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)

Stem cell factor (SCF) and its receptor, KIT, are essential to the migration and differentiation of melanocytes during embryogenesis. We previously demonstrated that apoptosis is induced by blocking survival function of the SCF/KIT interaction in a mouse neural crest cell (NCC) primary culture. Using the NCCmelb4 cell line, we investigated the occurrence of apoptosis in the cultured cells when KIT receptors were blocked by the monoclonal anti-KIT antibody (ACK2). Apoptosis following treatment with ACK2 was detected by DNA fragmentation assay, in situ apoptosis detection, and electron microscopy. We noted a decrease in extracellular signal-related kinase (ERK) and ribosomal S6 kinase (RSK) protein expression following ACK2 incubation. Western blot analysis and real-time quantitative RT-PCR revealed an apparent time-dependent reduction in Bcl-2 protein levels with respect to ACK2 within the NCCmelb4 cells. In terms of Bax expression, a difference was not found. Fas and caspase8 proteins increased time-dependently in proportion to ACK2 incubation. We noted apoptotic cell death upon addition of ACK2, with evidence of possible involvement of Bcl-2 and Fas in the induction of apoptosis. In contrast, no significant correlation between Fas ligand (Fas-L) expression and ACK2 was found. Fas activation appears to occur independent of Fas-L during ACK2-induced cell death. Therefore, we propose that Fas-L expression in NCCmelb4 cells does not play a major role in facilitating apoptosis. Furthermore, we hypothesize that these molecules combined with SCF/KIT play an important role in regulating the induction of vertebrate NCC apoptosis during embryogenesis.
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PMID:Bcl-2 reduced and fas activated by the inhibition of stem cell factor/KIT signaling in murine melanocyte precursors. 1565 78

Here, we determine the influence of aging on multiple markers of oxidative stress in the aorta of adult (6-month), aged (30-month) and very aged (36-month) Fischer 344/NNiaHSdxBrown Norway/BiNia (F344/NxBN) rats. Compared to adults, increases in as determined by oxidation of hydroethidine (HE) to ethidium (Et) were increased 79.7+/-7.0% in 36-month aortae and this finding was highly correlated with increases in medal thickness (r=0.773, p<0.01) and total protein nitration (r=0.706, p<0.01) but not Ki67, a marker for cell proliferation. Regression analysis showed that increases in aortic superoxide anion (O.-2) with aging were significantly correlated with changes in the expression and/or regulation of proteins involved in metabolic (AMPK-alpha), signaling (mitogen activated protein kinases (MAPKs) along with c-Src), apoptotic (Bax, Bcl-2, Traf-2) and transcriptional (NF-kappaB) activities. These results suggest that the aging F344/NxBN aorta may be highly suited for unraveling the molecular events that lead to age-associated alterations in aortic oxidative stress.
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PMID:Aging influences multiple incidices of oxidative stress in the aortic media of the Fischer 344/NNiaxBrown Norway/BiNia rat. 1639 Aug 28

AMP-activated protein kinase influences cellular metabolism, glucose-regulated gene expression, and insulin secretion of pancreatic beta cells. Its sustained activation by culture at low glucose concentrations or in the presence of 5-aminoimidazole-4-carboxamide riboside (AICAR) was shown to trigger apoptosis in beta cells. This study shows that both low glucose- and AICAR-induced apoptosis are associated with increased formation of mitochondrial superoxide-derived radicals and decreased mitochondrial activity. Mitochondrial dysfunction was reflected by an increased oxidized state of the mitochondrial flavins (FMN/FAD) but not of NAD(P)H. It was accompanied by suppression of glucose oxidation and glucose-induced insulin secretion, while palmitate oxidation appeared unaffected. When the cellular accumulation of superoxide-derived radicals was quenched by the ROS scavengers vitamin E, N-acetylcysteine, or the SOD-mimetic compound MnTBAP, apoptosis was significantly inhibited. Both low glucose and AICAR also elevated the expression of BH3-domain-only Bcl-2 antagonists, and induced caspase-3 activation, causing caspase-dependent truncation of Bcl-2. Overexpression of recombinant human Bcl-2 prevented caspase-3 activation, endogenous Bcl-2 processing, and apoptosis, but did not attenuate oxygen radical formation, AMPK activation, or JNK phosphorylation. We conclude that apoptosis by prolonged AMPK activation in beta cells results from enhanced production of mitochondria-derived oxygen radicals and onset of the intrinsic mitochondrial apoptosis pathway, followed by caspase activation and Bcl-2 cleavage which may amplify the death signal.
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PMID:Increased oxygen radical formation and mitochondrial dysfunction mediate beta cell apoptosis under conditions of AMP-activated protein kinase stimulation. 1715 94

Spermidine/spermine N-1-acetyl-transferase (SSAT) is a catabolic enzyme that participates in polyamine metabolism. SSAT has been reported to be induced in some organs subjected to ischemia-reperfusion, but its induction mechanism has not been clarified, and little is known about SSAT regulation by ischemia per se. We induced regional ischemia of rat heart by coronary ligation and found that SSAT expression increased in ischemic myocardium. In neonatal rat cardiomyocytes and HEK293 cells, SSAT was up-regulated at the transcriptional step primarily by ATP depletion rather than oxygen deprivation. Moreover, an AMPK inhibitor compound C and AMPKalpha1-silencing RNAs attenuated the SSAT induction by ATP depletion, and an AMPK activator AICAR induced SSAT expression even without ATP depletion. When SSAT was suppressed using siRNA, the caspase activities and Bax/Bcl-2 ratios further increased in ATP depletion. These results suggest that myocardial SSAT is induced by AMPK signaling and function as a cardioprotectant under ATP-depleted conditions.
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PMID:Myocardial SSAT induction via AMPK signaling and its implication for ischemic injury. 1806 19

Chronic kidney disease (CKD) in ageing is a burden on health systems worldwide. Rat models of age-related CKD linked with obesity and hypertension were used to investigate alterations in oxidant handling and energy metabolism to identify gene targets or markers for age-related CKD. Young adult (3 months) and old (21-24 months) spontaneously-hypertensive (SHR), normotensive Wistar-Kyoto (WKY) and Wistar rats (normotensive, obese in ageing) were compared for renal functional and physiological parameters, renal fibrosis and inflammation, oxidative stress (hemeoxygenase-1/HO-1), apoptosis and cell injury (including Bax:Bcl-2), phosphorylated and non-phosphorylated forms of oxidant and energy sensing proteins (p66Shc, AMPK), signal transduction proteins (ERK1/2, PKB), and transcription factors (NF-kappaB, FoxO1). All old rats were normoglycemic. Renal fibrosis, tubular epithelial apoptosis, interstitial macrophages and myofibroblasts (all p<0.05), p66Shc/phospho-p66 (p<0.05), Bax/Bcl-2 ratio (p<0.05) and NF-kappaB expression (p<0.01) were highest in old obese Wistars. Expression of phospho-FoxO/FoxO was elevated in old Wistars (p<0.001) and WKYs (p<0.01). SHRs had high levels in young and old rats. Expression of PKB, phospho-PKB, ERK1/2 and phospho-ERK1/2 were significantly elevated in all aged animals. These results suggest that obesity and hypertension have differing oxidant handling and signalling pathways that act in the pathogenesis of age-related CKD.
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PMID:Obesity and hypertension have differing oxidant handling molecular pathways in age-related chronic kidney disease. 1904 34

Cancer is a hyperproliferative disorder that is usually treated by chemotherapeutic agents that are toxic not only to tumor cells but also to normal cells, so these agents produce major side effects. In addition, these agents are highly expensive and thus not affordable for most. Moreover, such agents cannot be used for cancer prevention. Traditional medicines are generally free of the deleterious side effects and usually inexpensive. Curcumin, a component of turmeric (Curcuma longa), is one such agent that is safe, affordable, and efficacious. How curcumin kills tumor cells is the focus of this review. We show that curcumin modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK). How curcumin selectively kills tumor cells, and not normal cells, is also described in detail.
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PMID:Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? 1959 Sep 64

Ludwigia octovalvis is an aquatic plant widely distributed in Taiwan. It is traditionally used as a diuretic and is consumed as health drink. In this study, we evaluated the anti-proliferative activity of extracts and active constituent (chlorophyll a; CHL-a) of L. octovalvis in 3T3-L1 adipocytes; its mode of action on apoptosis was also investigated. Results showed that, among the different extracts and fractions, the ethylacetate layer (EAL) possessed the most potent anti-proliferative activity. Activity guided fractionation of the EAL obtained the bioactive constituent CHL-a (IC50: 24.10+/-0.83 nM). At concentrations 5-30 nM, CHL-a exhibited a dose-dependent accumulation of the Sub-G1 peak and caused cell cycle arrest at the G0/G1 phase. At 30 nM, it significantly reduced the cell viability, induced the appearance of DNA fragments, and enhanced the activation of caspase-3. Western blot data revealed that CHL-a decreased the level of Bcl-2, and increased the expression of CD95 (APO-1/CD95) and Bax. Furthermore, CHL-a up-regulated the AMPK and p-AMPK levels, and down-regulated the expression of PPAR-gamma. These results conclude that CHL-a possesses potent anti-proliferative activity, and its apoptotic effects on 3T3-L1 adipocytes are mediated through the activation of CD95 (APO-1/CD95) system and the AMPK signaling pathway.
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PMID:Chlorophyll a, an active anti-proliferative compound of Ludwigia octovalvis, activates the CD95 (APO-1/CD95) system and AMPK pathway in 3T3-L1 cells. 1996 29

Most cancer cells exhibit increased glycolysis for generation of their energy supply. This specificity could be used to preferentially kill these cells. In this study, we identified the signaling pathway initiated by glycolysis inhibition that results in sensitization to death receptor (DR)-induced apoptosis. We showed, in several human cancer cell lines (such as Jurkat, HeLa, U937), that glucose removal or the use of nonmetabolizable form of glucose (2-deoxyglucose) dramatically enhances apoptosis induced by Fas or by tumor necrosis factor-related apoptosis-inducing ligand. This sensitization is controlled through the adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is the central energy-sensing system of the cell. We established the fact that AMPK is activated upon glycolysis block resulting in mammalian target of rapamycin (mTOR) inhibition leading to Mcl-1 decrease, but no other Bcl-2 anti-apoptotic members. Interestingly, we determined that, upon glycolysis inhibition, the AMPK-mTOR pathway controlled Mcl-1 levels neither through transcriptional nor through posttranslational mechanism but rather by controlling its translation. Therefore, our results show a novel mechanism for the sensitization to DR-induced apoptosis linking glucose metabolism to Mcl-1 downexpression. In addition, this study provides a rationale for the combined use of DR ligands with AMPK activators or mTOR inhibitors in the treatment of human cancers.
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PMID:Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation. 1996 61

Hypoxia (approximately 3-0.1% oxygen) is capable of rapidly inducing, via the hypoxia-inducible factor (HIF-1), a cell survival response engaging autophagy. This process is mediated by the atypical BH3-only proteins the Bcl-2/E1B 19kDa-interacting protein 3 (BNIP3/BNIP3L (NIX)) that are induced by HIF-1. These mitochondrial associated BNIP proteins also mediate mitophagy, a metabolic adaptation for survival that is able to control reactive oxygen species (ROS) production and DNA damage. In contrast, severe hypoxic conditions or anoxia (<0.1% oxygen), where the latter is often confused with physiological hypoxia, are capable of inducing a HIF-independent autophagic response, generated via an extreme nutritional stress response implicating the AMPK-mTOR and unfolded protein response (UPR) pathways. The autophagic cell death that is often observed in these extreme stress conditions should be seen as the outcome of failed adaptation.
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PMID:Hypoxia-induced autophagy: cell death or cell survival? 2002 34

5'-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of cellular energy status. AMPK signaling regulates energy balance at the cellular, organ, and whole-body level. More recently, it has become apparent that AMPK plays also an important role in long-term decisions that determine cell fate, in particular cell cycle progression and apoptosis activation. Here, we describe the diverse mechanisms of AMPK activation and the role of AMPK in the regulation of cellular energy balance. We summarize recent studies implicating AMPK activation in the regulation of neuronal survival and as a key player during ischemic stroke. We also suggest that AMPK activation may have dual functions in the regulation of neuronal survival: AMPK provides a protective effect during transient energy depletion as exemplified in a model of neuronal Ca(2+) overloading, and this effect is partially mediated by the activation of neuronal glucose transporter 3. Prolonged AMPK activation, on the contrary, can lead to neuronal apoptosis via the transcriptional activation of the proapoptotic Bcl-2 family member, bim. Molecular switches that determine the protective versus cell death-inducing effects of AMPK activation are discussed.
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PMID:Role of 5'-adenosine monophosphate-activated protein kinase in cell survival and death responses in neurons. 2071 20


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