Caspases and proliferation

Abstract

Cysteine-proteases belonging to the family of caspases have been described as central executioners of apoptotic signals. The relevance of apoptosis in T cell homeostasis is primarily defined by the necessity to quickly and efficiently eliminate effector T lymphocytes subsequent to clonal expansion and differentiation. This process is executed through the activation of caspases. Apoptosis can be initiated by interaction of the death receptor Fas with its ligand, triggering a signaling cascade comprising Fas-associated death domain protein (FADD), caspase-8 and caspase-3, culminating in cell death. Surprisingly, emerging evidence suggests a contribution of these molecules also in non-apoptotic and even proliferative signals. The potentially dual role of caspases does not seem to be restricted to T cells but is observed in other cells of the hematopoietic lineage as well. A block of the FADD/caspase-signaling pathway, either by inserting mutations or by using pharmacological inhibitors, not only leads to resistance of cells to apoptotic stimuli, but also negatively affects growth responses. Despite large research effort, the exact molecular mechanism how caspases mediate proliferation remains to be clarified. This review summarizes facts and hypotheses about potential junctions, coupling the opposing signals leading to death or proliferation and discusses, under which circumstances active caspases might confer to either pathway.