Relationship of sequence-specific transactivation and p53-regulated apoptosis in interleukin 3-dependent...

The p53 tumor suppressor has been implicated in the control of apoptosis in response to various signals, including DNA damage, oncogene activation, and survival factor withdrawal. The p53 protein is a transcription factor capable of sequence-specific transactivation of target genes. The relationship between p53-mediated transactivation and apoptosis was probed in interleukin 3 (IL-3)-dependent DA-1 lymphoma cells. DA-1 cells express endogenous wild-type p53, which is required for the efficient induction of apoptosis by IL-3 deprivation. IL-3 withdrawal caused no detectable increase in p53 and no concomitant activation of p53-responsive promoters. Conversely, high levels of transfected, transcriptionally active p53 did not elicit any apoptosis as long as IL-3 was present; instead, the cells underwent a viable G1 arrest. IL-3 protected DA-1 cells from the apoptotic effect of low doses of radiation. However, higher doses triggered p53-dependent apoptosis, even in the presence of IL-3. Irrespective of their different effects on viability, sublethal and lethal radiation caused a comparable augmentation of p53-dependent transactivation. Lethal radiation induced an initial p53-dependent G1 arrest, but subsequent apoptosis was preceded by cell cycle re-entry. Our data support the conjecture that activities of p53 distinct from specific transcriptional activation may contribute to apoptosis, although activation of genes such as Bax is also likely to play a role.