Kang, R, Zeh, HJ, Lotze, MT and Tang, D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 18: 571-580

Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
Cell death and differentiation (Impact Factor: 8.18). 02/2011; 18(4):571-80. DOI: 10.1038/cdd.2010.191
Source: PubMed


Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP(3)R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy. In contrast, the BH3 domain of Beclin 1 is bound to, and inhibited by Bcl-2 or Bcl-XL. This interaction can be disrupted by phosphorylation of Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk between apoptosis and autophagy. Beclin 1 dysfunction has been implicated in many disorders, including cancer and neurodegeneration. Here, we summarize new findings regarding the organization and function of the Beclin 1 network in cellular homeostasis, focusing on the cross-regulation between apoptosis and autophagy.

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    • "The CISD2 protein has commonly been observed to interact with the autophagy regulator BCL2. BCL2 exerts anti-apoptotic effects by antagonizing Beclin 1; however, the binding of CISD2 to BCL2 regulates autophagy/apoptosis in response to stress [15]. CISD2 has also been shown to depress calcium stores in the endoplasmic reticulum (ER) [16]. "
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    ABSTRACT: Background: CISD2 is known to have roles in calcium metabolism, anti-apoptosis, and longevity. However, whether CISD2 is involved in the inflammatory response associated with injuries of the central nervous system (CNS) remains unclear. This issue is particularly relevant for traumatic spinal cord injuries (SCIs), which lack therapeutic targeting and often cause long-term disability in patients. The authors previously demonstrated the neuroprotective effects of curcumin against RANTES-mediated neuroinflammation. In this study, we investigated (1) the role of CISD2 in injury-induced inflammation and (2) whether curcumin influences CISD2 expression in acute SCI. Materials and methods: The efficacy of curcumin treatment (40mg/kg i.p.) was evaluated in an animal model of SCI. In a neural cell culture model, lipopolysaccharide (LPS) was administrated to induce inflammation with the aim of mimicking the situation commonly encountered in SCI. Additionally, knockdown of CISD2 expression by siRNA (siCISD2) in LPS-challenged neural cells was performed to verify the causal relationship between CISD2 and SCI-related inflammation. Results: The injuries were shown to reduce CISD2 mRNA and protein expression in vivo, and CISD2-positive cells were upregulated by the curcumin treatment. LPS led to a decrease in CISD2 expression in vitro; however, treatment with 1μM curcumin attenuated the downregulation of CISD2. Furthermore, in a cellular model of LPS-induced injury, the loss of CISD2 function caused by siCISD2 resulted in a pronounced iNOS increase as well as a decrease in BCL2 expression. Conclusions: To the best of our knowledge, this is the first study to report the following: (1) CISD2 exerts anti-apoptotic and anti-inflammatory effects in neural cells; and (2) curcumin can attenuate the downregulation of CISD2 in SCI and LPS-treated astrocytes.
    Injury 09/2015; DOI:10.1016/j.injury.2015.07.040 · 2.14 Impact Factor
    • "Beclin-1 is also an important protein during the autophagy process. The autophagy level can be up-regulated by the over-expression of Beclin-1 (Kang et al., 2011). In this study, the level of Beclin-1 expression was increased in MWCNTs-treated rats. "
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    ABSTRACT: Multi-walled carbon nanotubes (MWCNTs) have shown potential applications in many fields, especially in the field of biomedicine. Several studies have reported that MWCNTs induce apoptosis and oxidative damage in nerve cells during in vitro experiments. However, there are few studies focused on the neurotoxicity of MWCNTs used in vivo. Many studies have reported that autophagy, a cellular stress response to degrade damaged cell components, can be activated by diverse nanoparticles. In this study, we investigated the neurotoxic effects of MWCNTs on hippocampal synaptic plasticity and spatial cognition in rats. Then, we used an inhibitor of autophagy called chloroquine (CQ) to examine whether autophagy plays an important role in hippocampal synaptic plasticity, since this was damaged by MWCNTs. In this study, adult male Wister rats were randomly divided into three groups: a control group, a group treated with MWCNTs (2.5mg/kg/day) and a group treated with MWCNTs+CQ (20mg/kg/day). After two-weeks of intraperitoneal (i.p.) injections, rats were subjected to the Morris water maze (MWM) test, and the long-term potentiation (LTP) and other biochemical parameters were determined. Results showed that MWCNTs could induce cognitive deficits, histopathological alteration and changes of autophagy level (increased the ratio of LC3 II /LC3 I and the expression of Beclin-1). Furthermore, we found that CQ could suppress MWCNTs-induced autophagic flux and partly rescue the synapse deficits, which occurred with the down-regulation of NR2B (a subunit of NMDA receptor) and synaptophysin (SYP) in the hippocampus. Our results suggest that MWCNTs could induce cognitive deficits in vivo via the increased autophagic levels, and provide a potential strategy to avoid the adverse effects of MWCNTs. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Toxicology 08/2015; DOI:10.1016/j.tox.2015.08.011 · 3.62 Impact Factor
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    • "Beclin 1, the mammalian homolog of Atg6, enhances autophagy by combining with PI3KIII in the initiating stage of autophagy. And, the tumor suppressor function of Beclin 1 is supported by identification of its mediators in tumorigenesis (Kang et al., 2011). UVRAG, a major Beclin 1 positive mediator, can interact with Beclin 1 by interacting with Beclin1. "
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