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)

Nijmegen breakage syndrome (NBS) is a chromosomal instability syndrome associated with cancer predisposition, radiosensitivity, microcephaly, and growth retardation. The NBS gene product, NBS1 (p95) or nibrin, is a part of the hMre11 complex, a central player associated with double strand break repair. We previously demonstrated that c-Myc directly activates NBS1 expression. Here we have shown that constitutive expression of NBS1 in Rat1a and HeLa cells induces/enhances their transformation. Repression of endogenous NBS1 levels using short interference RNA reduces the transformation activity of two tumor cell lines. Increased NBS1 expression is observed in 40-52% of non-small cell lung carcinoma, hepatoma, and esophageal cancer samples. NBS1 overexpression stimulates phosphatidylinositol (PI) 3-kinase activity, leading to increased phosphorylation levels of Akt and its downstream targets such as glycogen synthase kinase 3beta and mammalian target of rapamycin in different cell lines and tumor samples. Transformation induced by NBS1 overexpression can be inhibited by a PI3-kinase inhibitor (LY294002). Repression of endogenous Akt expression by short interference RNA decreases the transformation activity of Rat1a cells overexpressing NBS1. These results indicate that overexpression of NBS1 is an oncogenic event that contributes to transformation through the activation of PI3-kinase/Akt.
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PMID:Overexpression of NBS1 contributes to transformation through the activation of phosphatidylinositol 3-kinase/Akt. 1603 16

Nijmegen breakage syndrome (NBS) is a chromosomal-instability syndrome. The NBS gene product, NBS1 (p95 or nibrin), is a part of the Mre11-Rad50-NBS1 complex. SIN1 is a component of the mTOR/Rictor/SIN1 complex mediating the activation of Akt. Here we show that NBS1 interacted with mTOR, Rictor, and SIN1. The specific domains of mTOR, Rictor, or SIN1 interacted with the internal domain (a.a. 221-402) of NBS1. Sucrose density gradient showed that NBS1 was located in the same fractions as the mTOR/Rictor/SIN1 complex. Knockdown of NBS1 decreased the levels of phosphorylated Akt and its downstream targets. Ionizing radiation (IR) increased the NBS1 levels and activated Akt activity. These results demonstrate that NBS1 interacts with the mTOR/Rictor/SIN1 complex through the a.a. 221-402 domain and contributes to the activation of Akt activity.
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PMID:Interaction between NBS1 and the mTOR/Rictor/SIN1 complex through specific domains. 2376 98

Human Nijmegen breakage syndrome, caused by the hypomorphic mutation of Nbn gene, is a hereditary instability disease, characterized by chromosomal instability, immunodeficiency, radiosensitivity, cancer predisposition and microcephaly. To study the roles of Nbn protein in microcephaly, Nbn gene was specifically deleted in the central nervous system of mice by nestin-Cre targeting gene system (Frappart et al. in Nat Med 11:538-544, 2005). Strikingly, newborn Nbn-deficient mice exhibit the evident microcephalic cerebellum, which contributes to severe ataxia and balance deficiency. In this study, we first report that PI3K/AKT/mTOR signaling pathway that performs neurotrophic-protecting role in neuronal growth is significantly inhibited in newborn Nbn-deficient cortex and cerebellum. In addition, JNK signaling and ATR signaling are likely to converge to regulate the cerebellar apoptosis of newborn Nbn-deficient mice.
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PMID:The distinct signaling regulatory roles in the cortical atrophy and cerebellar apoptosis of newborn Nbn-deficient mice. 2393 13

Nijmegen Breakage Syndrome (NBS) is a recessive genetic disorder characterized by immunodeficiency, elevated sensitivity to ionizing radiation, chromosomal instability, microcephaly, and high predisposition to malignancies. Since the underlying molecular mechanisms of the NBS microcephaly are still obscure, thus our group previously inactivated the Nbn gene in the central nervous system (CNS) of mice by nestin-Cre targeting gene system, and generated Nbn(CNS-del) mice. Interestingly, the newborn Nbn(CNS-del) mice exhibit obvious microcephaly, which is accompanied by severe ataxia and balance deficiency. In this study presented here, we report that Nbn-deficiency induces the enhanced apoptosis of the mature oligodendrocytes at postnatal day 7, which further affects the myelination of the nerve fibers of cerebrum and corpus callosum.The distinct regulatory roles of Ataxia telangiectasia mutated (ATM) signaling and protein kinase B(Akt)/the mammalian target of Rapamycin (AKT/mTOR) signaling are responsible for the enhanced apoptosis of the Nbn-deficient oligodendrocytes. In addition, a series of transcriptional factors including histonedeacetylase (HDAC), zinc finger protein 191 (ZFP-191) and myelin sheath regulatory factor (MRF) play distinct roles in regulating the myelination of the Nbn-deficient oligodendrocytes. Based on these results, it concludes that ATM-Chk2-P53-P21 signaling pathway and the AKT/mTOR signaling pathway are both responsible for the enhanced apoptosis of the Nbn-deficient oligodendrocytes. HDAC, ZFP-191, and MRF are also involved in the pathogenesis of the hypomyelination of the Nbn-deficient oligodendrocytes.
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PMID:Nbn gene inactivation in the CNS of mouse inhibits the myelinating ability of the mature cortical oligodendrocytes. 2427 8

Nijmegen breakage syndrome (NBS), caused by mutation of the Nbn gene, is a recessive genetic disorder characterized by immunodeficiency, elevated sensitivity to ionizing radiation, chromosomal instability, microcephaly, and high predisposition to malignancies. To explore the underlying molecular mechanisms of NBS microcephaly, Frappart et al. previously inactivated Nbn gene in the central nervous system (CNS) of mice by the nestin-Cre targeting gene system and generated Nbn(CNS-del) mice. Here we first report that Nbn gene inactivation induces the defective proliferation and enhanced apoptosis of the oligodendrocyte precursor cells (OPCs), contributing to the severe hypomyelination of the nerve fibers of the corpus callosum. Under conditions of DNA damage and oxidative stress, the distinct regulatory roles of ATM-Chk2 signaling and AKT/mTOR signaling are responsible for the defective proliferation and enhanced apoptosis of the Nbn-deficient OPCs. In addition, specific HDAC isoforms may play distinctive roles in regulating the myelination of the Nbn-deficient OPCs. However, brain-derived neurotrophic factor and nerve growth factor stimulation attenuates the oxidative stress and thereby increases the proliferation of the Nbn-deficient OPCs, which is accompanied by upregulation of the AKT/mTOR/P70S6K signaling pathway. Taken together, these findings demonstrate that DNA damage and oxidative stress resulting from Nbn gene inactivation are associated with hypomyelination of the nerve fibers of corpus callosum.
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PMID:DNA damage and oxidative injury are associated with hypomyelination in the corpus callosum of newborn Nbn(CNS-del) mice. 2427 91