Death-associated protein 5 (DAP5/p97/NAT1) contributes to retinoic acid-induced granulocytic differentiation and arsenic trioxide-induced apoptosis in acute promyelocytic leukemia.
Enviado por Pablo Vivas-Mejia el
Título | Death-associated protein 5 (DAP5/p97/NAT1) contributes to retinoic acid-induced granulocytic differentiation and arsenic trioxide-induced apoptosis in acute promyelocytic leukemia. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Autores | Ozpolat, B, Akar, U, Zorrilla-Calancha, I, Vivas-Mejia, P, Acevedo-Alvarez, M, Lopez-Berestein, G |
Journal | Apoptosis |
Volume | 13 |
Issue | 7 |
Pagination | 915-28 |
Date Published | 2008 Jul |
ISSN | 1573-675X |
Palabras clave | Apoptosis, Apoptosis Regulatory Proteins, Arsenicals, Base Sequence, Cell Differentiation, Cell Line, Tumor, Eukaryotic Initiation Factor-2, Eukaryotic Initiation Factor-4G, Granulocytes, HL-60 Cells, Humans, Leukemia, Promyelocytic, Acute, Models, Biological, Oxides, Phosphatidylinositol 3-Kinases, Protein Kinases, Proto-Oncogene Proteins c-akt, RNA, Small Interfering, RNA-Binding Proteins, Signal Transduction, TOR Serine-Threonine Kinases, Tretinoin, Up-Regulation |
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. |
DOI | 10.1007/s10495-008-0222-9 |
Alternate Journal | Apoptosis |
PubMed ID | 18491231 |
Grant List | U54 RFA CA096300 / CA / NCI NIH HHS / United States |