Cellular Mechanisms Controlling Caspase Activation and Function

Abstract

Caspases are the primary drivers of apoptotic cell death, cleaving cellular proteins that are critical for dismantling the dying cell. Initially translated as inactive zymogenic precursors, caspases are activated in response to a variety of cell death stimuli. In addition to factors required for their direct activation (e.g., dimerizing adaptor proteins in the case of initiator caspases that lie at the apex of apoptotic signaling cascades), caspases are regulated by a variety of cellular factors in a myriad of physiological and pathological settings. For example, caspases may be modified posttranslationally (e.g., by phosphorylation or ubiquitylation) or through interaction of modulatory factors with either the zymogenic or active form of a caspase, altering its activation and/or activity. These regulatory events may inhibit or enhance enzymatic activity or may affect activity toward particular cellular substrates. Finally, there is emerging literature to suggest that caspases can participate in a variety of cellular processes unrelated to apoptotic cell death. In these settings, it is particularly important that caspases are maintained under stringent control to avoid inadvertent cell death. It is likely that continued examination of these processes will reveal new mechanisms of caspase regulation with implications well beyond control of apoptotic cell death.

Inhibition of AKT/FoxO3a signaling induced PUMA expression in response to p53-independent cytotoxic effects of H1: A derivative of tetrandrine

“…For example, caspase-3 is a main caspase effector. 19 Thus, we detected the effect of H1 on activity of caspase-3. As seen in Figure 2D, H1 significantly increased the caspase-3 activity in a concentration-dependent manner.…”

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…ICE cleaves pro-IL-1b to yield active cytokine; however, it does so in the absence of apoptosis induction (Black et al 1989a;Kostura et al 1989). Based on multiple reports revealing the functional roles and activation mechanisms of caspases, caspases are now divided into three functional groups: apoptosis induction (caspase-2, -3, -6, -7, -8, -9, and -10) (Guo et al 2002;Kischkel et al 2001;Parrish et al 2013), inflammatory responses (caspase-1, -4, -5, and -12) (Bian et al 2011;Black et al 1989a;Kostura et al 1989;Lamkanfi et al 2004;Sollberger et al 2012), and differentiation (caspase-14) (Denecker et al 2008) (Fig. 1).…”

Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

“…It makes sure cells are destroyed in an organized manner, without losing the structure of the surrounding tissue [100] or bringing harmful molecules in its environment that could trigger inflammation [21].…”