ABSTRACT
Caspases are well known for their indispensable role in programmed cell death (apoptosis). Comparative genetic and developmental studies in C. elegans, Drosophila, and mammals have provided extensive knowledge of programmed cell death during development (Baehrecke 2002). Furthermore, these studies reveal that physiological cell death occurs as a means to regulate several developmental processes such as control of cell number, tissue formation and elimination of abnormal cells. Of the 14 caspases evolutionary conserved among various species, caspase-3 has been classifi ed as the primary executioner of irreversible cell death (Th ornberry et al. 1997). Apoptotic events following caspase activation have typically been characterized by cellular morphological changes such as chromatin condensation, DNA fragmentation, cell shrinkage and phagocytosis (Kerr et al. 1972). Although caspase proteases have been conserved among various species, the belief that these proteins evolved solely as killing proteases seems highly improbable from a number of vantage points. For example, if the activation of these enzymes resulted only in death/apoptosis, then the cell would have to expend enormous energy to ensure these killing proteases remained absolutely docile. Secondly, the selective pressure to eliminate death only proteins would be extreme over evolutionary time. Of course, these evolutionary constraints would be greatly mitigated if the cell developed additional use or need for caspase proteases beyond cell death. Indeed, despite the initial studies that identifi ed caspase activity with irreversible cell death, a plethora of studies since have shed new insight into the functional non-apoptotic role of these cysteine proteases to positively regulate cell fate. Moreover, depending on the type of development some classical apoptotic phenotypes are observed without death of the cell occurring. Th e above advancements in understanding caspases as determinants of cell fate support establishing a new dogma that includes these pleiotroptic functions. We term this phenomenon addovita (addo to inspire; vita life) to encompass caspase function that involves cell fate decisions and cellular adaptations that are independent of cell death. Currently, active caspases have been identifi ed to regulate the fate of various cells at multiple developmental stages: proliferation, maturation, diff erentiation and self-renewal (Fig. 1).
