Molecular machinery and signaling events in apoptosis

Abstract

Apoptosis is a process of major biomedical interest, since its ineffectiveness or inappropriate activation appears to be involved in the pathogenesis of a broad variety of human diseases (neoplasia, autoimmune disorders, viral and neurodegenerative diseases, to name a few). On this topic, extensive experimental work has allowed in the past years the clarification of the complex biochemical machinery that commits a cell to apoptosis and executes the death program. As to the signaling mechanisms, it is now evident that apoptosis can be initiated by different stimuli and/or genetic programs that are differentially decoded inside the cell. While the past years have witnessed a major advancement on this topic, much still needs to be learned of the cross-talk between the various signaling pathways involved in decoding the apoptotic stimuli, as well as the activation of other cell functions. In this review we first describe the properties and activation mechanisms of the caspases, the effector proteases of apoptosis. In the second part we discuss the current evidence for the involvement of calcium, the ubiquitous second-messenger decoding a wide variety of physiological stimuli, and highlight the potential targets of the apoptotic calcium signal. Drug Dev. Res. 52:558-570, 2001.

Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum

“…As to kinases and phosphatases, a broad literature associates calcineurin and the different isoforms of PKC to the modulation of apoptosis (with specific, even opposite effect of different isoforms). 70,71 In the past years, however, major attention has been devoted to mitochondria, triggered by two important discoveries. The first was the demonstration of the release during apoptosis of a specific subset of mitochondrial proteins into the cytosol.…”

Mitochondrial calcium signalling in cell death

“…It now appears evident that massive Ca 2+ loading (as in the case of glutamate excitotoxicity of neurons) and ⁄ or the combined action of apoptotic agents or pathophysiological conditions (e.g. oxidative stress) can induce a profound alteration of organelle structure and function [34][35][36]. As a consequence, bioenergetic dysfunction and ⁄ or release into the cytosol of proteins acting as caspase cofactors, such as cytochrome c [37,38], AIF [39] and Smac ⁄ Diablo [40], may lead the cell to necrotic or apoptotic cell death.…”

Structural Determinants of the Calpain Inhibitory Activity of Calpastatin Peptide B27-WT

“…Calpain (EC 3.4.22.17), a nonlysosomal, intracellular calcium-activated neutral cysteine proteinase, has been implicated in a variety of important physiological processes, including signal transduction, cell proliferation and differentiation, and apoptosis (1)(2)(3)(4). The consequences of uncontrolled calpain activation have been witnessed in certain pathological conditions associated with excessive increases in intracellular Ca 2ϩ levels, namely, in tissue destruction after spine and brain injuries, neuronal injury after cardiac and brain ischemia, demyelination diseases (multiple sclerosis), muscular dystrophy, Alzheimer's disease, arthritis, and cataract formation (5,6).…”

“…This observation demonstrates the vigorous regulation placed on the calpaincalpastatin system whereby both enzyme and inhibitor are under strict Ca 2ϩ control. The primary structure of calpastatin is divided into four repeating inhibitory domains (domains [1][2][3][4] and an NH 2 -terminal domain that lacks inhibitory function (domain L) (6, 15-19; see Fig. 1).…”