Activation of the MEK/MAPK pathway is involved in bryostatin1-induced monocytic differenciation and up-regulation of X-linked inhibitor of apoptosis protein.

Abstract

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.

• Authors: Hong Lin, Catheryne Chen, Xiaohua Li, Ben D Chen
• Journal: Experimental cell research (Exp Cell Res) Vol. 272 Issue 2 Pg. 192-8 (Jan 15 2002) ISSN: 0014-4827 [Print] United States
• PMID: 11777344 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: (c)2002 Elsevier Science.

Chemical References

• Bryostatins
• DNA-Binding Proteins
• Enzyme Inhibitors
• I-kappa B Proteins
• Lactones
• Macrolides
• NF-kappa B
• NFKBIA protein, human
• Proteins
• Proto-Oncogene Proteins
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• NF-KappaB Inhibitor alpha
• bryostatin 1
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase Kinases

Topics

• Apoptosis
• Bryostatins
• Cell Differentiation
• DNA-Binding Proteins
• Enzyme Activation
• Enzyme Inhibitors (metabolism)
• Gene Expression
• Humans
• I-kappa B Proteins
• Lactones (pharmacology)
• MAP Kinase Signaling System (physiology)
• Macrolides
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• Monocytes (cytology, metabolism)
• NF-KappaB Inhibitor alpha
• NF-kappa B (metabolism)
• Protein Biosynthesis
• Protein Serine-Threonine Kinases
• Proteins (genetics, metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Tumor Cells, Cultured
• Up-Regulation
• X-Linked Inhibitor of Apoptosis Protein