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dc.contributor.authorSalas, Arelis
dc.contributor.authorPonnusamy, Suriyan
dc.contributor.authorSenkal, Can E.
dc.contributor.authorMeyers-Needham, Marisa
dc.contributor.authorSelvam, Shanmugam Panneer
dc.contributor.authorSaddoughi, Sahar A.
dc.contributor.authorApohan, Elif
dc.contributor.authorSentelle, R. David
dc.contributor.authorSmith, Charles
dc.contributor.authorGault, Christopher R.
dc.contributor.authorObeid, Lina M.
dc.contributor.authorEl-Shewy, Hesham M.
dc.contributor.authorOaks, Joshua
dc.contributor.authorSanthanam, Ramasamy
dc.contributor.authorMarcucci, Guido
dc.contributor.authorBaran, Yusuf
dc.contributor.authorMahajan, Sandeep
dc.contributor.authorFernandes, Daniel
dc.contributor.authorStuart, Robert
dc.contributor.authorPerrotti, Danilo
dc.contributor.authorÖğretmen, Besim
dc.date.accessioned2017-03-16T12:50:18Z
dc.date.available2017-03-16T12:50:18Z
dc.date.issued2011-06
dc.identifier.citationSalas, A., Ponnusamy, S., Senkal, C. E., Meyers-Needham, M., Selvam, S. P., Saddoughi, S. A., Apohan, E., ... and Öğretmen, B. (2011). Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A. Blood, 117(22), 5941-5952. doi:10.1182/blood-2010-08-300772en_US
dc.identifier.issn0006-4971
dc.identifier.urihttp://doi.org/10.1182/blood-2010-08-300772
dc.identifier.urihttp://hdl.handle.net/11147/5075
dc.description.abstractThe mechanisms by which sphingosine kinase-1 (SK-1)/sphingosine 1-phosphate (S1P) activation contributes to imatinib resistance in chronic myeloid leukemia (CML) are unknown. We show herein that increased SK-1/S1P enhances Bcr-Abl1 protein stability, through inhibition of its proteasomal degradation in imatinib-resistant K562/IMA-3 and LAMA-4/IMA human CML cells. In fact, Bcr-Abl1 stability was enhanced by ectopic SK-1 expression. Conversely, siRNA-mediated SK-1 knockdown in K562/IMA-3 cells, or its genetic loss in SK-1-/- MEFs, significantly reduced Bcr-Abl1 stability. Regulation of Bcr-Abl1 by SK-1/S1P was dependent on S1P receptor 2 (S1P2) signaling, which prevented Bcr-Abl1 dephosphorylation, and degradation via inhibition of PP2A. Molecular or pharmacologic interference with SK-1/S1P2 restored PP2A-dependent Bcr-Abl1 dephosphorylation, and enhanced imatinib- or nilotinib-induced growth inhibition in primary CD34+ mononuclear cells obtained from chronic phase and blast crisis CML patients, K562/IMA-3 or LAMA4/IMA cells, and 32Dcl3 murine progenitor cells, expressing the wild-type or mutant (Y253H or T315I) Bcr-Abl1 in situ. Accordingly, impaired SK-1/S1P2 signaling enhanced the growth-inhibitory effects of nilotinib against 32D/T315I-Bcr-Abl1-derived mouse allografts. Since SK-1/S1P/S1P2 signaling regulates Bcr-Abl1 stability via modulation of PP2A, inhibition of SK-1/S1P2 axis represents a novel approach to target wild-type- or mutant-Bcr-Abl1 thereby overcoming drug resistance. © 2011 by The American Society of Hematology.en_US
dc.description.sponsorshipNational Institutes of Health (NIH); US Army; NIH, National Center for Research Resources (C06 RR015455)en_US
dc.language.isoengen_US
dc.publisherAmerican Society of Hematologyen_US
dc.relation.isversionof10.1182/blood-2010-08-300772en_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectDrug resistanceen_US
dc.subjectChronic myeloid leukemiaen_US
dc.subjectSmall interfering RNAen_US
dc.subjectCancer cellsen_US
dc.subjectProtein degradationen_US
dc.titleSphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2Aen_US
dc.typearticleen_US
dc.contributor.authorIDTR119193en_US
dc.contributor.iztechauthorBaran, Yusuf
dc.relation.journalBlooden_US
dc.contributor.departmentİYTE, Fen Fakültesi, Moleküler Biyoloji ve Genetik Bölümüen_US
dc.identifier.volume117en_US
dc.identifier.issue22en_US
dc.identifier.startpage5941en_US
dc.identifier.endpage5952en_US
dc.identifier.wosWOS:000291203200022
dc.identifier.scopusSCOPUS:2-s2.0-79957980683
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US


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