title: Caspase-2 is required for DNA damage-induced expression of the CDK inhibitor p21(WAF1/CIP1).
abstract: 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, whereas overexpression of a caspase-2 mutant increased p21 levels. Caspase-2 did not influence p21 mRNA transcription; moreover, 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 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, which prevented p21 expression and thereby reverted the γ-IR-induced senescent phenotype of wild-type HCT116 colon carcinoma cells into apoptosis, knockdown of none 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 also does not require known caspase-2-activating platforms.
authors.affiliation: Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, University of Düsseldorf, Universitätsstrasse 1, Düsseldorf 40225, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Sohn
authors.forename: W
authors.initials: W
authors.lastname: Budach
authors.forename: R U
authors.initials: RU
authors.lastname: Jänicke
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans
chemical_list: D020413:3' Untranslated Regions; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D053143:Caspase 2