Bcl-2 family members: Dual regulators of apoptosis and autophagy

Levine, Beth; Sinha, Sangita C.; Kroemer, Guido

doi:10.4161/auto.6260

Cited by 751 publications

(633 citation statements)

References 63 publications

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“…Why Beclin-1 is different from other BH3-only proteins is still unclear. The sufficiency of the Beclin-1 BH3-domain alone to induce apoptosis through its binding to Bcl-xL (Maiuri et al, 2007a, b) has raised the suggestion that there are counteracting regulatory sequences that may normally prevent the BH3 motif in Beclin-1 from activating apoptosis when present within the full-length protein, as discussed by Levine et al (2008). Different binding interactions for the BH3-domain of Beclin-1 bound to Bcl-xL compared with other BH3-domains were also reported (Feng et al, 2007;Oberstein et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, autophagy was required for necrotic death of neuronal cells in C. elegans (Samara et al, 2008), for stress-mediated necrosis in apoptosis-deficient BaxÀ/ÀBakÀ/À mouse embryonic fibroblasts (MEFs) (Shimizu et al, 2004;Ullman et al, 2008) and loss of autophagy through deletion of Atg7 rescued neurons from death after hypoxia/reperfusion (Koike et al, 2008). Resolving the relationship between autophagy and apoptosis is especially complex, as both are induced by similar stimuli and impact on each other's functions (Maiuri et al, 2007c;Levine et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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“…Accumulating evidence points to the existence of an interaction between Bcl-2 and Beclin1. The binding of Bcl-2 to Beclin1 inhibits autophagy via sequestration of Beclin1 away from class III phosphoinositide 3-kinase (PI3K) [20][21][22]. AMPK activation also results in the disruption of the association between Beclin1 and Bcl-2, allowing the free Beclin1 to bind to class III PI3K to form the kinase complex, which is essential for the induction of autophagy [8,23].…”

Section: Discussionmentioning

confidence: 99%

MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice

Zhang

et al. 2016

Diabetologia

110

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Aims/hypothesis Diabetic cardiomyopathy (DCM) is associated with suppressed autophagy and augmented apoptosis in the heart although the interplay between the two remains elusive. The ability of mammalian sterile 20-like kinase 1 to regulate both autophagy and apoptosis prompted us to investigate it as a possible candidate in the progression of DCM. Methods Wild-type, Mst1 (also known as Stk4) transgenic and Mst1-knockout mice were challenged with streptozotocin to induce experimental diabetes. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe mechanisms. Results Mst1 knockout alleviated while Mst1 overexpression aggravated cardiac dysfunction in diabetes. Diabetic Mst1 transgenic mice exhibited decreased LC3 expression and enhanced protein aggregation. In contrast, typical autophagosomes were observed in diabetic Mst1-knockout mice with increased LC3 expression and reduced protein aggregation. Mst1 downregulation promoted autophagic flux as demonstrated by increased LC3-II and decreased p62 expression in the presence of bafilomycin A1. Furthermore, Mst1 overexpression increased, while Mst1 knockout decreased, cardiomyocyte apoptosis both in vivo and in vitro. Coimmunoprecipitation assays showed that Mst1 overexpression promoted Beclin1 binding to B cell lymphoma 2 (Bcl-2) and induced dissociation of Bcl-2 from Bax in diabetic mice. Conversely, Mst1 knockout disrupted the Beclin1-Bcl-2 complex and enhanced the interaction between Bcl-2 and Bax. Conclusions/interpretation Mst1 knockout restores autophagy and protects against apoptosis in cardiomyocytes, en route to the rescue against DCM.

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“…BCL10 gene contributes to the proliferation of lymphocytes through activating NF-jB signaling and induces apoptosis through the recruitment of caspases (Du and Isaccson 2002;Willis et al 1999). B-cell lymphoma 2 (Bcl-2) gene encodes an anti-apoptotic protein, which is overexpressed in several types of cancer such as leukemia, breast cancer, melanoma, and prostate cancer and its overexpression often results in drug resistance (Karnak and Xu 2010;Levine et al 2008). In addition to the regulation of apoptosis, Bcl-2 also inhibits autophagy via forming a complex with Beclin-1 (Marquez and Xu 2012).…”

Section: Discussionmentioning

confidence: 99%

New indication for therapeutic potential of an old well-known drug (propranolol) for multiple myeloma

Kozanoğlu

Yandım

Çinçin

et al. 2012

J Cancer Res Clin Oncol

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Purpose Propranolol, a non-selective b-adrenergic receptor blocker, has been used for the treatment of the patients with hypertension for more than 50 years. There are several in vitro and in vivo evidences that b-adrenergic receptor antagonists inhibit proliferation and angiogenesis and also increase apoptosis in breast, skin, and colon cancers. The aim of this study was to investigate the cytotoxic and apoptotic effects of propranolol and the genes involved in propranololinduced apoptosis in multiple myeloma cells. Methods Time-dependent antiproliferation and apoptotic effects of propranolol were subsequently determined by MTT cell proliferation assay, changes in caspase-3 activity, loss of mitochondrial membrane potential (MMP), and also the localization of phosphatidylserine in the plasma membrane. Changes in expression levels of NF-JB pathway were examined by qRT-PCR array.Results IC50 values of propranolol on U266 cells were calculated as 141, 100, and 75 lM after 24-, 48-, and 72-h propranolol exposure, respectively. There were significant increases in caspase-3 activity, loss of MMP, and increases in apoptotic cell population in response to propranolol in U266 cells in a time-and dose-dependent manner. There were increases in expression levels of BCL10, TRAF family members, interleukins, TLR1-4, TNFRSF10B, NFjB, and the inhibitors of NF-jB genes, and significant decreases in expression levels of Bcl-2 in response to propranolol treatment were observed. Conclusion These results revealed that propranolol has antiproliferative and apoptotic effects on multiple myeloma cells. Being supported with in vivo analyses, propranolol can be a good and economical way to treat multiple myeloma patients.

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Bcl-2 family members: Dual regulators of apoptosis and autophagy

Cited by 751 publications

References 63 publications

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

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

MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice

New indication for therapeutic potential of an old well-known drug (propranolol) for multiple myeloma

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