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)

Small GTP-binding Rho GTPases regulate important signaling pathways in endothelial cells, but little is known about their role in endothelial cell apoptosis. Clostridial cytotoxins specifically inactivate GTPases by glucosylation [Clostridium difficile toxin B-10463 (TcdB-10463), C. difficile toxin B-1470 (TcdB-1470)] or ADP ribosylation (C. botulinum C3 toxin). Exposure of human umbilical cord vein endothelial cells (HUVEC) to TcdB-10463, which inhibits RhoA/Rac1/Cdc42, or to C3 toxin, which inhibits RhoA, -B, -C, resulted in apoptosis, whereas inactivation of Rac1/Cdc42 with TcdB-1470 was without effect, suggesting that Rho inhibition was responsible for endothelial apoptosis. Disruption of endothelial microfilaments as well as inhibition of p160ROCK did not induce endothelial apoptosis. Exposure to TcdB-10463 resulted in activation of caspase-9 and -3 but not caspase-8 in HUVEC. Moreover, Rho inhibition reduced expression of antiapoptotic Bcl-2 and Mcl-1 and increased proapoptotic Bid but had no effect on Bax or FLIP protein levels. Caspase-3 activity and apoptosis induced by TcdB-10463 were abolished by cAMP elevation. In summary, inhibition of Rho in endothelial cells activates caspase-9- and -3-dependent apoptosis, which can be antagonized by cAMP elevation.
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PMID:Rho protein inactivation induced apoptosis of cultured human endothelial cells. 1222 60

Apoptosis is a regulated cell death program controlled by extrinsic and intrinsic signaling pathways. The intrinsic pathway involves stress signals that activate pro-apoptotic members of the Bcl-2 family, inducing permeabilization of mitochondria and release of apoptogenic factors. These proteins localize to the outer mitochondrial membrane. Ian4, a mitochondrial outer membrane protein with GTP-binding activity, is normally present in thymocytes, T cells, and B cells. We and others have recently discovered that a mutation in the rat Ian4 gene results in severe T cell lymphopenia that is associated with the expression of autoimmune diabetes. The mechanism by which Ian4 controls T cell homeostasis is unknown. Here we show that the absence of Ian4 in T cells causes mitochondrial dysfunction, increased mitochondrial levels of stress-inducible chaperonins and a leucine-rich protein, and T cell-specific spontaneous apoptosis. T cell activation and caspase 8 inhibition both prevented apoptosis, whereas transfection of T cells with Ian4-specific small interfering RNA recapitulated the apoptotic phenotype. The findings establish Ian4 as a tissue-specific regulator of mitochondrial integrity.
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PMID:Ian4 is required for mitochondrial integrity and T cell survival. 1293 Aug 93

We previously reported that nicotine withdrawal up-regulates transcription of some immediately early genes (IEGs), c-fos (Ichino et al., 1999) and egr1, nur77 (Ichino et al., 2002) in cultures of pheochromocytoma PC12 cells, which are of neuronal lineage. In the present study we aimed at further elucidating the effects of nicotine withdrawal on the expression of the genes downstream of IEGs. We examined the changes in the protein levels of 2 GTP-binding proteins, Rab2 (Ras-related protein) and Rac1. PC12 cells were cultured in the presence of nicotine for 24 hours, and then the nicotine was removed from the medium. The protein level of Rab2 was low in the presence of nicotine, but was rapidly increased after nicotine withdrawal. In contrast, that of Rac1 did not change after the withdrawal. Considering the neuroprotective effect of nicotine, we also examined the level of Bag-1 protein, which is a binding protein for Bcl-2, an anti-apoptotic factor, and found a slight increase in the gene expression of Bag-1 following nicotine withdrawal. Among 56-kDa, 50-kDa, and 36-kDa protein components of the Bag-1 protein complex, the levels of 56-kDa and 50-kDa proteins were not changed by the addition or withdrawal of nicotine; but the level of the 36-kDa protein, which had been increased in the presence of nicotine, was markedly decreased after nicotine withdrawal. The present results suggest that such changes may also occur in individuals during abstaining from smoking and be related to the withdrawal symptoms experienced after smokers stop smoking.
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PMID:Expression levels of Rab2, a G protein, and Bag-1, a Bcl-2 binding protein are controlled by withdrawal of nicotine from cultured pheochromocytoma PC12 cells. 1578 59

The IAN (immune-associated nucleotide-binding protein) family is a family of functionally uncharacterized GTP-binding proteins expressed in vertebrate immune cells and in plant cells during antibacterial responses. Here we show that all eight IAN family genes encoded in a single cluster of mouse genome are predominantly expressed in lymphocytes, and that the expression of IAN1, IAN4, and IAN5 is significantly elevated upon thymic selection of T lymphocytes. Gain-of-function experiments show that the premature overexpression of IAN1 kills immature thymocytes, whereas short hairpin RNA-mediated loss-of-function studies show that IAN4 supports positive selection. The knockdown of IAN5 perturbs the optimal generation of CD4/CD8 double-positive thymocytes and reduces the survival of mature T lymphocytes. We also show evidence suggesting that IAN4 and IAN5 are associated with anti-apoptotic proteins Bcl-2 and Bcl-xL, whereas IAN1 is associated with pro-apoptotic Bax. Thus, the IAN family is a novel family of T cell-receptor-responsive proteins that critically regulate thymic development and survival of T lymphocytes and that potentially exert regulatory functions through the association with Bcl-2 family proteins.
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PMID:IAN family critically regulates survival and development of T lymphocytes. 2007 55

Development of chemotherapy resistance and evasion from apoptosis in osteosarcoma, a primary malignant bone tumor, is often correlated with constitutive nuclear factor-kappaB (NF-kappaB) activation. Here, we investigated the ability of a polyphenolic fraction of green tea (GTP) that has been shown to have antitumor effects on various malignant cell lines to inhibit growth and induce apoptosis in human osteosarcoma SAOS-2 cells. Treatment of SAOS-2 cells with GTP (20-60 microg/ml) resulted in reduced cell proliferation and induction of apoptosis, which correlated with decreased nuclear DNA binding of NF-kappaB/p65 and lowering of NF-kappaB/p65 and p50 levels in the cytoplasm and nucleus. GTP treatment of cells reduced IkappaB-alpha phosphorylation but had no effect on its protein expression. Furthermore, GTP treatment resulted in the inhibition of IKK-alpha and IKK-beta, the upstream kinases that phosphorylate IkappaB-alpha. The increase in apoptosis in SAOS-2 cells was accompanied with decrease in the protein expression of Bcl-2 and concomitant increase in the levels of Bax. GTP treatment of SAOS-2 cells also resulted in significant activation of caspases as was evident by increased levels of cleaved caspase-3 and caspase-8 in these cells. Treatment of SAOS-2 cells with a specific caspase-3 inhibitor Ac-Asp-Glu-Val-Asp-CHO (Ac-DEVD-CHO) and general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketone (Z-VAD-FMK) rescued SAOS-2 cells from GTP-induced apoptosis. Taken together, these results indicate that GTP is a candidate therapeutic for osteosarcoma that mediates its antiproliferative and apoptotic effects via activation of caspases and inhibition of NF-kappaB.
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PMID:Green tea polyphenols-induced apoptosis in human osteosarcoma SAOS-2 cells involves a caspase-dependent mechanism with downregulation of nuclear factor-kappaB. 1679 29

Bcl-2 family proteins are potent regulators of programmed cell death. Although their intracellular localization to mitochondria and the endoplasmic reticulum has focused research on these organelles, how they function remains unknown. Two members of the Bcl-2 family, Bax and Bak, change intracellular location early in the promotion of apoptosis to concentrate in focal clusters at sites of mitochondrial division. Here we report that in healthy cells Bax or Bak is required for normal fusion of mitochondria into elongated tubules. Bax seems to induce mitochondrial fusion by activating assembly of the large GTPase Mfn2 and changing its submitochondrial distribution and membrane mobility-properties that correlate with different GTP-bound states of Mfn2. Our results show that Bax and Bak regulate mitochondrial dynamics in healthy cells and indicate that Bcl-2 family members may also regulate apoptosis through organelle morphogenesis machineries.
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PMID:Role of Bax and Bak in mitochondrial morphogenesis. 1703 92

The life-or-death decision of immune cells makes an essential contribution to immune-system development and the regulation of immune responses. A new family of cell-survival regulators expressed in lymphocytes, termed immune-associated nucleotide-binding proteins (IANs) [also known as GTPase of immunity-associated proteins (GIMAPs)], has been described. The IAN/GIMAP family consists of GTP-binding proteins that share a unique primary structure and whose expression is finely regulated by T-cell receptor signals. Recent studies have shown that IAN/GIMAP family proteins crucially regulate the survival of T cells during development, selection and homeostasis, and are possibly linked to the onset of T-lymphopenia, leukemia and autoimmunity. IAN/GIMAP family proteins might also take part in mitochondrial regulation of lymphocyte apoptosis by interacting with Bcl-2 family proteins.
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PMID:The lymphocyte guard-IANs: regulation of lymphocyte survival by IAN/GIMAP family proteins. 1719 32

The mammalian target of rapamycin (mTOR) is a central controller of cell growth, and it regulates translation, cell size, cell viability, and cell morphology. mTOR integrates a wide range of extracellular and intracellular signals, including growth factors, nutrients, energy levels, and stress conditions. Rheb, a Ras-related small GTPase, is a key upstream activator of mTOR. In this study, we found that Bnip3, a hypoxia-inducible Bcl-2 homology 3 domain-containing protein, directly binds Rheb and inhibits the mTOR pathway. Bnip3 decreases Rheb GTP levels in a manner depending on the binding to Rheb and the presence of the N-terminal domain. Both knockdown and overexpression experiments show that Bnip3 plays an important role in mTOR inactivation in response to hypoxia. Moreover, Bnip3 inhibits cell growth in vivo by suppressing the mTOR pathway. These observations demonstrate that Bnip3 mediates the inhibition of the mTOR pathway in response to hypoxia.
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PMID:Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb. 1792 95

Inhibitory heterotrimeric GTP-binding proteins (Gi proteins) mediate a variety of signaling pathways by coupling receptors and effectors to regulate cellular proliferation, differentiation, and apoptosis. However, the role of Gi proteins in the modulation of hydrogen peroxide-induced apoptosis is not clearly understood. Thus, we investigated the effect of Gi proteins on hydrogen peroxide-induced apoptosis and the underlying mechanisms in H1299 human lung cancer cells. The stable expression of constitutively active alpha subunits of Gi1 (Galphai1QL), Gi2, or Gi3 inhibited hydrogen peroxide-induced apoptosis. The expression of Galphai1QL up-regulated Bcl-2 expression, and the knockdown of Bcl-2 with siRNA abolished the anti-apoptotic effect of Galphai1QL. Galphai1 induced the transcription of Bcl-2 by activation of NF-kappaB, which resulted from an increase in NF-kappaB p50 protein. We conclude that Galphai1 inhibits hydrogen peroxide-induced apoptosis of H1299 lung cancer cells by up-regulating the transcription of Bcl-2 through a p50-mediated NF-kappaB activation.
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PMID:Inhibitory heterotrimeric GTP-binding proteins inhibit hydrogen peroxide-induced apoptosis by up-regulation of Bcl-2 via NF-kappaB in H1299 human lung cancer cells. 1923 29

The IAN (immune-associated nucleotide-binding protein) family belongs to a family of AIG1-like GTPases. These functionally uncharacterized GTP-binding proteins have unique structures and are differentially expressed in both vertebrate immune cells and plant cells during antibacterial responses. In mammals, the IANs, as a novel family of T cell receptor-responsive proteins, play critical roles in regulation of thymic development and survival of T lymphocytes through the interaction with Bcl-2 family proteins. The Arabidopsis AIG1 and AIG2, which are first identified IAN proteins, are involved in plant resistance to bacteria. Recent analysis of the expression patterns of Arabidopsis IANs suggests that these IAN proteins may play regulatory roles during plant development and response to both biotic and abiotic stress.
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PMID:IAN/GIMAPs are conserved and novel regulators in vertebrates and angiosperm plants. 1972 41


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