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dc.contributor.authorHolloway, Ryan
dc.date.accessioned2019-11-28T14:48:36Z
dc.date.available2019-11-28T14:48:36Z
dc.identifier.urihttp://hdl.handle.net/10222/76662
dc.description.abstractAcute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia, is characterized by expression of the promyelocytic leukemia-retinoic acid receptor oncoprotein, PML/RARα, which blocks granulocyte differentiation. Patients with APL present fatal hemorrhagic complications from excessive generation of the fibrinolytic protease plasmin and the procoagulant protein, tissue factor (TF). We previously demonstrated that a cell surface regulator of plasmin generation, S100A10 (p11) is upregulated in APL promyelocytes. Treatment of APL promyelocytes with all-trans retinoic acid (ATRA) mitigates the hemorrhagic disorder concomitant with promoting the degradation of PML/RARα and p11. Here, we show PML/RARα up-regulates p11 transcript and protein levels concomitant with increased plasmin activity. Depletion of p11 from the PML/RARα expressing APL promyelocyte cell line, NB4, reduced plasmin activity, but not TF activity. ATRA treatment of NB4 cells reduced p11 transcripts and promoted its ubiquitin-independent proteasomal degradation. Unexpectedly, the ATRA-dependent loss of p11 increased the plasmin activity and decreased the TF activity of the NB4 cells. However, ATRA treatment of MCF-7 cells also blocked p11 transcription and protein levels suggesting that ATRA can regulate p11 levels independent of PML/RARα. These studies highlight the complex regulation of p11, demonstrate that changes in p11 do not always correspond with decreases in plasmin generation, and challenge the hypothesis that p11 is regulated by ubiquitin-mediated proteasomal degradation.en_US
dc.language.isoenen_US
dc.subjectS100A10en_US
dc.subjectAnnexin A2en_US
dc.subjectUbiquitinen_US
dc.subjectProteasomeen_US
dc.subjectAll-trans retinoic aciden_US
dc.subjectAcute Promyelocytic Leukemiaen_US
dc.subjectPlasminen_US
dc.subjectPlasminogenen_US
dc.titleTHE ROLE OF THE CELL SURFACE PROTEASE RECEPTOR S100A10 IN ACUTE PROMYELOCYTIC LEUKEMIA (APL) AND ITS REGULATION BY RETINOIC ACID THERAPYen_US
dc.typeThesisen_US
dc.date.defence2018-03-07
dc.contributor.departmentDepartment of Pathologyen_US
dc.contributor.degreeDoctor of Philosophyen_US
dc.contributor.external-examinerDr. Gary Shawen_US
dc.contributor.graduate-coordinatorDr. Wenda Greeren_US
dc.contributor.thesis-readerDr. Paola Marignanien_US
dc.contributor.thesis-readerDr. Paola Marcatoen_US
dc.contributor.thesis-readerDr, Jean S. Marshallen_US
dc.contributor.thesis-supervisorDr. David M. Waismanen_US
dc.contributor.ethics-approvalNot Applicableen_US
dc.contributor.manuscriptsYesen_US
dc.contributor.copyright-releaseNot Applicableen_US
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