RELATIONSHIP OF SEQUENCE-SPECIFIC TRANSACTIVATION AND P53-REGULATED APOPTOSIS IN INTERLEUKIN 3-DEPENDENT HEMATOPOIETIC-CELLS

The p53 tumor suppressor has been implicated in the control of apoptos is in response to various signals, including DNA damage, oncogene acti vation, and survival factor withdrawal. The p53 protein is a transcrip tion factor capable of sequence-specific transactivation of target gen es. The relationship between p53-mediated transactivation and apoptosi s was probed in interleukin 3 (IL-3)-dependent DA-1 lymphoma cells. DA -1 cells express endogenous wildtype p53, which is required for the ef ficient induction of apoptosis by IL-3 deprivation. IL-3 withdrawal ca used no detectable increase in p53 and no concomitant activation of p5 3-responsive promoters, Conversely, high levels of transfected, transc riptionally active p53 did not elicit any apoptosis as long as IL-3 wa s present; instead, the cells underwent a viable G(1) arrest. IL-3 pro tected 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 p 53-dependent transactivation. Lethal radiation induced an initial p53- dependent G(1) arrest, but subsequent apoptosis was preceded by cell c ycle re-entry. Our data support the conjecture that activities of p53 distinct from specific transcriptional activation may contribute to ap optosis, although activation of genes such as Saw is also likely to pl ay a role.