title: Relationship of sequence-specific transactivation and p53-regulated apoptosis in interleukin 3-dependent hematopoietic cells.
abstract: 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.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Gottlieb
authors.forename: S
authors.initials: S
authors.lastname: Lindner
authors.forename: M
authors.initials: M
authors.lastname: Oren
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004273:DNA, Neoplasm / Q000096:biosynthesis; D016193:G1 Phase; D015870:Gene Expression; D007377:Interleukin-3 / Q000502:physiology*; D008214:Lymphocytes / Q000166:cytology / Q000502:physiology*; D008223:Lymphoma; D051379:Mice; D011401:Promoter Regions, Genetic / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000096:biosynthesis; D011839:Radiation, Ionizing; D015533:Transcriptional Activation / Q000502:physiology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000502:physiology*; D051028:bcl-2-Associated X Protein
chemical_list: C494827:Bax protein, mouse; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein