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Prepublished online as a Blood First Edition Paper on July 18, 2002; DOI 10.1182/blood-2002-02-0504.
Submitted February 14, 2002
Accepted July 4, 2002
The death-promoting activity of p53 can be inhibited by distinct signalling pathways
Yunping Lin, Lauren Brown, David W Hedley, Dwayne L Barber, and Samuel Benchimol*
Ontario Cancer Institute and Departments of Medical Biophysics, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
* Corresponding author; email: benchimo{at}uhnres.utoronto.ca.
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°C by undergoing G1 cell cycle arrest and apoptosis. In the presence of EPO, p53 activation leads only to prolonged but viable G1 arrest. These findings indicate that EPO functions as a survival factor and that gp55:EPO receptor signalling is distinct from EPO:EPO receptor signalling. 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 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.
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