Caspase-2 is required for DNA damage-induced expression of the CDK inhibitor p21WAF1/CIP1

Reiner Udo Jänicke (1) , Dennis Sohn (1) , Wilfried Budach (1)

1 Laboratory of Molecular Radiooncology

Although caspase-2 represents the most conserved caspase across species and was the second caspase identified, its precise function remains enigmatic. In several cell types we show that knockdown of caspase-2 specifically impaired DNA damage-induced p21 expression, while overexpression of a caspase-2 mutant increased p21 levels. Caspase-2 did not influence p21 mRNA transcription, and also various inhibitors targeting proteasomal or non-proteasomal proteases including caspases could not restore p21 protein levels following knockdown of caspase-2. As, however, silencing of caspase-2 only impaired exogenous expression of p21 constructs containing 3'-UTR sequences, our results strongly indicate that caspase-2 regulates p21 expression at the translational level. Intriguingly, unlike depletion of caspase-2 that prevented p21 expression and thereby reverted the γ-irradiation-induced senescent phenotype of wild-type HCT116 colon carcinoma cells into apoptosis, neither knockdown of the caspase-2-interacting components RAIDD, RIP or DNA-PKcs was able to mimic these processes. Together, our data suggest that this novel role of caspase-2 as a translational regulator of p21 expression occurs not only independently of its enzymatic activity, but does also not require known caspase-2-activating platforms.

Mots clés: apoptosis; cell cycle; translational control; 3'-UTR; p53

Reiner Udo Jänicke, Dennis Sohn, Wilfried Budach. Caspase-2 is required for DNA damage-induced expression of the CDK inhibitor p21WAF1/CIP1. Cell Death and Differentiation, 2011, ⟨10.1038/cdd.2011.34⟩. ⟨hal-00630274⟩