FLIP(L) determines p53 induced life or death
Lees, A.; McIntyre, A. J.; Falcone, F.; Crawford, N. T.; McCann, C.; Quinn, G. P.; Roberts, J. Z.; Sessler, T.; Gallagher, P. F.; McAllister, K.; McLaughlin, K.; Allen, W. L.; Holohan, C.; Egan, L. J.; Ryan, A. E.; Labonte-Wilson, M.; Dunne, P. D.; Wappett, M.; Coyle, V. M.; Johnston, P.; Kerr, E. M.; Longley, D. B.; McDade, S. S.
Show abstract
How p53 differentially activates cell cycle arrest versus cell death remains poorly understood. Here, we demonstrate that upregulation of canonical pro-apoptotic p53 target genes in colon cancer cells imposes a critical dependence on the long splice form of the caspase-8 regulator FLIP (FLIP(L)), which we identify as a direct p53 transcriptional target. Inhibiting FLIP(L) expression with siRNA or Class-I HDAC inhibitors promotes apoptosis in response to p53 activation by the MDM2 inhibitor Nutlin-3A, which otherwise predominantly induces cell-cycle arrest. When FLIP(L) upregulation is inhibited, apoptosis is induced in response to p53 activation via a novel ligand-independent TRAIL-R2/caspase-8 complex, which, by activating BID, induces mitochondrial-mediated apoptosis. Notably, FLIP(L) depletion inhibits p53-induced expression of the cell cycle regulator p21 and enhances p53-mediated upregulation of PUMA, with the latter activating mitochondrial-mediated apoptosis in FLIP(L)-depleted, Nutlin-3A-treated cells lacking TRAIL-R2/caspase-8. Thus, we report two previously undescribed, novel FLIP(L)-dependent mechanisms that determine cell fate following p53 activation.
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