CYTOKINE RESCUE OF P53-DEPENDENT APOPTOSIS AND CELL-CYCLE ARREST IS MEDIATED BY DISTINCT JAK KINASE SIGNALING PATHWAYS

Exposure of hematopoietic progenitors to gamma-irradiation (IR) induce s p53-dependent apoptosis and a p53-independent G(2)/M cell cycle arre st. These responses to DNA-damage can be inhibited by treatment with c ytokine growth factors. Here rye report that gamma-IR-induced apoptosi s and cell cycle arrest are suppressed by specific cytokines (e.g., er ythropoietin and interleukin-3) and that activation of the Tak kinase is necessary and sufficient for these effects. Using myleoid cells exp ressing a series of erythropoietin receptor (EpoR) mutants, we have de monstrated that Jak kinase-dependent signals initiated from the membra ne proximal domain of EpoR were sufficient to prevent IR-induced apopt otic cell death, but failed to prevent cell cycle arrest. Cell surviva l by Epo did not require activation of other known signaling pathways including PI-3 kinase, PLC-gamma, Ras or Stats. Signaling targets of T ak kinase pathways included members of the Bcl-2 family of anti-apopto tic proteins, and enforced expression of Bcl-2 or Bcl-x(L) was as effe ctive as cytokine treatment in blocking IR-induced apoptosis but did n ot prevent growth arrest. A distinct signal derived from a membrane di stal domain of EpoR is required to overcome growth arrest associated w ith DNA damage. These findings functionally link the Tak signaling pat hway to suppression of p53-mediated cell death by cytokines and demons trate that the apoptotic and growth arrest responses to DNA damage in hematopoietic cells are modulated by distinct, cytokine specific signa l transduction pathways.