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)

COS cells are resistant to cell death induced either by interleukin-1beta-converting enzyme (*ICE) and ICE homolog (ICH-1L) overexpression or by serum deprivation. COS cells deprived of serum undergo apoptosis after transfection with an ICE expression construct, but not an ICH-1L construct. ICE-mediated apoptosis of COS cells in serum-free medium is suppressed by insulin-like growth factor (IGF)-1 and insulin. Viability of Rat-1 cell line (Rat-1/ICE) expressing low levels of ICE-LacZ fusion protein is lower than those of cell lines expressing either both Bcl-2 and ICE or mutant ICEGly-->Ser during serum deprivation. Enzymatic activation and processing of ICE are observed in cells induced to die by serum deprivation, which are suppressed by IGF-1. IGF-1 or insulin suppresses ICE-mediated cell death without affecting the expression levels of Bcl-2, Bcl-x, or Bax. Taken together, these results indicate that ICE is activated by growth factor deprivation, and IGF-1 is able to suppress ICE-mediated cell death through a mechanism independent of the expression of Bcl-2, Bcl-x, or Bax.
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PMID:Suppression of interleukin-1 beta-converting enzyme-mediated cell death by insulin-like growth factor. 861 90

Insulin-like growth factor (IGF)-1 inhibits apoptosis, but its mechanism is unknown. Myocyte stretching activates p53 and p53-dependent genes, leading to the formation of angiotensin II (Ang II) and apoptosis. Therefore, this in vitro system was used to determine whether IGF-1 interfered with p53 function and the local renin-angiotensin system (RAS), decreasing stretch-induced cell death. A single dose of 200 ng/ml IGF-1 at the time of stretching decreased myocyte apoptosis 43% and 61% at 6 and 20 hours. Ang II concentration was reduced 52% at 20 hours. Additionally, p53 DNA binding to angiotensinogen (Aogen), AT1 receptor, and Bax was markedly down-regulated by IGF-1 via the induction of Mdm2 and the formation of Mdm2-p53 complexes. Concurrently, the quantity of p53, Aogen, renin, AT1 receptor, and Bax was reduced in stretched myocytes exposed to IGF-1. Conversely, Bcl-2 and the Bcl-2-to-Bax protein ratio increased. The effects of IGF-1 on cell death, Ang II synthesis, and Bax protein were the consequence of Mdm2-induced down-regulation of p53 function. In conclusion, the anti-apoptotic impact of IGF-1 on stretched myocytes was mediated by its capacity to depress p53 transcriptional activity, which limited Ang II formation and attenuated the susceptibility of myocytes to trigger their endogenous cell death pathway.
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PMID:Insulin-like growth factor-1 induces Mdm2 and down-regulates p53, attenuating the myocyte renin-angiotensin system and stretch-mediated apoptosis. 1002 14

The promotion of cell survival and regeneration in acute renal failure (ARF) is important for restitution of renal function. This study analyzes the temporal and spatial relationship between expression of pro- and anti-apoptotic members of the Bcl-2 gene family (Bcl-2, Bcl-X(L), Bax) and epidermal growth factor (EGF), insulin-like growth factor- (IGF-1), and transforming growth factor-beta (TGF-beta), growth factors that are thought to be reparative in ARF. A rat model of ischemic ARF involving 30 min of bilateral renal artery occlusion followed by reperfusion for 0 to 14 d was used. Apoptosis and mitosis were quantified and qualitative assessment was made of other cellular damage including necrosis and loss of cellular adhesion. Locality and level of expression of the Bcl-2 and growth factor proteins were determined using immunohistochemistry. Apoptosis peaked between 4 and 14 d postischemia in both proximal and distal tubules. Mitosis peaked at 2 d in proximal tubules and 4 to 14 d in the distal tubules. A spatio-temporal relationship was observed between anti-apoptotic Bcl-2 gene family members and growth factors after ischemia-reperfusion. In control kidneys, expression of Bcl-2, Bcl-X(L) was low in epithelium of distal tubules, Bax had low-to-moderate expression in the proximal tubule and had low expression in the distal tubule, EGF and IGF-1 had low-to-moderate expression in the distal tubule, and TGF-beta had low expression in the proximal tubule. In contrast, within 24 h of reperfusion, distal tubules showed a marked increase in expression of Bcl-2 and a moderate increase in Bcl-X(L) and Bax. Proximal tubules showed a marked increase in Bax expression and a moderate increase in Bcl-X(L). Twenty-four hours after expression of the Bcl-2 proteins was increased, IGF-1 and EGF protein levels were increased in the distal tubule, similar to the Bcl-2 anti-apoptotic proteins, and were also detected in the adjacent proximal tubules, suggestive of paracrine action in these tubules. TGF-beta expression was moderately increased in regenerating proximal tubules, but no relationship was seen with the pattern of expression of the Bcl-2 genes. An explanation of these results is that the distal tubule is adaptively resistant to ischemic injury via promotion of survival by anti-apoptotic Bcl-2 genes, and its survival allows expression of growth factors critical not only to the maintenance and regeneration of its own cell population (autocrine action), but also to the adjacent ischemia-sensitive proximal tubular cells (paracrine action).
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PMID:Relationship between expression of Bcl-2 genes and growth factors in ischemic acute renal failure in the rat. 1070 69

As survival regulation is a key process in multiple myeloma biology, we have studied the Bcl-2 family proteins that can be regulated by three myeloma cell survival factors: interleukin-6 (IL-6), interferon-alpha (IFN-alpha) and insulin-like growth factor (IGF-1). Eleven myeloma cell lines, whose survival and proliferation are dependent on addition of IL-6, variably expressed 10 anti-apoptotic or pro-apoptotic proteins of the Bcl-2-family. When myeloma cells from four cell lines were IL-6 starved and activated with IL-6 or IFN-alpha, we observed that only Mcl-1 expression was up-regulated with myeloma cell survival induction. Nor was obvious regulation of these 10 pro-apoptotic or anti-apoptotic proteins found with IGF-1, another potent myeloma cell survival factor. Our results indicate that the myeloma cell survival activity of IL-6 linked to Bcl-xL regulation cannot be generalized and emphasize that Mcl-1 is the main target of IL-6 and IFN-alpha stimulation. However, other changes in the activity of the Bcl-2 protein family or other apoptosis regulators must be identified to elucidate the IGF-1 action mechanism. Cell Death and Differentiation (2000) 7, 1244 - 1252.
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PMID:Regulation of Bcl-2-family proteins in myeloma cells by three myeloma survival factors: interleukin-6, interferon-alpha and insulin-like growth factor 1. 1117 62

Bcl-2 family proteins play a crucial role in the cytoprotective action of insulin-like growth factor-I (IGF-I) by regulating cell death signaling at the mitochondrial level. The present study examined the effect of IGF-I on the expression of Bcl-2 family proteins in the rat heart mitochondria in relation to myocardial protection against ischemia-reperfusion injury. Systemic IGF-I (1 mg) treatment in the rat increased Bcl-xL and attenuated Bax 12-24 h later in the heart mitochondria fraction. Permeability transition and cytochrome c release occurred in a Ca(2+) concentration-dependent manner in the vehicle-treated mitochondria. This was significantly inhibited by the IGF-I-pretreatment. Moreover, ATP synthesis was significantly greater in the IGF-I-pretreated mitochondria. IGF-I pretreatment 24 h before 25 min of global ischemia in the isolated rat heart model significantly improved recovery of isovolumic left ventricular function and inhibited creatine kinase release during reperfusion. This was associated with a significantly less number of terminal transferase labeling-positive myocytes and nonmyocytes 2 h after reperfusion. These results suggest that IGF-1 differentially regulates Bcl-xL and Bax in heart mitochondria, which may be causally related to myocardial protection against ischemia-reperfusion injury.
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PMID:IGF-I differentially regulates Bcl-xL and Bax and confers myocardial protection in the rat heart. 1117 63

We have previously demonstrated that IGFBP-5 production by mammary epithelial cells increases dramatically during involution of the mammary gland. To demonstrate a causal relationship between IGFBP-5 and cell death we created transgenic mice expressing IGFBP-5 in the mammary gland using a mammary-specific promoter, beta-lactoglobulin. DNA content in the mammary glands of transgenic mice was decreased as early as day 10 of pregnancy. Histological analysis indicated reduced numbers of alveolar end buds, with decreased ductal branching. Transgenic dams produced IGFBP-5 in their milk at concentrations similar to those achieved at the end of normal lactation. Mammary cell number and milk synthesis were both decreased by approximately 50% during the first 10 days of lactation. BrdU labelling was decreased, whereas DNA ladders were increased in transgenic animals on day 1 of lactation. On day 2 postpartum, the epithelial invasion of the mammary fat pad was clearly impaired in transgenic animals. The concentrations of the pro-apoptotic molecule caspase-3 and of plasmin were both increased in transgenic animals whilst the concentrations of 2 prosurvival molecules Bcl-2 and Bcl-x(L)were both decreased. In order to examine whether IGFBP-5 acts by inhibiting the survival effect of IGF-I we examined IGF receptor phosphorylation and Akt phosphorylation and showed that both were inhibited. We attempted to "rescue" the transgenic phenotype by using growth hormone to increase endogenous IGF-I concentrations or by implanting minipumps delivering an IGF-1 analogue, R(3)-IGF-1, which binds weakly to IGFBP-5. Growth hormone treatment failed to affect mammary development suggesting that increased concentrations of endogenous IGF-1 are insufficient to overcome the high concentrations of IGFBP-5 produced by these transgenic animals. In contrast mammary development (gland weight and DNA content) was normalised by R3-IGF-I although milk production was only partially restored. This is the first demonstration that over-expression of IGFBP-5 can lead to; impaired mammary development, increased expression of the pro-apoptotic molecule caspase-3, increased plasmin generation and decreased expression of pro-survival molecules of the Bcl-2 family. It clearly demonstrates that IGF-I is an important developmental/survival factor for the mammary gland and, furthermore, this cell death programme may be utilised in a wide variety of tissues.
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PMID:Insulin-like growth factor binding protein-5 (IGFBP-5) induces premature cell death in the mammary glands of transgenic mice. 1222 11

The proteasome inhibitor PS-341 inhibits IkappaB degradation, prevents NF-kappaB activation, and induces apoptosis in several types of cancer cells, including chemoresistant multiple myeloma (MM) cells. PS-341 has marked clinical activity even in the setting of relapsed refractory MM. However, PS-341-induced apoptotic cascade(s) are not yet fully defined. By using gene expression profiling, we characterized the molecular sequelae of PS-341 treatment in MM cells and further focused on molecular pathways responsible for the anticancer actions of this promising agent. The transcriptional profile of PS-341-treated cells involved down-regulation of growth/survival signaling pathways, and up-regulation of molecules implicated in proapoptotic cascades (which are both consistent with the proapoptotic effect of proteasome inhibition), as well as up-regulation of heat-shock proteins and ubiquitin/proteasome pathway members (which can correspond to stress responses against proteasome inhibition). Further studies on these pathways showed that PS-341 decreases the levels of several antiapoptotic proteins and triggers a dual apoptotic pathway of mitochondrial cytochrome c release and caspase-9 activation, as well as activation of Jun kinase and a Fas/caspase-8-dependent apoptotic pathway [which is inhibited by a dominant negative (decoy) Fas construct]. Stimulation with IGF-1, as well as overexpression of Bcl-2 or constitutively active Akt in MM cells also modestly attenuates PS-341-induced cell death, whereas inhibitors of the BH3 domain of Bcl-2 family members or the heat-shock protein 90 enhance tumor cell sensitivity to proteasome inhibition. These data provide both insight into the molecular mechanisms of antitumor activity of PS-341 and the rationale for future clinical trials of PS-341, in combination with conventional and novel therapies, to improve patient outcome in MM.
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PMID:Molecular sequelae of proteasome inhibition in human multiple myeloma cells. 1239 22

The activated insulin-like growth factor-1 receptor (IGF-1R) protects cells from a wide range of apoptotic stimuli. Hyperglycemia promotes the intracellular generation of superoxide anion and hydrogen peroxide, both of which have been linked to the activation of the mitochondrial apoptosis program. Here, we report for the first time that ligand activation of the IGF-1R protects normal human mesangial cells and SV40 murine mesangial cells from the glycol-oxidant-induced apoptosis program. The IGF-1R antiapoptosis program was dependent on the recruitment of both Akt/PKB and the ERK subfamily of mitogen-activated protein kinases. IGF-1 treatment also protected the redox potential of mesangial cells maintained at high ambient glucose concentration, by inhibiting the generation of reactive oxygen intermediates and preserving mitochondrial transmembrane potential. IGF-1R survival signals targeted the Bcl-2 family of proteins to protect against glucose-induced apoptosis and oxidative stress. IGF-1-treated cells exhibited a decrease in the Bax/Bcl-2 ratio; increased phosphorylation/inactivation of Bad at Ser112 and Ser136; inhibition of cytochrome c release; perturbations directionally opposed to the initiation of the apoptosis program. In addition, we demonstrate IGF-1R-activated ERK signaling modules phosphorylate Ser112 of the mitochondrial Bad protein, establishing a direct link between surface IGF-1R and the survival program in mitochondria. Our findings indicate that in mesangial cells maintained at high ambient glucose concentration, IGF-1 activates a survival program that maintains the integrity of mitochondria and prevents the expression of the genetic program for apoptosis.
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PMID:IGF-1 inhibits the mitochondrial apoptosis program in mesangial cells exposed to high glucose. 1287 69

GH has antiapoptotic effects on several cells. However, the antiapoptotic mechanisms of GH on colonic mucosa cells are not completely understood. Peroxisome proliferator activated receptor-gamma (PPARgamma) activation enhances apoptosis, and a link between GH and PPARgamma in the colonic epithelium of acromegalic patients has been suggested. We investigated the effects of GH and of PPARgamma ligands on apoptosis in colonic cancer cell lines. Colonic cells showed specific binding sites for GH, and after exposure to 0.05-50 nm GH, their apoptosis reduced by 45%. The antiapoptotic effect was due to either GH directly or GH-dependent local production of IGF-1. A 55-85% reduction of PPARgamma expression was observed in GH-treated cells, compared with controls (P < 0.05). However, treatment of the cells with 1-50 microm ciglitazone (cig), induced apoptosis and reverted the antiapoptotic effects of GH by increasing the programmed cell death up to 3.5-fold at 30 min and up to 1.7-fold at 24 h. Expression of Bcl-2 and TNF-related apoptosis-induced ligand was not affected by either GH or cig treatment, whereas GH reduced the expression of Bax, which was increased by cig treatment. In addition, GH increased the expression of signal transducer and activator of transcription 5b, which might be involved in the down-regulation of PPARgamma expression. In conclusion, GH may exert a direct antiapoptotic effect on colonic cells, through an increased expression of signal transducer and activator of transcription 5b and a reduction of Bax and PPARgamma. The reduced GH-dependent apoptosis can be overcome by PPARgamma ligands, which might be useful chemopreventive agents in acromegalic patients, who have an increased colonic polyps prevalence.
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PMID:Growth hormone inhibits apoptosis in human colonic cancer cell lines: antagonistic effects of peroxisome proliferator activated receptor-gamma ligands. 1507 Aug 54

Caveolin-1 is an essential structural constituent of caveolae that has been implicated in mitogenic signaling and oncogenesis. Utilizing MCF-7 human breast cancer cells, stably transfected with caveolin-1 (MCF-7/Cav1), we previously demonstrated that caveolin-1 expression decreases MCF-7 cell proliferation and colony formation in soft agar. However, the loss of anchorage-independent growth is associated with inhibition of anoikis, as MCF-7/Cav1 cells exhibit increased survival after detachment. Herein we show that this phenotype is associated with suppression of detachment-induced activation of p53 and of the consequent induction of cyclin-dependent kinase inhibitor p21(WAF1/Cip1). In contrast, activation of p53 and p21(WAF1/Cip1) induced by doxorubicin in MCF-7/Cav1 cells remains largely unaffected. The phenotypic changes observed in MCF-7/Cav1 cells are not accompanied by changes in caspase-6, -7, -8 and -9 and cannot be explained by changes in Bid and Bcl-2 expression. However, MCF-7/Cav1 cells exhibit a constitutively phosphorylated Akt kinase and at least one phosphorylated high molecular weight putative Akt substrate which we designated pp340. In addition, MCF-7/Cav1 cells exhibit elevated expression of insulin-like growth factor-I (IGF-I) receptor expression and increased IGF-I signaling to Erk1/2 and to Akt, as well as IGF-I-induced stimulation of pp340 phosphorylation. The addition of IGF-I to the medium rescues the parental MCF-7 cells from anoikis, indicating that IGF-1 can act as a survival factor for suspended MCF-7 cells. Finally, the levels of caveolin-1 are dramatically elevated in a time-dependent manner upon detachment of anoikis-resistant MCF-7/Cav1 cells and HT-29-MDR human multidrug resistant colon cancer cells. We conclude that expression of caveolin-1 in human breast cancer cells enhances matrix-independent cell survival that is mediated by upregulation of IGF-I receptor expression and signaling.
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PMID:Caveolin-1 inhibits cell detachment-induced p53 activation and anoikis by upregulation of insulin-like growth factor-I receptors and signaling. 1559 98


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