Role of phosphatidylinositol 3-kinase and specific protein kinase B isoforms in the suppression of apoptosis mediated by the Abelson protein-tyrosine kinase.
Leukemogenic oncogenes, such as the Abelson protein-tyrosine kinases (PTK), disrupt the normal regulation of survival, proliferation, and differentiation in hemopoietic progenitor cells. In the absence of cytokines, hemopoietic progenitor cells die by apoptosis. Abl PTKs mediate suppression of this apoptotic response leading to aberrant survival. To investigate the mechanism of Abl PTK action, we have used an interleukin-3-dependent murine mast cell line that expresses a temperature-sensitive form of the v-ABL PTK, which is active at the permissive temperature of 32 degrees C and inactive at 39 degrees C. At the permissive temperature, these cells are resistant to apoptosis induced both by the withdrawal of the hemopoietic growth factor (interleukin-3) and the addition of cytotoxic drugs. We demonstrate that v-Abl associates with and stimulates activation of phosphatidylinositol 3-kinase (PI3K) and, crucially, that this activation results in enhanced cellular levels of the mass of the second messenger phosphatidylinositol-3,4,5-trisphosphate. Activation of PI3K leads to enhanced activity of PKB and increased levels of the anti-apoptotic protein Bcl-X(L). Transfection of cells with a dominant negative PKB reduces both the Abl-stimulated PKB activity and the survival effect conferred by activation of this oncogene. Thus, PI3K and PKB are required for the anti-apoptotic effects of Abl PTK.
Tang
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X
Department of Biochemistry, University of Dundee, Dundee DD1 5EH, United Kingdom.
Downes
C P
CP
Whetton
A D
AD
Owen-Lynch
P J
PJ
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D004789:Enzyme Activation; D015151:Immunoblotting; D007527:Isoenzymes; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D013696:Temperature; D013997:Time Factors; D014162:Transfection; D051020:bcl-X Protein
D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C494812:Bcl2l1 protein, mouse