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Cytokine rescue of p53-dependent apoptosis and cell cycle arrest is mediated by distinct Jak kinase signaling pathways. Genes Dev 1998 Apr 15;12(8):1099-107

Date

05/30/1998

Pubmed ID

9553040

Pubmed Central ID

PMC316716

DOI

10.1101/gad.12.8.1099

Scopus ID

2-s2.0-0032522453   92 Citations

Abstract

Exposure of hematopoietic progenitors to gamma-irradiation (IR) induces p53-dependent apoptosis and a p53-independent G2/M cell cycle arrest. These responses to DNA-damage can be inhibited by treatment with cytokine growth factors. Here we report that gamma-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-gamma, 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-xL 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.

Author List

Quelle FW, Wang J, Feng J, Wang D, Cleveland JL, Ihle JN, Zambetti GP

Author

Demin Wang PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Cell Cycle
Cell Division
Cell Line
DNA Damage
Enzyme Activation
Erythropoietin
Humans
Interleukin-3
Janus Kinase 2
Mice
Protein-Tyrosine Kinases
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-bcl-2
Receptors, Erythropoietin
Serum Albumin, Bovine
Signal Transduction
Tumor Suppressor Protein p53
bcl-X Protein
jenkins-FCD Prod-469 c3fc8ab87196149f9b23743c01b947d47e7319e5