Activation of the MEK/MAPK pathway is involved in bryostatin1-induced monocytic differenciation and up-regulation of X-linked inhibitor of apoptosis protein.
Induction of monocytic differentiation by bryostatin1 (bryo1) conferred on THP-1 leukemia cells the ability to resist Z-LLL-CHO-induced apoptosis. The mechanism of resistance developed during this process was investigated. Apoptosis resistance was associated with an enhanced expression of X-linked inhibitor of apoptosis protein (XIAP), an endogenous caspase inhibitor, in differentiated THP-1 cells. Bryo1 also increased the level of c-IAP-1, yet decreased the level of c-IAP-2 in THP-1 cells, indicating that distinct regulatory mechanisms are operative. In addition, treatment of THP-1 cells with bryo1 induced a rapid and sustained activation of MEK, prior to the upregulation of XIAP and monocytic differentiation. Pretreatment of THP-1 cells with MEK inhibitors (U0126 and PD98059) prior to bryo1 induction blocked the expression of both XIAP and the c-fms product (M-CSF receptor), a hallmark of monocytic differentiation, but not Bcl-2. In addition, the expression of XIAP in bryo1-treated cells was inhibited by CAPE, a NF-kappaB-specific inhibitor, indicating that its expression is under the transcriptional regulation of NF-kappaB downstream of the MEK/MAPK pathway. The importance of XIAP in mediating apoptosis resistance was illustrated in cells transiently transfected with XIAP, which conferred on THP-1 cells the ability to resist Z-LLL-CHO-induced apoptosis. These findings suggest that the expression of XIAP is linked to monocytic differentiation in bryo1-treated THP-1 cells and represents one of the potential antiapoptotic mechanisms acquired during this process.
Lin
Hong
H
Division of Hematology-Oncology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Chen
Catheryne
C
Li
Xiaohua
X
Chen
Ben D
BD
D017209:Apoptosis; D054713:Bryostatins; D002454:Cell Differentiation; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D020672:I-kappa B Proteins; D007783:Lactones / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D018942:Macrolides; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051636:X-Linked Inhibitor of Apoptosis Protein
D054713:Bryostatins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007783:Lactones; D018942:Macrolides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000072000:NF-KappaB Inhibitor alpha; C046785:bryostatin 1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases