Tumor suppressor p73 transcriptionally regulates c-FLIP to impede its priming of extrinsic apoptosis while a switcher compound degrades c-FLIP protein
The tumor suppressor p73 is a member of the p53 family, and transcriptionally activates multiple p53-targets involved in cell cycle regulation and apoptosis. In addition to pro-apoptotic signaling, outcomes of p73 activation include cell survival signals. Thus, p73 activity and targets may provide insight in cell fate outcomes between cell survival and apoptosis following cellular stress. We report that cellular FLICE inhibitory protein (c-FLIP), a master antiapoptotic factor, is a transcriptional target of p73. The activation of p73 (alpha and beta isoforms) transcriptionally upregulates c-FLIP-L/S expression in cancer cells. The cell fate decision following p73 activation is determined by the adjustment of the balance of outcomes of p73 activation between p73-induced pro-apoptotic signaling and c-FLIP-L/S expression in cancer cells. p73 primes extrinsic apoptosis via an autocrine death ligand-DR5 axis, and the priming appears to be titrated at the level of c-FLIP-L/S. The p73-upregul