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dc.creatorYalcin, Safak
dc.creatorMarinković, Dragan
dc.creatorMungamuri, Sathish Kumar
dc.creatorZhang, Xin
dc.creatorTong, Wei
dc.creatorSellers, Rani
dc.creatorGhaffari, Saghi
dc.date.accessioned2021-06-09T13:34:26Z
dc.date.available2021-06-09T13:34:26Z
dc.date.issued2010
dc.identifier.issn0261-4189
dc.identifier.urihttp://rfasper.fasper.bg.ac.rs/handle/123456789/377
dc.description.abstractReactive oxygen species (ROS) participate in normal intracellular signalling and in many diseases including cancer and aging, although the associated mechanisms are not fully understood. Forkhead Box O (FoxO) 3 transcription factor regulates levels of ROS concentrations, and is essential for maintenance of hematopoietic stem cells. Here, we show that loss of Foxo3 causes a myeloproliferative syndrome with splenomegaly and increased hematopoietic progenitors (HPs) that are hypersensitive to cytokines. These mutant HPs contain increased ROS, overactive intracellular signalling through the AKT/mammalian target of rapamycin signalling pathway and relative deficiency of Lnk, a negative regulator of cytokine receptor signalling. In vivo treatment with ROS scavenger N-acetyl-cysteine corrects these biochemical abnormalities and relieves the myeloproliferation. Moreover, enforced expression of Lnk by retroviral transfer corrects the abnormal expansion of Foxo3(-/-) HPs in vivo. Our combined results show that loss of Foxo3 causes increased ROS accumulation in HPs. In turn, this inhibits Lnk expression that contributes to exaggerated cytokine responses that lead to myeloproliferation. Our findings could explain the mechanisms by which mutations that alter Foxo3 function induce malignancy. More generally, the work illustrates how deregulated ROS may contribute to malignant progression. The EMBO Journal (2010) 29, 4118-4131. doi: 10.1038/emboj.2010.292; Published online 26 November 2010en
dc.publisherWiley, Hoboken
dc.relationNational Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [RO1 DK077174]
dc.relationAmerican Cancer Society Research Scholarship [RSG LIB-110480]
dc.relationBlack Family Stem Cell Institute
dc.relationRoche Foundation for Anemia Research (RoFAR)
dc.relationUnited States Department of Health & Human Services, National Institutes of Health (NIH), National Heart Lung & Blood Institute (NHLBI) [R01HL095675, R01HL110806]
dc.relationUnited States Department of Health & Human Services, National Institutes of Health (NIH), National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK077174]
dc.rightsopenAccess
dc.sourceEmbo Journal
dc.subjectFoxOen
dc.subjectLnken
dc.subjectmTORen
dc.subjectmyeloproliferationen
dc.subjectROSen
dc.titleROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(-/-) miceen
dc.typearticle
dc.rights.licenseARR
dc.citation.epage4131
dc.citation.issue24
dc.citation.other29(24): 4118-4131
dc.citation.rankaM21
dc.citation.spage4118
dc.citation.volume29
dc.identifier.doi10.1038/emboj.2010.292
dc.identifier.fulltexthttp://rfasper.fasper.bg.ac.rs/bitstream/id/410/374.pdf
dc.identifier.pmid21113129
dc.identifier.scopus2-s2.0-78650302424
dc.identifier.wos000285407200008
dc.type.versionpublishedVersion


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