Cell death in the third millennium

Drug Development Research, 2001

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.

Current Opinion in Cell Biology, 2002

Biochemical and Biophysical Research Communications, 1997

these cysteine proteases, the caspases, has been Programmed cell death (PCD), a genetically conadopted (2). The activation of pro-caspase zymogens trolled cell deletion process, plays an important role has been detected in numerous cell systems and apin the regulation of cellular and tissue homeostasis. pears to function as a potential pathway through which The requisite for proteolysis during PCD-induced PCD mechanisms may operate. The interaction beapoptosis is well documented. The cellular proteolytic tween other enzyme activities, either proximal or distal machinery includes numerous proteases localized in to the cleavage and activation of the pro-caspases, is membranes, cytoplasm, and nucleus. This machinery the subject of rapidly evolving research. Therefore, it may function to remove denatured or misfolded probecomes necessary to outline the activation potential tein from the cytoplasm on a routine basis and may of the pro-caspases as currently understood.

Journal of Research and Practice in Dentistry, 2014

Apoptosis is considered as a tightly regulated active process signified by specific morphological and biochemical. On contrary to apoptosis, necrosis is a passive, energy independent pathologic process. The significance of understanding the apoptosis cascade mechanism is imperative as apoptosis being component of both physiological and pathological process. Apoptosis can be stimulated by both physiological and pathological conditions and hence play a role in maintenance of normal homeostasis and in pathogenesis of several diseases. Signaling for apoptosis occurs via caspase dependent and independent pathways that are initiated either from triggering events within the cell or from outside the cell by ligation of death receptors. Present review aims to provide an overview regarding apoptosis, its morphological and biochemical characterstics, its mechanism and its implication in health and diseases.

Experimental oncology, 2012

The story of cell death began with the origins of cell biology, including important observations by Elie (Ilya) Metchnikoff, who realized that phagocytes engulfed dying cells. Most of the early studies were observational. By the middle of the 20th C, researchers were beginning to explore how cells died, had recognized that cell death was a physiologically controlled process, that the most common mode of death ("shrinkage necrosis", later apoptosis) was tightly controlled, and were speculating whether lysosomes were "suicide bags". Just prior to 1990 several discoveries led to rapid expansion of interest in the field and elucidation of the mechanisms of apoptosis. Closer to the beginning of the 21st C comprehensive analysis of the molecules that controlled and effected apoptosis led to the conclusion that autophagic processes were linked to apoptosis and could serve to limit or increase cell death. Today, realizing that knowledge of the components of cell death ha...

Cell Death and Differentiation, 1999

Apoptosis, 2006

Apoptosis is the regulated form of cell death utilized by metazoans to remove unneeded, damaged, or potentially deleterious cells. Certain manifestations of apoptosis may be associated with the proteolytic activity of caspases. These changes are often held as hallmarks of apoptosis in dying cells. Consequently, many regard caspases as the central effectors or executioners of apoptosis. However, this "caspase-centric" paradigm of apoptotic cell death does not appear to be as universal as once believed. In fact, during apoptosis the efficacy of caspases may be highly dependent on the cytotoxic stimulus as well as genetic and epigenetic factors. An ever-increasing number of studies strongly suggest that there are effectors in addition to caspases, which are important in generating apoptotic signatures in dying cells. These seemingly caspase-independent effectors may represent evolutionarily redundant or failsafe mechanisms for apoptotic cell elimination. In this review, we will discuss the molecular regulation of caspases and various caspaseindependent effectors of apoptosis, describe the potential context and/or limitations of these mechanisms, and explore why the understanding of these processes may have relevance in cancer where treatment is believed to engage apoptosis to destroy tumor cells.

Oncogene, 2001

Trends in Immunology, 2001

Biological Chemistry, 2002

activation of pro-inflammatory cytokines or in the promotion and execution of apoptosis (Zheng et al., 1999; Ranger et al., 2001). Caspases, which in their active form are heterodimers, consist of two identical catalytic domains with the exception of caspase-9. They are synthesized as single chain precursors and remain in their latent form (zymogen) in the cytosol until the apoptotic stimuli are transmitted (Salvesen and Dixit, 1997). Caspase activation, which requires proteolytic processing at Asp residues in order to generate the heavy and the light chain and to remove the N-terminal propeptide, is therefore a critical step in apoptosis and can be achieved in several ways (Figure 1). There are two major ways of initiating the caspase-activation cascade. The first, also called the extrinsic pathway, involves TNF receptor family members oligomerization and subsequent recruitment of procaspases 8 and probably 10 through DED/DD domain containing adaptor molecules (e.g. FADD) to the DISC (death-inducing signaling complex) complex (Krammer, 2000; Kischkel et al., 2001). In the other, so-called intrinsic pathway, cytochrome c, released from mitochondria, induces cytosolic factor (APAF-1) oligomerization and apoptosome formation (Acehan et al., 2002). Procaspase 9 is then recruited to the apoptosome through CARD-CARD domain interaction (Cain et al., 2000; Bratton et al., 2001). In both pathways, DISC or apoptosome-bound initiator procaspases 8 and 9 are activated by autoactivation due to their increased local concentration and the intrinsic activity of the zymogen (Salvesen and Dixit, 1999). In the next step, common to both pathways, activated initiator caspases directly activate executioner caspases (3, 6, 7), followed by death substrate cleavage-and the execution phase of apoptosis has started (Nicholson, 1999; Hengartner, 2000). The whole signal can be amplified in case of the caspase 9 pathway by caspase 3 activating caspases 8 and 10 (Slee et al., 1999; Van de Craen et al., 1999). BID, a pro-apoptotic member of the Bcl-2 family serves as a link between the extrinsic and intrinsic apoptotic pathways (Li et al., 1998; Luo et al., 1998). Following cleavage by caspase 8 at Asp 59, which removes the N-terminal helix, tBid (truncated Bid) is targeted to mitochondria, where it induces a conformational change in Bax or Bak. This conformational change is necessary to induce Bax/Bak oligomerization and integration within the mitochondrial membrane and subsequent cytochrome c release (Korsmeyer et al., 2000; Wei et al., 2001). The whole system is additionally regulated and accidentally activated caspases are inhibited by IAPs (Deveraux and Reed,