Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The beclin 1 (BECN1) gene encodes a 60-kDa coiled-coil protein that interacts with the prototypic apoptosis inhibitor Bcl-2. Previous studies indicate that beclin 1 maps to a region approximately 150 kb centromeric to BRCA1 on chromosome 17q21 that is commonly deleted in breast, ovarian, and prostate cancer. The complete cDNA sequence of beclin 1 encodes a 2098-bp transcript, with a 120-bp 5' UTR, 1353-bp coding region, and 625-bp 3' UTR. Hybridization screening of a human genomic PAC library identified PAC 452O8, which contains the complete beclin 1 gene. Determination of the exon-intron structure of beclin 1 reveals 12 exons, ranging from 61 to 794 bp, which extend over 12 kb of the human genome. FISH analysis of human breast carcinoma cell lines using PAC 452O8 as probe identified allelic beclin 1 deletions in 9 of 22 cell lines. Sequencing of genomic DNA from 10 of these cell lines revealed no mutations in coding regions or splice junctions. Additionally, Northern blot analysis of 11 cell lines did not identify any abnormalities in beclin 1 transcripts. These results indicate that human breast carcinoma cell lines frequently contain allelic deletions of beclin 1, but not beclin 1 coding mutations.
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PMID:Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. 1039

The process of autophagy, or bulk degradation of cellular proteins through an autophagosomic-lysosomal pathway, is important in normal growth control and may be defective in tumour cells. However, little is known about the genetic mediators of autophagy in mammalian cells or their role in tumour development. The mammalian gene encoding Beclin 1, a novel Bcl-2-interacting, coiled-coil protein, has structural similarity to the yeast autophagy gene, apg6/vps30, and is mono-allelically deleted in 40-75% of sporadic human breast cancers and ovarian cancers. Here we show, using gene-transfer techniques, that beclin 1 promotes autophagy in autophagy-defective yeast with a targeted disruption of agp6/vps30, and in human MCF7 breast carcinoma cells. The autophagy-promoting activity of beclin 1 in MCF7 cells is associated with inhibition of MCF7 cellular proliferation, in vitro clonigenicity and tumorigenesis in nude mice. Furthermore, endogenous Beclin 1 protein expression is frequently low in human breast epithelial carcinoma cell lines and tissue, but is expressed ubiquitously at high levels in normal breast epithelia. Thus, beclin 1 is a mammalian autophagy gene that can inhibit tumorigenesis and is expressed at decreased levels in human breast carcinoma. These findings suggest that decreased expression of autophagy proteins may contribute to the development or progression of breast and other human malignancies.
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PMID:Induction of autophagy and inhibition of tumorigenesis by beclin 1. 1060 74

Beclin 1 encodes a Bcl-2-interacting coiled-coil protein with autophagy and tumor suppressor function and is monoallelically deleted in 40-75% of sporadic human breast and ovarian cancers. Beclin 1 contains a leucine-rich nuclear export signal motif raising the possibility that its autophagy and/or tumor suppressor function may require regulated, CRM1-dependent, nucleocytoplasmic transport. In this study, we show that wild-type Beclin 1 colocalizes with both intracytoplasmic organelles and nuclei in COS7 monkey kidney and MCF7 human breast carcinoma cells. Inhibition of CRM1-dependent nuclear export with leptomycin B or mutation of the nuclear export signal motif of Beclin 1 results in predominantly nuclear localization. Unlike wild-type Beclin 1, the nuclear export mutant of Beclin 1 fails to promote nutrient deprivation-induced autophagy and fails to inhibit in vitro clonigenicity and in vivo tumorigenicity of MCF7 cells. Thus, beclin 1 has a leptomycin B-sensitive leucine-rich nuclear export signal that is required for its autophagy and tumor suppressor function. These findings suggest that the CRM1 nuclear export pathway may be important in the functional regulation of autophagic growth control.
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PMID:Beclin 1 contains a leucine-rich nuclear export signal that is required for its autophagy and tumor suppressor function. 1130 6

Beclin 1/Atg6 is an essential component of the evolutionary conserved PtdIns(3)-kinase (Vps34) protein complex that regulates macroautophagy (autophagy) in eukaryotic cells and also interacts with antiapoptotic Bcl-2 family members, Bcl-2, and Bcl-x(L). To elucidate the physiological function of Beclin 1, we generated transgenic mice producing a green fluorescent Beclin 1 protein (Beclin 1-GFP) under Beclin 1 endogenous regulation. The beclin 1-GFP transgene is functional because it completely rescues early embryonic lethality in beclin 1-deficient mice. The transgenic mice appear normal, with undetected change in basal autophagy levels in different tissues, despite the additional expression of functional Beclin 1-GFP. Staining of Beclin 1-GFP shows mostly diffuse cytoplasmic distribution in various tissues. Detailed analysis of the transgene expression by flow cytometry reveals a Bcl-2-like biphasic expression pattern in developing T and B cells, as well as differential regulation of expression in mature versus immature thymocytes following in vitro stimulation. Moreover, thymocytes expressing high Beclin 1-GFP levels appear increasingly sensitive to glucocorticoid-induced apoptosis in vitro. Our results, therefore, support a role for Beclin 1 in lymphocyte development involving cross talk between autophagy and apoptosis.
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PMID:BAC-mediated transgenic expression of fluorescent autophagic protein Beclin 1 reveals a role for Beclin 1 in lymphocyte development. 1845 70

Autophagy, an intracellular bulk degradation process of cellular constituents, plays a key role in cell homeostasis and can be induced by stresses, such as nutrient depletion, closed head injury or focal cerebral ischemia. This study focuses on the role of autophagy in neonatal hypoxia-ischemia (HI). Enhanced beclin 1 expression, a Bcl-2-interacting protein required for autophagy, has been used as a marker of autophagy. Beclin 1 was significantly increased at short times after HI, both in the hippocampus and in the cerebral cortex. Beclin 1-positive cells were found in the injured but not in the contralateral side and co-localized with MAP2 but not with GFAP or ED1, indicating that the protein is over-expressed in neurons. Beclin 1-positive cells were also TUNEL-positive. 3-Methyladenine and wortmannin, that inhibit autophagy, significantly reduced beclin 1 expression and switched the mechanism of the cell death mode from apoptosis to necrosis. Conversely, rapamycin, that increases autophagy, augmented beclin 1 expression, reduced necrotic cell death, and decreased brain injury. A prophylactic treatment with simvastatin or hypoxic preconditioning also increased beclin 1 expression. Taken together, these data indicate that autophagy is increased in neuronal cells after neonatal hypoxia-ischemia and suggest that over-activation of autophagic pathways represents a potential protective mechanism in the early stage of the brain injury.
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PMID:Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. 1876 Mar 64

Autophagy, an evolutionarily conserved process, has functions both in cytoprotective and programmed cell death mechanisms. Beclin 1, an essential autophagic protein, was recently identified as a BH3-domain-only protein that binds to Bcl-2 anti-apoptotic family members. The dissociation of beclin 1 from its Bcl-2 inhibitors is essential for its autophagic activity, and therefore should be tightly controlled. Here, we show that death-associated protein kinase (DAPK) regulates this process. The activated form of DAPK triggers autophagy in a beclin-1-dependent manner. DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy. These results reveal a substrate for DAPK that acts as one of the core proteins of the autophagic machinery, and they provide a new phosphorylation-based mechanism that reduces the interaction of beclin 1 with its inhibitors to activate the autophagic machinery.
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PMID:DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. 1918 Jan 16

Autophagy constitutes one of the major responses to stress in eukaryotic cells, and is regulated by a complex network of signaling cascades. Not surprisingly, autophagy is implicated in multiple pathological processes, including infection by pathogens, inflammatory bowel disease, neurodegeneration and cancer. Both oncogenesis and tumor survival are influenced by perturbations of the molecular machinery that controls autophagy. Numerous oncoproteins, including phosphatidylinositol 3-kinase, Akt1 and anti-apoptotic members of the Bcl-2 family suppress autophagy. Conversely, several tumor suppressor proteins (e.g., Atg4c; beclin 1; Bif-1; BH3-only proteins; death-associated protein kinase 1; LKB1/STK11; PTEN; UVRAG) promote the autophagic pathway. This does not entirely apply to p53, one of the most important tumor suppressor proteins, which regulates autophagy in an ambiguous fashion, depending on its subcellular localization. Irrespective of the controversial role of p53, basal levels of autophagy appear to inhibit tumor development. On the contrary, chemotherapy- and metabolic stress-induced activation of the autophagic pathway reportedly contribute to the survival of formed tumors, thereby favoring resistance. In this context, autophagy inhibition would represent a major therapeutic target for chemosensitization. Here, we will review the current knowledge on the dual role of autophagy as an anti- and pro-tumor mechanism.
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PMID:Anti- and pro-tumor functions of autophagy. 1937 98

In vivo administration of the mitochondrial inhibitor 3-nitropropionic acid (3-NP) produces striatal pathology mimicking Huntington's disease (HD). However, the mechanisms of cell death induced by metabolic impairment are not fully understood. Previous studies showed that 3-NP triggered p53-depedent autophagy activation and cell death. The present study investigated the contribution of the Bcl-2 signaling pathway to autophagy activation and cell death induced by 3-NP. Rat striatum was intoxicated with 3-NP by stereotaxic injection. 3-NP up-regulated the expression of the autophagic protein beclin 1 but down-regulated the expression of the antiapoptotic protein Bcl-2. Pretreatment with the autophagy inhibitor 3-methyladenine (3-MA) significantly inhibited the 3-NP-induced alterations in beclin 1 and Bcl-2 protein levels. Similarly, the 3-NP-induced decline in Bcl-2 was also prevented by the lysosomal inhibitor E64, indicating degradation of Bcl-2 by lysosomes. In agreement with the time course of 3-NP-induced cell death, an increase in the release of cytochrome c from mitochondria was observed. 3-MA also attenuated the 3-NP-induced release of cytochrome c. On the other hand, 3-NP-induced elevations in proapoptotic protein Bax and autophagic protein beclin 1 and LC3-II were significantly enhanced by the Bcl-2-specific inhibitor HA14-1. Furthermore, HA14-1 increased the release of cytochrome c and 3-NP-induced striatal damage. These results suggest that induction of autophagy leads to degradation of Bcl-2. Meanwhile, down-regulation of Bcl-2 amplifies autophagy activation and apoptotic signaling. Bcl-2 thus plays important roles in mitochondria dysfunction-induced apoptotic death of stritatal neurons by modulating both autophagic and apoptotic processes.
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PMID:Down-regulation of Bcl-2 enhances autophagy activation and cell death induced by mitochondrial dysfunction in rat striatum. 1956 56

The present study sought to investigate mechanisms by which p53 induction contributes to excitotoxic neuronal injury. Rats were intrastriatally administered the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid (QA), the changes in the expression of p53 and its target genes involved in apoptosis and autophagy, including p53-upregulated modulator of apoptosis (PUMA), Bax, Bcl-2, damage-regulated autophagy modulator (DRAM) and other autophagic proteins including microtubule-associated protein 1 light chain 3 (LC3) and beclin 1 were assessed. The contribution of p53-mediated autophagy activation to apoptotic death of striatal neurons was assessed with co-administration of the nuclear factor-kappaB (NF-kappaB) inhibitor SN50, the p53 inhibitor Pifithrin-alpha (PFT-alpha) or the autophagy inhibitor 3-methyladenine (3-MA). The increased formation of autophagosomes and secondary lysosomes were observed with transmission electron microscope after excitotoxin exposure. QA induced increases in the expression of p53, PUMA, Bax and a decrease in Bcl-2. These changes were significantly attenuated by pre-treatment with SN50, PFT-alpha or 3-MA. SN50, PFT-alpha or 3-MA also reversed QA-induced upregulation of DRAM, the ratio of LC3-II/LC3-I and beclin 1 protein levels in the striatum. QA-induced internucleosomal DNA fragmentation and loss of striatal neurons were robustly inhibited by SN50, PFT-alpha or 3-MA. These results suggest that overstimulation of NMDA receptors can induce NF-kappaB-dependent expression of p53. p53 participates in excitotoxic neuronal death probably through both apoptotic and autophagic mechanisms.
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PMID:p53 induction contributes to excitotoxic neuronal death in rat striatum through apoptotic and autophagic mechanisms. 2009 69

Curcumin (1), a natural polyphenolic compound, has shown strong antioxidant and anticancer activities. Several molecular mechanisms have been attributed to its inhibitory effects on a wide range of tumor cells. In this study, the response of the chronic myeloid leukemia cell line K562 cells to 1 is investigated. Curcumin inhibited the viability of K562 cells in a dose- and time-dependent manner. Furthermore, curcumin-induced cell death was associated with the formation of the apoptosome complex, the collapse of the mitochondrial membrane potential, and caspase-3 activation. Curcumin treatment also induced Bid cleavage and downregulated the expression of Bcl-2 protein. Surprisingly, even with these molecular features of apoptosis, we showed that 1 stimulated autophagy, which was evidenced by microtubule-associated protein light chain 3 (LC3) immunoreactivty. Curcumin also increased the protein levels of beclin 1 and membrane form LC3 (LC3-II). Autophagy inhibitor bafilomycin A1 and the pan-caspase inhibitor Z-VAD-fmk suppressed curcumin-induced K562 cell death. Overall, these results suggest that curcumin induces autophagic and apoptotic death of K562 cells. These findings suggest that both apoptotic and autophagic mechanisms contribute to the curcumin-induced K562 cell death.
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PMID:Autophagic and apoptotic mechanisms of curcumin-induced death in K562 cells. 2018 54


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