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ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(-/-) mice
dc.creator | Yalcin, Safak | |
dc.creator | Marinković, Dragan | |
dc.creator | Mungamuri, Sathish Kumar | |
dc.creator | Zhang, Xin | |
dc.creator | Tong, Wei | |
dc.creator | Sellers, Rani | |
dc.creator | Ghaffari, Saghi | |
dc.date.accessioned | 2021-06-09T13:34:26Z | |
dc.date.available | 2021-06-09T13:34:26Z | |
dc.date.issued | 2010 | |
dc.identifier.issn | 0261-4189 | |
dc.identifier.uri | http://rfasper.fasper.bg.ac.rs/handle/123456789/377 | |
dc.description.abstract | Reactive 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 2010 | en |
dc.publisher | Wiley, Hoboken | |
dc.relation | National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [RO1 DK077174] | |
dc.relation | American Cancer Society Research Scholarship [RSG LIB-110480] | |
dc.relation | Black Family Stem Cell Institute | |
dc.relation | Roche Foundation for Anemia Research (RoFAR) | |
dc.relation | United States Department of Health & Human Services, National Institutes of Health (NIH), National Heart Lung & Blood Institute (NHLBI) [R01HL095675, R01HL110806] | |
dc.relation | United States Department of Health & Human Services, National Institutes of Health (NIH), National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK077174] | |
dc.rights | openAccess | |
dc.source | Embo Journal | |
dc.subject | FoxO | en |
dc.subject | Lnk | en |
dc.subject | mTOR | en |
dc.subject | myeloproliferation | en |
dc.subject | ROS | en |
dc.title | ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(-/-) mice | en |
dc.type | article | |
dc.rights.license | ARR | |
dc.citation.epage | 4131 | |
dc.citation.issue | 24 | |
dc.citation.other | 29(24): 4118-4131 | |
dc.citation.rank | aM21 | |
dc.citation.spage | 4118 | |
dc.citation.volume | 29 | |
dc.identifier.doi | 10.1038/emboj.2010.292 | |
dc.identifier.fulltext | http://rfasper.fasper.bg.ac.rs/bitstream/id/410/374.pdf | |
dc.identifier.pmid | 21113129 | |
dc.identifier.scopus | 2-s2.0-78650302424 | |
dc.identifier.wos | 000285407200008 | |
dc.type.version | publishedVersion |