The pseudo-caspase FLIP(L) regulates cell fate following p53 activation
2020; National Academy of Sciences; Volume: 117; Issue: 30 Linguagem: Inglês
10.1073/pnas.2001520117
ISSN1091-6490
AutoresAndrea Lees, Alexander J. McIntyre, Nyree Crawford, Fiammetta Falcone, Christopher McCann, Caitriona Holohan, Gerard P. Quinn, Jamie Z. Roberts, Tamas Sessler, Peter F. Gallagher, Gemma Gregg, Katherine McAllister, Kirsty M. McLaughlin, Wendy L. Allen, Laurence J. Egan, Aideen E. Ryan, Melissa J. LaBonte, Philip D. Dunne, Mark Wappett, Vicky M. Coyle, Patrick G. Johnston, Emma Kerr, Daniel B. Longley, Simon S. McDade,
Tópico(s)DNA Repair Mechanisms
ResumoSignificance p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. We unexpectedly identify a critical role for the only human pseudo-caspase FLIP(L) in regulating this switch. Genetically or pharmacologically inhibiting expression of FLIP(L), which we identify as a new p53 transcriptional target, promoted apoptosis over cell-cycle arrest in response to p53 activation. Mechanistically, FLIP(L) inhibited p53-induced apoptosis by blocking ligand-independent activation of caspase-8 by the TRAIL-R2/DR5 death receptor. Notably, FLIP(L) also modulated transcription of canonical p53 target genes: increasing expression of cell-cycle regulator p21 and suppressing upregulation of apoptosis-inducing PUMA. Thus, we report unexpected, therapeutically exploitable roles for FLIP(L) in regulating the switch from p53-induced cell-cycle arrest to apoptosis.
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