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

In an earlier study, we demonstrated that PAN-811 (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a novel neuroprotectant, provides protection against glutamate, staurosporine, veratridine, or hypoxia/hypoglycemia toxicities in primary cortical neuronal cultures by upregulating Bcl-2 expression [R.-W. Chen, C. Yao, X.C. Lu, Z.-G. Jiang, R. Whipple, Z. Liao, H.A. Ghanbari, B. Almassian, F.C. Tortella, J.R. Dave. PAN-811 (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a novel neuroprotectant, elicits its function in primary neuronal cultures by upregulating Bcl-2 expression. Neuroscience 135 (2005) 191-201]. Both JNK (c-Jun N-terminal kinase) and p38 MAP (mitogen-activated protein) kinase activation have a direct inhibitory action on Bcl-2 by phosphorylation. In the present study, we continued to explore the mechanism of PAN-811 neuroprotection. Our results indicate that treatment of cultured cortical neurons with glutamate (100 microM) induces phosphorylation of both JNK and p38 MAPK. Specifically, pretreatment of neurons with 10 microM PAN-811 (an optimal neuroprotective concentration) for 1h, 4h, or 24h significantly suppresses glutamate-mediated activation of both JNK and p38 MAPK. Furthermore, the p38 MAPK-specific inhibitor SB203580 and the JNK-specific inhibitor SP600125 prevented glutamate-induced neuronal death in these primary cultures. Our results demonstrate that glutamate-induced phosphorylation of JNK and p38 MAPK is suppressed by PAN-811, which might contribute to Bcl-2 upregulation and PAN-811 neuroprotection.
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PMID:PAN-811 provides neuroprotection against glutamate toxicity by suppressing activation of JNK and p38 MAPK. 1760 Jun 21

Recent investigations have solidified the importance of negative selection in controlling autoimmunity. Loss of autoimmune regulator (AIRE), required for thymic stromal-cell differentiation and thymic expression of peripheral antigens, results in multi-organ autoimmunity. Mice with AIRE/Foxp3 double mutations suffer from exacerbated autoimmunity when compared with mice with only one mutation, supporting the important contributions of both central and peripheral tolerance. In thymocytes, Cbl is a negative regulator of thymocyte apoptosis while MINK, a MEKK kinase, is required for negative selection. This is consistent with the requirement of JNK, p38 and possibly ERK5 MAP kinases in thymocyte apoptosis. ERK5 induces the Nur77 orphan steroid receptor family members. In cell lines, Nur77 interaction with Bcl-2 turns Bcl-2 into a pro-apoptotic molecule. This and other possibilities will be discussed to explain the unresolved finding that negative selection is defective in Bim(-/-) but is not efficiently blocked in Bcl-2 transgenic mice.
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PMID:Apoptosis during negative selection of autoreactive thymocytes. 1765 79

Progesterone (P4) is frequently used in the treatment of threatened abortion, prevention of recurrent miscarriage and threatened preterm labor. However, little is known about the molecular mechanism of P4 in the regulation of extravillous trophoblasts' (EVTs) function. This study was designed to examine the presence of progesterone receptor (PR) in the human trophoblast-derived HTR-8/SV neo cell line, which is a possible model of EVTs, and the effects of P4 on apoptosis in those cells. The HTR-8/SV neo cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 100 U/ml penicillin and 100 microg/ml streptomycin. When the cell the population reached 50% confluency, the cells were stepped down to serum-free conditions in the presence or absence of graded concentrations of P4 (1, 10 and 100 ng/ml) for 48 h. The cultured cells were used for RT-PCR, terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) assay, immunocytochemistry and western blot analyses. Immunocytochemistry and western blot analyses revealed that PR was evident in HTR-8/SV neo cells. Compared with untreated cultures, treatment with P4 (10 and 100 ng/ml) resulted in significant decreases in the TUNEL-positive rate, Fas, Fas ligand (Fas-L), caspase-8, caspase-3 and poly (ADP-ribose) polymerase (PARP) expression in HTR-8/SV neo cells, and a significant increase in Bcl-2 expression in those cells. Consistently, Fas mRNA expression in those cells was significantly inhibited by the treatment with 10 ng/ml P4 compared with untreated cultures. This study suggests that PR exists in HTR-8/SV neo cells and that P4 inhibits apoptosis by down-regulating Fas, Fas-L, caspase-8, caspase-3 and PARP expression as well as up-regulating Bcl-2 expression in HTR-8/SV neo cells.
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PMID:The effects of progesterone on apoptosis in the human trophoblast-derived HTR-8/SV neo cells. 1796 76

The intracellular signaling pathways mediating the neurotrophic actions of pituitary adenylate cyclase-activating polypeptide (PACAP) were investigated in human neuroblastoma SH-SY5Y cells. Previously, we showed that SH-SY5Y cells express the PAC(1) and VIP/PACAP receptor type 2 (VPAC(2)) receptors, and that the robust cAMP production in response to PACAP and vasoactive intestinal peptide (VIP) was mediated by PAC(1) receptors (Lutz et al. 2006). Here, we investigated the ability of PACAP-38 to differentiate SH-SY5Y cells by measuring morphological changes and the expression of neuronal markers. PACAP-38 caused a concentration-dependent increase in the number of neurite-bearing cells and an up-regulation in the expression of the neuronal proteins Bcl-2, growth-associated protein-43 (GAP-43) and choline acetyltransferase: VIP was less effective than PACAP-38 and the VPAC(2) receptor-specific agonist, Ro 25-1553, had no effect. The effects of PACAP-38 and VIP were blocked by the PAC(1) receptor antagonist, PACAP6-38. As observed with PACAP-38, the adenylyl cyclase activator, forskolin, also induced an increase in the number of neurite-bearing cells and an up-regulation in the expression of Bcl-2 and GAP-43. PACAP-induced differentiation was prevented by the adenylyl cyclase inhibitor, 2',5'-dideoxyadenosine (DDA), but not the protein kinase A (PKA) inhibitor, H89, or by siRNA-mediated knock-down of the PKA catalytic subunit. PACAP-38 and forskolin stimulated the activation of extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAP; p38 MAP kinase) and c-Jun N-terminal kinase (JNK). PACAP-induced neuritogenesis was blocked by the MEK1 inhibitor PD98059 and partially by the p38 MAP kinase inhibitor SB203580. Activation of exchange protein directly activated by cAMP (Epac) partially mimicked the effects of PACAP-38, and led to the phosphorylation of ERK but not p38 MAP kinase. These results provide evidence that the neurotrophic effects of PACAP-38 on human SH-SY5Y neuroblastoma cells are mediated by the PAC(1) receptor through a cAMP-dependent but PKA-independent mechanism, and furthermore suggest that this involves Epac-dependent activation of ERK as well as activation of the p38 MAP kinase signaling pathway.
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PMID:PACAP-38 induces neuronal differentiation of human SH-SY5Y neuroblastoma cells via cAMP-mediated activation of ERK and p38 MAP kinases. 1799 38

Progesterone plays a pivotal role in controlling uterine leiomyoma growth. The authors review studies they conducted to evaluate the comparative effects of asoprisnil on proliferation, apoptosis, and growth factor expression in cultured leiomyoma and normal myometrial cells. Treatment with asoprisnil decreased the proliferating cell nuclear antigen-positive rate and the number of viable cells and increased the terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling- positive rate in cultured leiomyoma cells in a dose-dependent manner ( P < .05). Similarly, asoprisnil decreased Bcl-2 expression and increased cleaved caspase-3 and cleaved poly(adenosine 5'-diphosphate-ribose) polymerase in leiomyoma cells but not in normal myometrial cells. Similarly, asoprisnil decreased epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and transforming growth factor (TGF) beta mRNA and protein expression, as well as EGF receptor, IGF-IR alpha, and TGF RII protein expression in leiomyoma cells but not in cultured normal myometrial cells. These results suggest that asoprisnil selectively inhibits proliferation by downregulating the growth factors and their receptor expression and induces apoptosis in leiomyoma cells without affecting proliferation and apoptosis in normal myometrial cells.
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PMID:Comparative effects of SPRM asoprisnil (J867) on proliferation, apoptosis, and the expression of growth factors in cultured uterine leiomyoma cells and normal myometrial cells. 1808 6

We have reported earlier a novel combination of four structurally designed synthetic neuropeptide analogs of vasoactive intestinal peptide (VIP), bombesin, substance P and somatostatin, code-named DRF 7295 which have anti-tumor efficacy for adenocarcinomas in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). The discovery, synthesis, in vitro and in vivo efficacy was reported (Jaggi et al., Invest New Drugs, 2008). Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to most sensitive to DRF7295 in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). We have further investigated and report here the modulation of cellular signaling in gastrointestinal carcinomas by DRF 7295, which may be mediating its observed anticancer activity in these cancer types. DRF 7295 inhibits the binding of specific neuropeptides initiating a cascade of cellular signaling events leading to programmed cell death. It down regulates the second messenger cAMP, epidermal growth factor (EGF) dependent proliferation and the phosphorylated MAP Kinase pERK1/2 in gastrointestinal carcinomas, thus depriving the tumour cells of critical pro-proliferative cellular signals. It triggers bcl2 and Caspase 3 dependent apoptotic cell death and induces p53 tumor suppressor protein in the treated carcinoma cells in vitro. It has significant anti-angiogenic potential as reflected in the inhibition of tube like formation in the endothelial cells and down regulation of VEGF levels. Tumour xenograft studies confirmed the in vivo efficacy of DRF 7295 for gastrointestinal carcinomas (Jaggi et al., Invest New Drugs, 2008). The Phase I clinical trials have shown DRF 7295 to be well tolerated and devoid of systemic toxicities of the conventional cytotoxics (Mukherjee et al., Phase I dose escalating study of DRF7295: a new class of peptide based drugs. "Abstract" ASCO ID:948, 2003). The drug may have a promising role in disease stabilization in colorectal and other cancers. Thus DRF 7295 is a novel targeted drug in the class of signal transduction modulators, with potential for treatment of gastrointestinal carcinomas.
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PMID:Modulation of key signal transduction molecules by a novel peptide combination effective for the treatment of gastrointestinal carcinomas. 1832 52

Hemorrhagic shock (HS) is an oxidative stress that causes intestinal tissue injury. Heme oxygenase 1 (HO-1) is induced by oxidative stress and is thought to play an important role in the protection of tissues from oxidative injury. We previously reported the ileum to be the most susceptible to HS-induced tissue injury site in the intestine because HO-1 induction is the lowest at this site. We also previously demonstrated that glutamine (GLN) significantly induced HO-1 in the lower intestinal tract. In the present study, we investigated whether GLN pretreatment improves HS-induced intestinal tissue injury in the ileum by HO-1 induction. Treatment of rats with GLN (0.75 g/kg, i.v.) markedly induced functional HO-1 protein in mucosal epithelial cells in the ileum. Glutamine treatment before HS (MAP of 30 mmHg for 60 min) significantly ameliorated HS-induced mucosal inflammation and apoptotic cell death in the ileum, as judged by significant decreases in gene expression of TNF-alpha, iNOS, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1, myeloperoxidase activity, the number of infiltrated neutrophils, DNA fragmentation by in situ oligo ligation assay, and activated caspase-3 expression, and by increases in gene expression of IL-10 and Bcl-2. In contrast, treatment with tin mesoporphyrin, a specific inhibitor of HO activity, abolished the beneficial effect of GLN pretreatment. These findings indicate that GLN pretreatment significantly ameliorated tissue injury in the ileum after HS by inducing HO-1. Glutamine treatment may thus protect mucosal cells from HS-induced oxidative damage via the anti-inflammatory and antiapoptotic properties of HO-1.
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PMID:Prevention of hemorrhagic shock-induced intestinal tissue injury by glutamine via heme oxygenase-1 induction. 1849 9

The effect of external zinc supplementation (10 and 35 micromol) on cell proliferation and mitogenic signaling of Hep-2 tumor cells was examined during 72 h of treatment. Zinc levels were manipulated by using zinc-free cultivation medium with or without addition of zinc ions. Proliferation of Hep-2 cells exposed to zinc-free medium decreased in a time-dependent manner and corresponded to decreasing intracellular zinc content. Hep-2 cells accumulated in G(0)/G(1) phase, showed reduced abundance of AKT and NF-kappaB as well as of anti-apoptotic Bcl-2 and Bcl-XL proteins. Zinc supplied to Hep-2 cells maintained in the presence of zinc-free medium stimulated their proliferation as well as mitogenic signaling which paralleled increasing intracellular zinc content. In zinc-exposed Hep-2 cells, several changes in various mitogenic signaling pathways were noted such as enhanced expression of p53, AKT and MAP kinases, NF-kappaB and increased DNA binding of AP-1 family. Also, supplementation with zinc of Hep-2 cells resulted in the suppression of key apoptotic molecules such as Bax protein and increased expression of anti-apoptotic Bcl-2 and Bcl-XL proteins. Since only the highest supplied zinc concentration (35 micromol) induced oxidative stress, it is reasoned that the observed activation of pro-survival signaling occurs both directly and indirectly. These data show that zinc may stimulate growth and proliferation of some tumor cells by a combination of internal mechanisms with a varying contribution of external signaling pathways too.
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PMID:External zinc stimulates proliferation of tumor Hep-2 cells by active modulation of key signaling pathways. 1856 27

Programmed cell death of mononuclear cells in conditions of oxidative stress in vitro and selective inhibitors of MAP-kinases JNK, p38 were investigated. Levels of active and inactive forms of MAP-kinases, factors of transcription P53, NF-kB and proteins-regulators of apoptosis Bcl-X(L), Bad, Bcl-2 were determined by immunoblotting (Western blotting). The increasing of number of annexin-plus mononuclears/lymphocytes in the culture associated with enhance of the level of intracellular reactive oxygen species was shown. The treatment of selective inhibitors JNK SP600125 and p38 ML3403 in vitro prevents peroxide-induced appearance of P53 and NF-kB in blood mononuclear cells, associated with increasing of their apoptotic activity. The disturbance of the balance of pro- and antiapoptotic proteins of Bcl-2, family (the increase of the Bax level without changes of Bcl-X(L) and Bcl-2) leads to the growth of apoptosis process of mononuclear leucocytes activity in oxidative stress conditions.
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PMID:[Redox-dependent regulation of apoptosis as a function of intracellular reactive oxygen species in oxidative stress]. 1872 80

c-Jun N-terminal kinases (JNKs), a family of MAP kinases, are central mediators of apoptosis and neurodegeneration, but also of plasticity and regeneration. Current concepts suggest that the compartmentalisation i.e. the distribution within cellular organelles and structures rather than substrate affinity determines the pathological and physiological function of individual JNKs. In contrast to JNK mediated activation of pro-apoptotic Bcl-2/BH3-only substrates, findings on the presence and activation of JNK isoforms in mitochondria are rare. Here we have analysed the specific localisation and activation of JNK1, JNK2 and JNK3 as well as of their upstream MKK4/7 in brain mitochondria following transient middle cerebral artery occlusion (MCAo). The mitochondrial preparations were free of cytoskeletal, nuclear and ER contaminations, the specificity of antibodies was demonstrated in brain mitochondria from JNK deficient untreated mice. All JNKs were present in mitochondria with JNK1 as the major carrier of a strong basal JNK activity. Surprisingly, JNK activity was hardly detectable in the remaining cytoplasm. Between 2 and 18 h following MCAo, the pattern of JNK isoforms in mitochondria completely changed. Presence and activation of JNK1 almost completely disappeared. In striking contrast, presence and activation of JNK2 and, even more pronounced, of JNK3 substantially increased. At the level of the upstream MKKs, complexes of MKK4:JNK1 were diminished, whereas complexes of JNK3 with MKK4 and MKK7 were enhanced. These data strongly suggest that the basal physiological JNK1 activity is replaced in mitochondria by activated JNK2 and JNK3 following neurodegenerative events. This pattern of "JNK1 goes and JNK3 comes" might be essential for the initiation of apoptosis and suggests the search for targets of compartment-specific neuroprotective strategies.
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PMID:Cerebral ischemia provokes a profound exchange of activated JNK isoforms in brain mitochondria. 1928 69


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