management of this disease. VHL is the gene for clear cell kidney cancer. The VHL protein forms a complex that targets the hypoxia-inducible factors for ubiquitin-mediated degradation. Knowledge of this pathway provided the foundation for the development of novel therapeutic approaches now approved for treatment of this disease. MET is the gene for the hereditary form of type 1 papillary renal carcinoma and is mutated in a subset of sporadic type 1 papillary kidney cancers. Clinical trials are currently ongoing with agents targeting the tyrosine kinase domain of MET in sporadic and hereditary forms of papillary kidney cancer. BHD is the gene for the hereditary type of chromophobe kidney cancer. It is thought to be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways. Hereditary leiomyomatosis renal cell carcinoma, a hereditary form of type 2 papillary renal carcinoma, is caused by inactivation of a Krebs cycle enzyme due to mutation. Knowledge of these kidney cancer gene pathways has enabled new approaches in the management of this disease and has provided the foundation for the development of targeted therapeutics.
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PMID:Molecular diagnosis and therapy of kidney cancer. 2005 41

The ubiquitin-proteasome system and macroautophagy are two complementary pathways for protein degradation. Emerging evidence suggests that proteasome inhibition might be a promising approach for the treatment of cancer. In this study, we show that proteasome inhibitor MG-132 suppressed gastric cancer cell proliferation and induced macroautophagy. The induction of macroautophagy was evidenced by the formation of LC3(+) autophagosomes and the accumulation of acidic vesicular organelles and autolysosomes and was accompanied by the suppression of mammalian target of rapamycin complex 1 activity. Abolition of macroautophagy by knockdown of Class III phosphatidylinositol-3 kinase Vps34 or ATG5/7 sensitized gastric cancer cells to the antiproliferative effect of MG-132 by promoting G(2)/M cell cycle arrest. In addition, MG-132 increased ERK phosphorylation whose inhibition by MEK inhibitor significantly enhanced the antiproliferative effect of proteasome inhibition. To conclude, this study demonstrates that macroautophagy and ERK phosphorylation serve as protective mechanisms to counteract the antiproliferative effect of proteasome inhibition. This discovery may have implications for the application of proteasome-directed therapy for the treatment of cancer.
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PMID:Macroautophagy and ERK phosphorylation counteract the antiproliferative effect of proteasome inhibitor in gastric cancer cells. 2008 64

Myc proteins (c-myc, Mycn and Mycl) target proliferative and apoptotic pathways vital for progression in cancer. Amplification of the MYCN gene has emerged as one of the clearest indicators of aggressive and chemotherapy-refractory disease in children with neuroblastoma, the most common extracranial solid tumor of childhood. Phosphorylation and ubiquitin-mediated modulation of Myc protein influence stability and represent potential targets for therapeutic intervention. Phosphorylation of Myc proteins is controlled in-part by the receptor tyrosine kinase/phosphatidylinositol 3-kinase/Akt/mTOR signaling, with additional contributions from Aurora A kinase. Myc proteins regulate apoptosis in part through interactions with the p53/Mdm2/Arf signaling pathway. Mutation in p53 is commonly observed in patients with relapsed neuroblastoma, contributing to both biology and therapeutic resistance. This review examines Myc function and regulation in neuroblastoma, and discusses emerging therapies that target Mycn.
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PMID:Myc proteins as therapeutic targets. 2010 Dec 14

The serine/threonine protein kinase B (PKB, also known as Akt) constitutes an important node in diverse signaling cascades downstream of growth factor receptor tyrosine kinases. Akt plays an essential role in cell survival, growth, migration, proliferation, polarity, and metabolism (lipid and glucose); cell cycle progression; muscle and cardiomyocyte contractility; angiogenesis; and self-renewal of stem cells. Altered Akt activity has been associated with cancer and other disease conditions, such as diabetes mellitus, neurodegenerative diseases, and muscle hypotrophy. In the past decade, the upstream signals that lead to Akt activation, the downstream substrates that exert the effects of Akt, and the secondary binding proteins that regulate Akt activation have been well documented. Recent reports from our group and others have revealed how the stability of Akt protein is regulated through phosphorylation on its Thr-Pro motifs. This literature review details findings of those reports and others relevant to the regulation of Akt activation by its upstream kinases, with a focus on mammalian target of rapamycin complexes (mTORCs) and inactivation by PHLDA3 and the protein phosphatases PP2A and pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP). Reports on ubiquitin-dependent Akt degradation, caspase-dependent cleavage, and the roles of molecular chaperone heat shock protein 90 (Hsp90) in the regulation of Akt stability are summarized. The highlight will be on the role of "turn motif" phosphorylation and an isomerase, Pin1, in the regulation of Akt stability. We also discuss issues related to the intricate mTORC2-AktmTORC1 loop and the contradictory regulation of Akt phosphorylation and stabilization of Akt by mTORC2. Finally, we offer perspective on potential future directions for investigation, particularly on translating the knowledge we learned on the regulation of Akt stability into therapeutic intervention on human cancer with Akt alteration.
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PMID:Physiological regulation of Akt activity and stability. 2018 80

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

Of 20 natural amino acids, leucine is particularly important for promoting cellular protein synthesis. The effect of leucine involves mammalian target of rapamycin (mTOR), a key protein kinase controlling cell growth. Leucine enhances mTOR-mediated phosphorylation of S6K1 and 4E-BP, thereby promoting protein synthesis. However, how the presence of leucine is sensed and transmitted to mTOR is poorly understood. Here, we show evidence that UBR1 and UBR2 might be cellular targets of leucine. UBR1 and UBR2 are E3 ubiquitin ligases that recognize the identity of N-terminal residues and contribute to selective destabilization of target proteins according to the N-end rule. Using leucine-immobilized affinity beads, we identified UBR1 and UBR2 as leucine-binding proteins from leucine-responsive rat hepatoma H4IIE cells. Over-expression of UBR1 or UBR2 resulted in a reduction in mTOR-dependent S6K1 phosphorylation, whereas knockdown of UBR1 or UBR2 increased S6K1 phosphorylation in amino acid-starved human 293T cells. We also found that leucine binds to the substrate-recognition domain of UBR2 and inhibits degradation of N-end rule substrates in vitro. These findings suggest that UBR1 and UBR2 are negative regulators of the leucine-mTOR signaling pathway. Leucine might activate this pathway in part through inhibition of their ubiquitin ligase activity.
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PMID:Role of N-end rule ubiquitin ligases UBR1 and UBR2 in regulating the leucine-mTOR signaling pathway. 2029 36


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