The death-promoting activity of p53 can be inhibited by distinct signaling pathways.
Various cytokines have been shown to protect cells from p53-dependent apoptosis. To investigate the mechanism underlying cytokine-mediated survival, we used a Friend virus-transformed erythroleukemia cell line that expresses a temperature-sensitive p53 allele. These cells express the spleen focus-forming virus-encoded envelope glycoprotein gp55 that allows the cells to proliferate in the absence of erythropoietin (EPO). These cells respond to p53 activation at 32 degrees C by undergoing G(1) cell cycle arrest and apoptosis. In the presence of EPO, p53 activation leads only to prolonged but viable G(1) arrest. These findings indicate that EPO functions as a survival factor and that gp55/EPO receptor signaling is distinct from EPO/EPO receptor signaling. We demonstrate that p53-dependent apoptosis results in mitochondrial damage as shown by loss of mitochondrial membrane potential, increase in intracellular calcium, and release of mitochondrial cytochrome c into the cytosol. EPO prevented all of these changes including the subsequent activation of caspases. We identify an intrinsic phosphatidylinositol-3'-OH kinase/protein kinase B (PI3'K/PKB)-dependent survival pathway that is constitutively active in these cells. This survival pathway limits p53-dependent apoptosis. We propose that EPO promotes survival through a distinct pathway that is dependent on JAK2 but independent of STAT5 and PI3'K.
Lin
Yunping
Y
Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Ontario, Canada.
Brown
Lauren
L
Hedley
David W
DW
Barber
Dwayne L
DL
Benchimol
Samuel
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004336:Drug Antagonism; D004921:Erythropoietin / Q000494:pharmacology*; D053614:Janus Kinase 2; D051379:Mice; D008894:Milk Proteins; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D024101:Mitochondrial Proteins / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000502:physiology; D051020:bcl-X Protein
D004268:DNA-Binding Proteins; D004921:Erythropoietin; D053614:Janus Kinase 2; D008894:Milk Proteins; D024101:Mitochondrial Proteins; 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; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; C494812:Bcl2l1 protein, mouse; C507926:Jak2 protein, mouse