Journal article
Cytokine rescue of p53-dependent apoptosis and cell cycle arrest is mediated by distinct Jak kinase signaling pathways
Genes & development, Vol.12(8), pp.1099-1107
04/15/1998
DOI: 10.1101/gad.12.8.1099
PMCID: PMC316716
PMID: 9553040
Abstract
Exposure of hematopoietic progenitors to γ-irradiation (IR) induces p53-dependent apoptosis and a p53-independent G
2
/M cell cycle arrest. These responses to DNA-damage can be inhibited by treatment with cytokine growth factors. Here we report that γ-IR-induced apoptosis and cell cycle arrest are suppressed by specific cytokines (e.g., erythropoietin and interleukin-3) and that activation of the Jak kinase is necessary and sufficient for these effects. Using myleoid cells expressing a series of erythropoietin receptor (EpoR) mutants, we have demonstrated that Jak kinase-dependent signals initiated from the membrane proximal domain of EpoR were sufficient to prevent IR-induced apoptotic cell death, but failed to prevent cell cycle arrest. Cell survival by Epo did not require activation of other known signaling pathways including PI-3 kinase, PLC-γ, Ras or Stats. Signaling targets of Jak kinase pathways included members of the Bcl-2 family of anti-apoptotic proteins, and enforced expression of Bcl-2 or Bcl-x
L
was as effective as cytokine treatment in blocking IR-induced apoptosis but did not prevent growth arrest. A distinct signal derived from a membrane distal domain of EpoR is required to overcome growth arrest associated with DNA damage. These findings functionally link the Jak signaling pathway to suppression of p53-mediated cell death by cytokines and demonstrate that the apoptotic and growth arrest responses to DNA damage in hematopoietic cells are modulated by distinct, cytokine specific signal transduction pathways.
Details
- Title: Subtitle
- Cytokine rescue of p53-dependent apoptosis and cell cycle arrest is mediated by distinct Jak kinase signaling pathways
- Creators
- Frederick W Quelle - Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105JinLing Wang - Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105Jian Feng - Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105Demin Wang - Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105John L Cleveland - Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105James N Ihle - Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105Gerard P Zambetti - Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105
- Resource Type
- Journal article
- Publication Details
- Genes & development, Vol.12(8), pp.1099-1107
- Publisher
- Cold Spring Harbor Laboratory Press
- DOI
- 10.1101/gad.12.8.1099
- PMID
- 9553040
- PMCID
- PMC316716
- ISSN
- 0890-9369
- eISSN
- 1549-5477
- Language
- English
- Date published
- 04/15/1998
- Academic Unit
- Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040455802771
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