Caspase-3 triggers a TPCK-sensitive protease pathway leading to degradation of the BH3-only protein puma

Abstract

The protein Puma (p53-upregulated modulator of apoptosis) belongs to the BH3-only group of the Bcl-2 family and is a major regulator of apoptosis. Although the transcriptional regulation of Puma is clearly established, little is known about the regulation of its expression at the protein levels. We show here that various signals--including the cytokine TGFβ, the death effector TRAIL or chemical drugs such as anisomycin--downregulate Puma protein levels via a novel pathway based on the sequential activation of caspase-3 and a protease inhibited by the serpase inhibitor N-tosyl-L-phenylalanine chloromethyl ketone. This pathway is specific for Puma because (1) the levels of other BH3-only proteins, such as Bim and Noxa were not modified by these stimuli and (2) this caspase-mediated degradation was dependent on both the BH3 and C-terminal domains of Puma. Our data also show that Puma is regulated during the caspase-3-dependent differentiation of murine embryonic stem cells and suggest that this pathway may be relevant and important during caspase-mediated cell differentiation not associated with apoptosis.

Synergistic killing of colorectal cancer cells by oxaliplatin and ABT-737

“…Recently it was shown that Puma (but not Noxa) is sensitive to caspase-3-dependent proteolytic destruction [5]. In line with these results, we found that caspase-3 processing in cells treated with the drug combination was associated with strongly reduced levels of Puma, but not Noxa.…”

APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma

“…Furthermore, we noted that p21, PUMA and NOXA levels decreased with the onset of apoptosis. As these mediators can be cleaved by activated caspase-3,30 31 an additional layer of complexity needs to be considered when expression data is used as a surrogate marker of p53 activity.…”

Apoptosis Induction by SAHA in Cutaneous T-Cell Lymphoma Cells Is Related to Downregulation of c-FLIP and Enhanced TRAIL Signaling

“…Caspase-mediated processing may be considered because of strong caspase 3 activation in CTCL cells. Caspase-mediated degradation of Mcl-1 (Wardle et al, 2011), XIAP (Muhlethaler-Mottet et al, 2008, and Puma (Hadji et al, 2010) has been reported in neutrophils, neuroblastoma cells, and Jurkat cells, respectively. Nevertheless, gene regulation appears as a major target of HDACi activity (Dickinson et al, 2010).…”