title: Differential regulation of the apoptotic machinery during megakaryocyte differentiation and platelet production by inhibitor of apoptosis protein Livin.
abstract: Livin is a member of the inhibitor of apoptosis proteins (IAP) family of intracellular antiapoptotic proteins that act by binding and inhibiting caspases. Upon strong apoptotic stimuli, it is then specifically cleaved by caspases to produce a truncated protein (tLivin) with a paradoxical proapoptotic activity. Intriguingly, we have detected robust protein levels of Livin in normal mature bone marrow megakaryocyte (MK) and platelets. To evaluate the potential role of Livin in thrombopoiesis, we used the human BCR-ABL+ cell line, LAMA-84, and cord blood CD34+ cells to induce differentiation toward MKs. Upon differentiation, induced by phorbol myristate acetate and concurrent with increase in Livin protein expression, LAMA-84 cells formed functional platelet-like particles. Livin overexpression in CD34+ progenitor cells induced higher endoreplication in the MKs generated. Furthermore, overexpression of Livin increased the ability of both primary MKs and differentiated LAMA-84 cells to produce functional platelets. In the differentiated LAMA-84 cells, we observed accumulation of proapoptotic tLivin concomitant with increased caspase-3 activity. Downregulation of Livin with small interfering RNA in both leukemic and primary MK cells decreased their ability to produce functional platelets. We suggest that Livin has a role in thrombopoiesis by regulating the apoptotic and antiapoptotic balance in MK endoreplication and platelet production.
authors.affiliation: Division of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Abd-Elrahman
authors.forename: V
authors.initials: V
authors.lastname: Deutsch
authors.forename: M
authors.initials: M
authors.lastname: Pick
authors.forename: S
authors.initials: S
authors.lastname: Kay
authors.forename: T
authors.initials: T
authors.lastname: Neuman
authors.forename: R
authors.initials: R
authors.lastname: Perlman
authors.forename: D
authors.initials: D
authors.lastname: Ben-Yehuda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001792:Blood Platelets / Q000166:cytology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008533:Megakaryocytes / Q000166:cytology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34; C419866:BIRC7 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering