Transcriptional repression by p53 promotes a Bcl-2-insensitive and mitochondria-independent pathway of apoptosis

• Published in: Nucleic acids research 2004-01, Vol.32 (15), p.4480-4490
• Main Authors: Godefroy, Nelly, Bouleau, Sylvina, Gruel, Gaëtan, Renaud, Flore, Rincheval, Vincent, Mignotte, Bernard, Tronik-Le Roux, Diana, Vayssière, Jean-Luc
• Format: Article
• Language: English
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; Animals; Apoptosis; Caspase Inhibitors; Cell Line; Cysteine Proteinase Inhibitors - pharmacology; Gene Expression Profiling; Gene Expression Regulation; Life Sciences; Mitochondria - physiology; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Repressor Proteins - physiology; Signal Transduction; Transcription, Genetic; Transcriptional Activation; Tumor Suppressor Protein p53 - physiology
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gkh773

p53 can induce apoptosis in various ways including transactivation, transrepression and transcription-independent mechanisms. What determines the choice between them is poorly understood. In a rat embryo fibroblast model, caspase inhibition changed the outcome of p53 activation from standard Bcl-2-regulated apoptosis to caspase-independent and Bcl-2-insensitive cell death, a phenomenon not described previously. Here, we show that caspase inhibition affects cell death commitment decisions by modulating the apoptotic functions of p53. Indeed, in the Bcl-2-sensitive pathway, transactivation-dependent signalling is activated leading to a rapid MDM2-mediated degradation of p53. In contrast, in the Bcl-2-insensitive pathway, p53 is stable and this is associated with transrepression-dependent signalling. A study with microarrays identified these genes regulated by p53 in the absence of active caspases.