Rapamycin pre-treatment protects against apoptosis

Ravikumar, Brinda; Berger, Zdenek; Vacher, Coralie; O’Kane, Cahir J.; Rubinsztein, David C.

doi:10.1093/hmg/ddl036

Cited by 378 publications

(294 citation statements)

References 35 publications

Supporting

Mentioning

266

Contrasting

Unclassified

Order By: Relevance

“…We also measured the amount of apoptosis in HeLa cells when autophagy was inhibited by 3-methyladenine (Supplementary Figure S5). Although 3-methyladenine was toxic and its toxicity synergized with that of STS, as shown earlier in other cell systems (Ravikumar et al, 2006), nevertheless, the same amount of protection by Bcl-2 variants was found in cells expressing Bcl-2 alone, or Bcl-2 and Beclin-1 (measured by PARP cleavage). These results strengthen the conclusion that Beclin-1 does not prevent Bcl-2 from inhibiting apoptosis irrespective of whether autophagy is active or inactive.…”

Section: Resultssupporting

confidence: 72%

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

et al. 2009

View full text Add to dashboard Cite

The binding of Bcl-2 to Beclin-1 reduces Beclin-1's capacity to induce autophagy. Here, we have tested whether the interaction is reciprocated by loss of Bcl-2's anti-apoptotic function. We targeted Bcl-2 to mitochondria or endoplasmic reticulum (ER) and induced apoptosis using several apoptotic stimuli that initiate ER and/or mitochondrial signaling pathways (UV radiation, TNF and cycloheximide, staurosporine, thapsigargin and tunicamycin). When Beclin-1 and Bcl-2 were expressed together in HeLa cells, Beclin-1 (but not Beclin-1 lacking the Bcl-2-binding domain) followed Bcl-2 to the appropriate organelle with complete or near-complete overlap (comprising 60 and 30% of cells, respectively). The interaction between Beclin-1 and Bcl-2 was verified by immunoprecipitation, and a membrane-proximate localization of Beclin-1 was shown by immunoelectron microscopy. Apoptosis was followed by measuring changes in nuclear morphology, caspase-3 activity, poly-ADP-ribose polymerase cleavage or punctation of mRFP-Bax on mitochondria. Binding of Beclin-1 to Bcl-2 did not modify apoptosis irrespective of Bcl-2 concentration, location or apoptotic stimulus. A similar result was obtained in Atg5À/À cells that are autophagy-deficient, arguing against compensation for the loss of protection by Bcl-2 by autophagy-mediated survival induced by Beclin-1. Hence, although Beclin-1 contains a BH3-only motif typical of pro-apoptotic proteins, it is a negligible modulator of Bcl-2's anti-apoptotic function.

show abstract

Section: Resultssupporting

confidence: 72%

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

et al. 2009

View full text Add to dashboard Cite

show abstract

“…It has been shown that autophagy can either collaborate with apoptosis either to promote cell death or to prevent apoptotic cell death [38][39][40][41].…”

Section: Discussionmentioning

confidence: 99%

“…Given the potential role of both autophagy and BNIP3 in the regulation of cell death and cell survival, we investigated their putative role in etoposide-induced cell death and the protection provided by hypoxia. 40,000 cells were seeded on glass coverslips in 24-well culture plates. At the end of the incubation in serum-free CO 2 -independent medium (Invitrogen, Carlsbad, USA) supplemented with 1 mM L-glutamine (Sigma, St Louis, USA) with or without etoposide (Sigma, St Louis, USA) at 50 μM, under hypoxia or under normoxia, medium was removed and cells were fixed for 10 min with PBS containing 4% paraformaldehyde and then washed 3 x 5 min in PBS.…”

Section: Introductionmentioning

confidence: 99%

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

Cosse

Rommelaere

Ninane

et al. 2010

Biochemical Pharmacology

View full text Add to dashboard Cite

Tumor hypoxia is a common characteristic of most solid tumors and is correlated with poor prognosis for patients partly because hypoxia promotes resistance to cancer therapy. Hypoxia selects cancer cells that are resistant to apoptosis and allows the onset of mechanisms that promote cancer cells survival including autophagy. Previously, we showed that human hepatoma HepG2 cells were protected under hypoxia against the etoposide-induced apoptosis.In this study, respective putative contribution of autophagy and BNIP3 in the protection conferred by hypoxia against the etoposide-induced apoptosis was investigated. We report that autophagy is induced by etoposide, a process that is not affected by hypoxic conditions. Using Atg5 siRNA, we show that etoposide-induced autophagy promotes apoptotic cell death under normoxia but not under hypoxia. Then, we investigated whether the hypoxia-induced protein BNIP3 could explain the different effect of autophagy on cell death under hypoxia or normoxia. We show that the silencing of BNIP3 does not affect autophagy whatever the pO 2 but participates in the protective effect of hypoxia against etoposide-induced apoptosis.Together, these results suggest that autophagy might be involved in etoposide-induced cell death only under normoxia and that BNIP3 is a major effector of the protective mechanism conferred by hypoxia to protect cancer cells against etoposide-induced apoptotic cell death.

show abstract

“…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 in the cytoplasm.…”

mentioning

confidence: 99%

“…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 in the cytoplasm. Recent work suggests that autophagy can also protect cells from caspaseindependent death that occurs after Mitochondrial Outer Membrane Permeabilization (MOMP) in the presence of caspase inhibitors.…”

mentioning

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

Rapamycin pre-treatment protects against apoptosis

Cited by 378 publications

References 35 publications

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

Apoptosis and autophagy: regulatory connections between two supposedly different processes

Contact Info

Product

Resources

About