Caspase‐2 exists as two main isoforms: the caspase‐2L long isoform, which is pro‐apoptotic, and the caspase‐2S short isoform, which may be anti‐apoptotic. Topoisomerase inhibitors drive inclusion of exon 9, specific for Casp‐2S mRNA, and lower Casp‐2S mRNA and protein. With cell lines engineered to express various PKC isoforms, we demonstrate that PKC zeta, but not PKCalpha, positively regulates Casp‐2S mRNA assembly triggered by topoisomerase inhibitors. In addition, exon 9 inclusion is lowered in mitosis but increased in the G1/S phase. Hence, the control of caspase‐2 exon 9 inclusion by topoisomerase inhibitors depends on phosphorylation and/or dephosphorylation events, and on the cell cycle phase.