p53-mediated cell cycle arrest and apoptosis.

We have generated a series of murine erythroleukemia clones that ectopically express a temperature sensitive mutant p53 allele. In many clones, activation of p53 at low temperature resulted in the accumulation of cells in G1 and in apoptosis. Several cytokines including erythropoietin, IL-3 and the ligand for the Kit receptor blocked p53-dependent apoptosis in p53ts-expressing cells at 32 degrees C. Cytokine-treated cells were reversibly arrested in G1 and resumed growth upon return to 37 degrees C. Certain clones exhibited only a G1 arrest in response to p53 activation at 32 degrees C. One of the these clones secreted erythropoietin and another secreted IL-3. We tested the possibility that autocrine secretion of IL-3 played a role in preventing apoptosis and showed that disruption of the autocrine loop by cell dilution or with neutralizing antibodies to IL-3 restored p53-dependent apoptosis at 32 degrees C. Thus, two properties of p53 protein, namely, its ability to arrest cells in G1 and its ability to promote apoptosis could be uncoupled by cytokines acting as survival factors.