Cooperative and redundant effects of STAT5 and Ras signaling in BCR/ABL transformed hematopoietic cells.
The Akt, Ras and STAT5 signaling pathways have each been linked to transformation of hematopoietic cells by BCR/ABL. However the relative contributions of these signaling pathways to BCR/ABL mediated cytokine-independent survival, proliferation and resistance to DNA damage-induced apoptosis have not been systematically defined. Here we report that activation of either Akt, Ras or STAT5 confers cytokine-independent survival to IL-3 dependent BaF3 cells. Ras or STAT5, but not Akt, also drives cytokine-independent proliferation and imparts sustained resistance to DNA damage-induced apoptosis. We also show that dominant negative (DN) inhibition of STAT5, but not Ras or Akt, significantly reduces resistance to DNA damage-induced apoptosis in BCR/ABL transformed BaF3 cells. Whereas inhibition of STAT5 or Ras alone does not compromise cytokine-independent proliferation of BaF3-BCR/ABL cells, simultaneous blockade of both STAT5 and Ras reduces proliferation and maximally sensitizes BaF3-BCR/ABL cells to DNA damage induced by gamma-irradiation, suggesting a cooperative role for these two signaling pathways in BCR/ABL transformation. The anti-apoptotic properties of BCR/ABL can be partly explained by an increase in the expression of Pim-1 and Bcl-XL, as ectopic expression of these STAT5 target genes imparts both cytokine-independent survival and partial gamma-radiation resistance. These data illustrate both cooperative and redundant effects of STAT5 and Ras signaling in BCR/ABL transformed cells, with STAT5 playing a dominant role in resistance to DNA damage-induced apoptosis.
Hoover
R R
RR
Whitehead Institute, 9 Cambridge Center, Cambridge, MA 02142, USA.
Gerlach
M J
MJ
Koh
E Y
EY
Daley
G Q
GQ
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology*; D007377:Interleukin-3 / Q000494:pharmacology; D008894:Milk Proteins; D010677:Philadelphia Chromosome; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1; D012190:Retroviridae; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic; D051020:bcl-X Protein; D018631:ras Proteins / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D007377:Interleukin-3; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D051020:bcl-X Protein; D016044:Fusion Proteins, bcr-abl; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1; D018631:ras Proteins