期刊
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
卷 134, 期 8, 页码 861-872出版社
SPRINGER
DOI: 10.1007/s00432-008-0356-8
关键词
AML; APL; NB4; MAPK; PI3-kinase
类别
Purpose In acute promyelocytic leukemia (APL) the chromosome translocation t(15;17) resulting in the PML-RAR alpha fusion protein is responsible for a blockage of myeloid differentiation. In this study we investigated the expression of different Phosphatidylinositol 3-kinase (PI3K) isoforms during granulocyte differentiation of NB4 cells induced by all-trans-retinoic acid (ATRA), 9-cis-retinoic acid (9cisRA) or retinoic acid receptor (RAR) agonists. Methods NB4 cells were analysed for their ability to differentiate into granulocytic lineage by the use of ATRA, 9cisRA or RAR agonists. Expression of signalling proteins was investigated by western blot and real-time PCR. PI3K activity was determined by in vitro kinase assays. Results Co-treatment of NB4 cells with either LY294002 to inhibit PI3Ks or PD98059 in order to suppress MEK activity led to significant reduction of CD11b surface expression during ATRA, 9cisRA or the RAR alpha agonist Ro40-6055 dependent NB4 cells granulocyte differentiation. We also show that only the G-protein coupled receptor activated PI3K gamma isoform demonstrates up-regulated protein and mRNA expression during myeloid differentiation of NB4 cells via RAR alpha and RAR beta-dependent mechanism. Furthermore, activation of MAPK cascade including phosphorylation of MEK increases during retinoid induced differentiation of NB4 cells. Interestingly, protein kinase assays of immunoprecipitated PI3K gamma revealed a protein of about 50 kDa that is phosphorylated when NB4 cells were treated with the RAR alpha agonist Ro40-6055. Conclusion Collectively, our data suggest additive effects of PI3K and MAPK activity on ATRA-dependent NB4 cells granulocyte differentiation.
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