The death-promoting activity of p53 can be inhibited by distinct signaling pathways

Blood. 2002 Dec 1;100(12):3990-4000. doi: 10.1182/blood-2002-02-0504. Epub 2002 Jul 18.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • DNA-Binding Proteins / metabolism
  • Drug Antagonism
  • Erythropoietin / pharmacology*
  • Janus Kinase 2
  • Mice
  • Milk Proteins*
  • Mitochondria / drug effects
  • Mitochondria / physiology
  • Mitochondrial Proteins / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Serine-Threonine Kinases*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • STAT5 Transcription Factor
  • Signal Transduction*
  • Trans-Activators / metabolism
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / physiology
  • bcl-X Protein

Substances

  • Bcl2l1 protein, mouse
  • DNA-Binding Proteins
  • Milk Proteins
  • Mitochondrial Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • STAT5 Transcription Factor
  • Trans-Activators
  • Tumor Suppressor Protein p53
  • bcl-X Protein
  • Erythropoietin
  • Protein-Tyrosine Kinases
  • Jak2 protein, mouse
  • Janus Kinase 2
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt