Caspase-2 as a master regulator of genomic stability.

Genomic instability underlies genesis and the development of various types of cancer. During tumorigenesis, cancer initiating cells assume a set of features, which allow them to survive and proliferate. Different mutations and chromosomal alterations promote a selection of the most aggressive cancer clones that worsen the prognosis of the disease. Despite that caspase-2 was described as a protease fulfilling an initiator and an effector function in apoptosis, it has recently been discovered to play an important role in the maintenance of genomic integrity and normal chromosome configuration. This protein is able to stabilize p53 and affect the level of transcription factors, which activates cell response to oxidative stress. Here we focus on the discussion on the mechanism(s) of how caspase-2 regulates genomic stability and decreases tumorigenesis. Tumors in caspase-2 knockout mice grow rapidly and contain more cells with chromosomal aberrations in contrast to wild-type littermates. An accumulation of genomic disturbances, such as supernumerary centrosomes, activates caspase-2 via PIDDosome formation that restricts the proliferation of polyploid cells. Active caspase-2 can cleave Mdm2 and promote the stabilization of p53 level in response to centrosome amplification, which promotes genomic instability and cell neoplastic transformation. Caspase-2 helps to maintain genomic stability, decreasing the level of oxidative stress and DNA damage. Caspase-2 acts as tumor suppressor via its ability to eliminate cells with chromosomal perturbations or after mitotic insults. [ABSTRACT FROM AUTHOR]