Caspase-2: the reinvented enzyme

Abstract

On the basis of evidences that caspase-2 gene targeting in several generated mouse models accelerates tumor formation, this enzyme was recently implicated in tumor suppression. The observed function, however, compels other molecular perturbations harboring tumorigenic properties. Therefore, the question remains as to whether or not caspase-2 can be considered a true tumor suppressor? The traditional view of caspase-2 being vital for the apoptotic response to induced cell stress in some systems is in line with these findings. Yet, caspase-2 has also been associated with other processes which equally might interfere with tumorigenic potential, including the oxidative stress response, aging and genome surveillance. By different mechanisms, this enzyme has been proposed to function as a checkpoint regulator in the cell cycle. Together, these data indicate that caspase-2 is a highly versatile factor, a view that is contrasted by the alternative explanation where the enzyme harbors a mechanism affecting a discrete process, which in turn is functionally connected to other cell systems. In any case, it is clear that the general view of caspase-2 as a protein mainly involved in apoptotic cell death is shattered. Hence, we wish to discuss the perspectives of recent achievements in caspase-2-related research.

The Golgi complex in stress and death

“…Caspase-2 is an unusual caspase in that it possesses a long prodomain like inititator caspases, but does not activate effector caspases (Fava et al, 2012 ). Recent evidence suggests non-apoptotic roles for caspase-2 in maintaining genome stability, checkpoint regulation in the cell cycle, response to oxidative stress, tumor suppression and in aging (Olsson et al, 2015 ).…”

Protease signaling in animal and plant‐regulated cell death

“…The caspases can be divided into apoptotic caspases (red) and inflammatory caspases (orange). We have not included caspase-2 in the apoptotic caspases, as some would do, simply because the evidence for its role is so bewildering with many conflicting reports [181][182][183][184][185]. Caspase-14 is not an apoptotic caspase, and the closest relative to the caspases, the paracaspase MALT1 is a survival protease that operates via the NFkB pathway [186].…”

Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease

“…13 The primary function of caspase-2 remains to be determined, however, because it has also been implicated in several other vital processes including regulation of cell cycle checkpoints, oxidative stress responses, autophagy and senescence. 14, 15, 16, 17 Intriguingly, caspase-2 mRNA expression is elevated in adipose tissue of rats fed high-fat diet. 18 Recently, caspase-2-initiated apoptosis was associated with lipotoxicity caused by accumulation of saturated fatty acids in frog oocytes, 19 cultured mouse hepatocytes, and in mouse and human NAFLD.…”