The p53-caspase-2 axis in the cell cycle and DNA damage response

Cancer: Enzyme stabilizes tumor suppressor protein Under conditions such as DNA damage or mitotic stress, the enzyme caspase-2 plays a vital role in regulating the stability of p53, a tumor suppressor protein. Caspases play multiple roles in cellular homeostasis, inflammation and programmed cell death. Sharad Kumar and colleagues at the Centre for Cancer Biology, UniSA in Adelaide, Australia, review current understanding of caspase-2 and its links with p53. Caspase-2 deficiency leads to defective p53 signaling, suggesting a regulatory link between the two molecules. Recent studies suggest that following DNA damage or cytokinesis failure caspase-2 cleaves MDM2, the p53 ubiquitin ligase, to stabilize p53. This prevents the proliferation of damaged cells, aneuploidy and accumulation of potentially premalignant cells. Reduced caspase-2 levels are associated with enhanced cancer progression in several models. The p53 regulatory function may explains this tumor suppressive activity of caspase-2. Caspase-2 was discovered almost three decades ago. It was one of the first two mammalian homologs of CED-3, the other being interleukin 1 beta-converting enzyme (ICE/caspase-1). Despite high similarity with CED-3 and its fly and mammalian counterparts (DRONC and caspase-9, respectively), the function of caspase-2 in apoptosis has remained enigmatic. A number of recent studies suggest that caspase-2 plays an important role in the regulation of p53 in response to cellular stress and DNA damage to prevent the proliferation and accumulation of damaged or aberrant cells. Here, we review these recent observations and their implications in caspase-2-mediated cellular death, senescence, and tumor suppression.

Automated summary

Caspase-2 plays a crucial role in response to cellular stress and DNA damage by stabilizing tumor suppressor protein p53, thereby preventing the proliferation and accumulation of damaged cells, thus suppressing cancer progression.