Ways of dying: multiple pathways to apoptosis

Adams, Jerry M.

doi:10.1101/gad.1126903

Cited by 708 publications

(566 citation statements)

References 155 publications

Supporting

Mentioning

538

Contrasting

Unclassified

Order By: Relevance

“…Apoptotic caspases include "initiator caspases" (caspase-2, −8, −9 and −10) that start an apoptotic cascade and "effector caspases" (caspase-3, −6 and −7) that disassemble the cell. Different pathways leading to caspase activation have been characterized (44). Diverse stimuli cause release of mitochondrial proteins to activate the intrinsic apoptosis pathway (45) leading to MOMP and the release of cytochrome c and other apoptogenic proteins (46).…”

Section: Regulation Of Apoptosismentioning

confidence: 99%

Apoptosis and autophagy: regulatory connections between two supposedly different processes

2007

View full text Add to dashboard Cite

Apoptosis and autophagy are genetically-regulated, evolutionarily-conserved processes that regulate cell fate. Both apoptosis and autophagy are important in development and normal physiology and in a wide range of diseases. Recent studies show that despite the marked differences between these two processes, their regulation is intimately connected and the same regulators can sometimes control both apoptosis and autophagy. In this review, I discuss some of these findings, which provide possible molecular mechanisms for crosstalk between apoptosis and autophagy and suggest that it may be useful to think of these processes as different facets of the same cell death continuum rather than completely separate processes. KeywordsAutophagy; Apoptosis; Bcl-2, FADD; Atg 5In the early to mid 1990s there was a rapid increase in our understating about the regulation of apoptosis. Fifteen or so years later we are in the midst of a similarly exciting period for understanding autophagy with very rapid growth of publications on the regulation and function of this process (1). Autophagy (the form of autophagy discussed here is macroautophagy, other forms-microautophagy and chaperone-mediated autophagy share the same lysosomal degradation mechanism but differ in the way that material is delivered to the lysosome) is a degradative process involving sequestration of parts of the cytoplasm in double membrane vesicles (autophagic vesicles or autophagosomes) that fuse with lysosomes forming the autophagolysosome. In the autophagolysosome, the cytoplasmic material that was engulfed is hydrolyzed and the resulting amino acids and other macromolecular precursors can be recycled (2-4), see Fig 1 for a schematic of the process. Autophagy is a mechanism by which organelles are removed and is the primary degradation mechanism for long-lived proteins and thus maintains quality control for proteins and organelles. Autophagy is ubiquitous in eukaryotic cells and important in development and in diverse pathophysiological conditions (5)-for example providing protection against neurodegeneration (6,7), infections (8,9) and tumor development (10-13). Cells that are deficient in autophagy also demonstrate enhanced chromosomal instability (14,15), which may be related to the tumorigenesis associated with autophagy deficiency.Autophagy is important in cell death decisions and can protect cells by preventing them from undergoing apoptosis. For example, increased autophagy in nutrient deprived or growth factorwithdrawn cells allows cell survival (16,17) by inhibiting apoptosis. Autophagy also protects cells from various other apoptotic stimuli (18). It is not clear how autophagy stops cells from undergoing apoptosis; one suggested mechanism is the sequestration of damaged mitochondria (18) thus preventing released cytochrome c from being able to form a functional apoptosome NIH Public Access Autophagic cell death (also known as Type II programmed cell death to distinguish it from apoptosis or Type I programmed cell death) (20-22) has been describ...

show abstract

Section: Regulation Of Apoptosismentioning

confidence: 99%

Apoptosis and autophagy: regulatory connections between two supposedly different processes

2007

View full text Add to dashboard Cite

show abstract

“…t-Bid-mediated MOMP has also been reported to involve obligatory interactions with carnitine palmitoyl transferase 1 (Giordano et al, 2005) or mitochondrial carrier homolog 2 (Grinberg et al, 2005). Other proapoptotic proteins from the Bcl-2 family such as Bcl-2 antagonist of cell death (Bad), Bcl-2-interacting mediator of cell death (Bim), and Noxa are believed to induce apoptosis via an interaction with either Bax or Bak and/or by generating stable complexes with antiapoptotic Bcl-2/Bcl-X L (Adams, 2003).…”

Section: Mitochondrial Membrane Permeabilization: the Central Event Omentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

View full text Add to dashboard Cite

Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

show abstract

“…As pointed out by Adams (2003) in their review, apoptosis can be simultaneously mediated by two or more signal pathways, but their relative importance is different in response to specific stimuli. For instance, many cell types such as astrocytes (Liu et al 2004), mouse embryonic fibroblasts (Masud et al 2007;Sanges and Marigo 2006), Hela cells (Xu et al 2006), and human teratoma cells (Ferreiro et al 2008) undergo apoptosis through both mitochondrial and ER pathway, and there is evidence showing that both death receptor and mitochondrial pathway simultaneously contribute to disc cell apoptosis (Park et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Both endoplasmic reticulum and mitochondria are involved in disc cell apoptosis and intervertebral disc degeneration in rats

Zhao

Zhang

Jiang

et al. 2009

AGE

View full text Add to dashboard Cite

Intervertebral disc cell apoptosis occurs through either death receptor or mitochondrial pathway, but whether disc cell apoptosis is also mediated by the endoplasmic reticulum (ER) pathway remains unclear. The objective of this study was to investigate whether ER and mitochondria are co-involved in disc cell apoptosis and intervertebral disc degeneration (IVDD) in rats. Forty-eight rats were used for in vivo experiments. IVDD was characterized by X-ray and histomorphology examination, disc cell apoptosis was detected by TUNEL staining, and the co-involvement of ER and mitochondria in apoptosis was determined by immunohistochemical staining for GRP78, GADD153, caspase-12, and cytochrome C. Additional eight rats were used for annular cell isolation and culture. After sodium nitroprusside treatment, annular cell apoptosis was observed morphologically and quantified by flow cytometry; the expression of biomarkers of ER stress and mitochondrial dysfunction were analyzed by reverse transcriptase PCR (RT-PCR), fluorescence double labeling, and Western blot; and mitochondrial membrane potential was detected by 5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbo cyanine iodide (JC-1) staining. Finally, NS3694 and Z-ATAD-FMK were employed to inhibit the formation of apoptosome complex and the activation of caspase-12, respectively, and apoptotic incidence and caspase-9 activity were assayed. We found that IVDD, induced by unbalanced dynamic and static forces in the rats, was accompanied by increased disc cell apoptosis and enhanced expression of GRP78, GADD153, caspase-12, and cytochrome C. Annular cell apoptosis induced by sodium nitroprusside was confirmed by morphologic observation and flow cytometry. With increased apoptosis, the expression of GRP78, GADD153, and caspase-12 upregulated, mitochondrial membrane potential decreased, and accumulation of cytochrome C in the cytosol manifested. Furthermore, NS3694 and Z-ATAD-FMK dramatically suppress annular cell apoptosis and caspase-9 activity. In conclusion, disc cell apoptosis mediated simultaneously by ER and mitochondria plays a potent role in IVDD.

show abstract

Ways of dying: multiple pathways to apoptosis

Cited by 708 publications

References 155 publications

Apoptosis and autophagy: regulatory connections between two supposedly different processes

Apoptosis and autophagy: regulatory connections between two supposedly different processes

Mitochondria as therapeutic targets for cancer chemotherapy

Both endoplasmic reticulum and mitochondria are involved in disc cell apoptosis and intervertebral disc degeneration in rats

Contact Info

Product

Resources

About