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Bcr-Abl-mediated molecular mechanism for apoptotic suppression in multipotent haemopoietic cells: a role for PKCβII.

Research output: Contribution to Journal/MagazineJournal articlepeer-review

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  • Dia Xenaki
  • Andrew Pierce
  • Nick Underhill-Day
  • Anthony D. Whetton
  • P. Jane Owen-Lynch
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<mark>Journal publication date</mark>02/2004
<mark>Journal</mark>Cellular Signalling
Issue number2
Volume16
Number of pages12
Pages (from-to)145-156
Publication StatusPublished
<mark>Original language</mark>English

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 PKCβII isoform to the nucleus. Furthermore, expression of a constitutively activated PKCβII in haemopoietic progenitor FDCP-Mix cells stimulates enhanced cell survival when IL-3 is withdrawn.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.