Ways of dying: multiple pathways to apoptosis.

By Jerry M. Adams. Genes & Development, 2003

839 citations recorded by the source corpus.

In order to eliminate cells that are redundant, damaged, or infected, metazoan organisms have evolved the cell suicide mechanism termed apoptosis (Kerr et al. 1972). This genetic program is vital for normal development, for maintenance of tissue homeostasis, and for an effective immune system. Not surprisingly therefore, its disturbance is implicated in numerous pathological conditions, ranging from degenerative disorders to autoimmunity and cancer (Cory and Adams 2002; Cory et al. 2003). The cell’s death throes are choreographed by a set of previously dormant proteases, the caspases, which cleave several hundred cellular substrates (Thornberry and Lazebnik 1998). Two principal pathways to caspase activation have been recognized. One is triggered by engagement of so called “death receptors” on the cell surface (Strasser et al. 2000; Ashkenazi 2002). The other, of more ancient origin, is provoked by various forms of stress, including inadequate cytokine support and diverse types of intracellular damage. During stress, the cell’s decision on whether to invoke the suicide program—“to be or not to be”—rests primarily with the Bcl-2 family. Its interacting opposing members integrate developmental cues with the signals received from other cells and assess intracellular damage to determine whether to throw the caspase execution switch (Gross et al. 1999; Cory and Adams 2002; Cory et al. 2003). Early in stress-induced apoptosis of vertebrate cells, the outer membrane of the mitochondria is permeabilized, releasing cytochrome c and other death-promoting proteins (Newmeyer and Ferguson-Miller 2003). Because Bcl-2 can prevent this change, it has been widely assumed that commitment to all forms of stress-induced apoptosis, that is, all those regulated by the Bcl-2 family, requires this step to initiate all relevant caspase activation, and hence that Bcl-2 and its anti-apoptotic relatives function as guardians of mitochondrial integrity (Green and Reed 1998; Gross et al. 1999; Wang 2001). That viewpoint is challenged by recent findings. It will be argued here that in stress-induced apoptosis, as in death receptor signaling (Strasser et al. 2000; Ashkenazi 2002), caspases can be activated upstream or independently of mitochondria, and hence that the mitochondrial breach may often simply deliver the coup de grace to a cell already on the path to death. A related theme is that the Bcl-2 cohort must man checkpoints at several sites in the cell. Finally, the vexed unresolved issue of how the opposing factions of the Bcl-2 family govern caspase activation is addressed.

Subfields: Epidemiology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2be09be4f4e99eb027ac4eb18912bec78ff1057e

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Citations in the corpus

Free radicals and antioxidants in normal physiological functions and human disease. (2007, background): “More detailed accounts on apoptosis can be found in recent excellent reviews (Adams, 2003; Danial & Korsmeyer, 2004; Orrenius, Zhivotovsky, & Nicotera, 2003; Newmeyer & Ferguson-Miller, 2003).”
Life in the balance: how BH3-only proteins induce apoptosis. (2005, background): “Models for the activation of Bak and Bax Although BH3-only proteins require either Bax or Bak for cell killing [3,4], it remains unresolved whether they control the activation of Bax and Bak directly or indirectly [10].”
The role of mitochondria in apoptosis. (2008, background): “by providing many important factors including those that induce caspase activation and chromosome fragmentation (3).”
Apoptosis and cancer: mutations within caspase genes (2009, background): “10 Biochemically, the main features of apoptosis include caspase cascade activation and DNA fragmentation.(11) Mitochondria also play a key role in mediating apoptosis induced by diverse stimuli.”
Alkylating DNA damage stimulates a regulated form of necrotic cell death. (2004, background): “Apoptosis is characterized by the ordered cellular degradation of proteins and organelles, maintenance of plasma membrane integrity, and noninflammatory phagocytosis of the dying cell (Wang 2001; Adams 2003).”
Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. (2005, background): “…both Bax and Bak change conformation, and Bax translocates to the organellar membranes, where both Bax and Bak then form homooligomers that can associate, leading to membrane permeabilization (Hsu et al. 1997; Wolter et al. 1997; Antonsson et al. 2001; Wei et al. 2001; Mikhailov et al. 2003).”
Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. (2006, background): “Apoptosis is a well-defined process of cellular dismantling that leads to cell corpses that are engulfed by phagocytosis in the absence of an inflammatory response and is a means for cell elimination in development (Adams, 2003; Danial and Korsmeyer, 2004).”
Inhibition of Macroautophagy Triggers Apoptosis (2005, background): “At the biochemical level, apoptosis of mammalian cells is characterized by mitochondrial membrane permeabilization (MMP) and/or massive caspase activation (1, 21, 68).”
Role of Bcl-2 family proteins and caspases in the regulation of apoptosis (2011, background): “Apoptosis, also known as programmed cell death (PCD), plays an integral role in a variety of biological events including morphogenesis, tissue homeostasis, aging, and removal of unwanted harmful cells [2].”
Crosstalk between apoptosis, necrosis and autophagy. (2013, background): “Apoptosis may be triggered either by extrinsic stimuli through cell surface death receptors, such as TNF α (tumor necrosis factor-α ), Fas (CD95/APO1) and TRAIL (TNF related apoptosis inducing ligand) receptors or by intrinsic stimuli via the mitochondrial signaling pathway [2,3].”