title: Death-associated protein 5 (DAP5/p97/NAT1) contributes to retinoic acid-induced granulocytic differentiation and arsenic trioxide-induced apoptosis in acute promyelocytic leukemia.
abstract: All-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) induce differentiation and apoptosis in acute promyelocytic leukemia (APL) cells. Here we investigated the role and regulation of death-associated protein-5 (DAP5/p97/NAT1), a novel inhibitor of translational initiation, in APL cell differentiation and apoptosis. We found that ATRA markedly induced DAP5/p97 protein and gene expression and nuclear translocation during terminal differentiation of APL (NB4) and HL60 cells but not differentiation-resistant cells (NB4.R1 and HL60R), which express very low levels of DAP5/p97. At the differentiation inducing concentrations, ATO (<0.5 microM), dimethyl sulfoxide, 1,25-dihydroxy-vitamin-D3, and phorbol-12-myristate 13-acetate also significantly induced DAP5/p97 expression in NB4 cells. However, ATO administered at apoptotic doses (1-2 microM) induced expression of DAP5/p86, a proapoptotic derivative of DAP5/p97. ATRA and ATO-induced expression of DAP5/p97 was associated with inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Furthermore, DAP5/p97 expression was upregulated by inhibition of the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway via LY294002 and via rapamycin. Finally, knockdown of DAP5/p97 expression by small interfering RNA inhibited ATRA-induced granulocytic differentiation and ATO-induced apoptosis. Together, our data reveal new roles for DAP5/p97 in ATRA-induced differentiation and ATO-induced apoptosis in APL and suggest a novel regulatory mechanism by which PI3K/Akt/mTOR pathway inhibition mediates ATRA- and ATO-induced expression of DAP5/p97.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Box 422, Houston, TX 77030, USA.
authors.forename: Bulent
authors.initials: B
authors.lastname: Ozpolat
authors.forename: Ugur
authors.initials: U
authors.lastname: Akar
authors.forename: Isabel
authors.initials: I
authors.lastname: Zorrilla-Calancha
authors.forename: Pablo
authors.initials: P
authors.lastname: Vivas-Mejia
authors.forename: Marian
authors.initials: M
authors.lastname: Acevedo-Alvarez
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008954:Models, Biological; D010087:Oxides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D000077237:Arsenic Trioxide; D001152:Arsenicals; D015852:Eukaryotic Initiation Factor-2; D039603:Eukaryotic Initiation Factor-4G; D010087:Oxides; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D058570:TOR Serine-Threonine Kinases; D014212:Tretinoin; C491300:EIF4G2 protein, human; C114487:PDCD4 protein, human; C546842:MTOR protein, human