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Bcr-Abl-mediated molecular mechanism for apoptotic suppression in multipotent haemopoietic cells: a role for PKCbetaII.
Xenaki D, Pierce A, Underhill-Day N, Whetton A, Owen-Lynch P
Cell Signal. 2004;16( 2):145-56.
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Abstract
Bcr-Abl protein tyrosine kinase (PTK) activity is a feature of chronic myeloid leukaemia and confers a survival advantage on haemopoietic progenitor cells. We have expressed conditional mutant of the Bcr-Abl PTK in the FDCP-Mix A4 multipotent haematopoietic cell line in order to examine the molecular mechanisms whereby Bcr-Abl PTK leads to enhanced cell survival under conditions in which normal cells die. Activation of Bcr-Abl PTK does not phosphorylate or activate either ERK-1/2 or JAK-2/STAT-5b, suggesting that these signal transduction pathways are not involved in Abl PTK-mediated suppression of apoptosis in FDCP-Mix cells. However, protein kinase C (PKC) does have a role to play. Inhibition of PKC results in a reversal of Bcr-Abl PTK-mediated survival in the absence of growth factor and Bcr-Abl stimulates translocation of the PKCbetaII isoform to the nucleus. Furthermore, expression of a constitutively activated PKCbetaII in haemopoietic progenitor FDCP-Mix cells stimulates enhanced cell survival when IL-3 is withdrawn. However, expression of this constitutively activated PKC isoform does not suppress cytotoxic drug-induced apoptosis. Thus Bcr-Abl PTK has pleiotropic effects which can suppress cell death induced by a number of stimuli.
Keyword(s)
Coculture Techniques; Humans; Milk Proteins; Mitogen-Activated Protein Kinase 3; Mutation; Phosphorylation; Proto-Oncogene Proteins; Research Support, Non-U.S. Gov't; Signal Transduction; deficiency: Interleukin-3; metabolism: DNA-Binding Proteins; metabolism: Hematopoietic Stem Cells; metabolism: Mitogen-Activated Protein Kinase 1; metabolism: Mitogen-Activated Protein Kinases; metabolism: Multipotent Stem Cells; metabolism: Protein Kinase C; metabolism: Protein-Tyrosine Kinase; metabolism: Trans-Activators; physiology: Apoptosis; physiology: Cell Survival