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Apoptotic Cell Death (apoptotic + cell_death)
Selected AbstractsA Nonfibrillar Form of the Fusogenic Prion Protein Fragment [118-135] Induces Apoptotic Cell Death in Rat Cortical NeuronsJOURNAL OF NEUROCHEMISTRY, Issue 6 2000Thierry Pillot Abstract: Neuronal loss is a salient feature of prion diseases.However, its cause and mechanism, particularly its relationship with theaccumulation and precipitation of the pathogenic, protease-resistant isoformPrPSc of the cellular prion protein PrPC, are still anenigma. Several studies suggest that neuronal loss could occur through aprocess of programmed cell death, which is consistent with the lack ofinflammation in these conditions. By analogy with the pathological eventsoccurring during the development of Alzheimer's disease, controversies stillexist regarding the relationship between amyloidogenesis, prion aggregation,and neuronal loss. We recently demonstrated that a prion protein fragment(118-135) displayed membrane-destabilizing properties and was able to induce,in a nonfibrillar form, the fusion of unilamellar liposomes. To unravel themechanism of prion protein neurotoxicity, we characterize the effects of thehuman Pr[118-135] peptide on rat cortical neurons. We demonstrate that lowconcentrations of the Pr[118-135] peptide, in a nonfibrillar form, induce atime- and dose- dependent apoptotic cell death, including caspase activation,DNA condensation, and fragmentation. This toxicity might involve oxidativestress, because antioxidant molecules, such as probucol and propyl gallate,protect neurons against prion peptide toxicity. By contrast, a nonfusogenicvariant Pr[118-135, 0°] peptide, which displays the same amino acidcomposition but several amino acid permutations, is not toxic to corticalneurons, which emphasizes the critical role of the fusogenic properties of theprion peptide in its neurotoxicity. Taken together, our results suggest thatthe interaction between the Pr[118-135] peptide and the plasma membrane ofneurons might represent an early event in a cascade leading toneurodegeneration. [source] Hypoxia-Induced Apoptotic Cell Death is Prevented by Oestradiol Via Oestrogen Receptors in the Developing Central Nervous SystemJOURNAL OF NEUROENDOCRINOLOGY, Issue 3 2008V. M. Pozo Devoto The neuroprotective effects of oestrogens have been demonstrated against a variety of insults, including excitotoxicity, oxidative stress and cerebral ischemia under certain conditions. However, the molecular mechanisms underlying oestrogen neuroprotection are still unclear. We aimed to determine whether 17,-oestradiol (E2) administration post-hypoxia (p-hx) was neuroprotective and whether these actions were mediated through oestrogen receptors (ER). For this purpose, 12-embyonic day-old chickens were subjected to acute hypoxia [8% (O2), 60 min], followed by different reoxygenation periods. To test the neuroprotective effect of E2 and its mechanism, embryos were injected 30 min after the end of hypoxia with E2 alone or with ICI 182 780, a competitive antagonist of ER. Cytochrome c (cyt c) release, an indicator of mitochondrial apoptotic pathway, was measured by western blot in optic lobe cytosolic extracts. DNA fragmentation by TUNEL fluorescence and caspase-3 fragmentation by immunofluorescence were detected on optic lobe sections. Acute hypoxia produces a significant increase in cyt c release from mitochondria at 4 h p-hx, followed by an increase in TUNEL positive cells 2 h later (6 h p-hx). Administration of E2 (0.5 mg/egg) produced a significant decrease in cytosolic cyt c levels at 4 h p-hx, in casapse-3 activation and in TUNEL positive cells at 6 h p-hx compared to vehicle treated embryos. In the E2 -ICI 182 780 treated embryos, cyt c release, caspase-3 fragmentation and TUNEL positive cells were similar to the hypoxic embryos, thus suggesting the requirement of an E2,ER interaction for E2 mediated neuroprotective effects. In conclusion, E2 prevents hypoxia-induced cyt c release and posterior cell death and these effects are mediated by oestrogen receptors. [source] Akt1-mediated Intracellular Oxidation after UVB Irradiation Suppresses Apoptotic Cell Death Induced by Cell Detachment and Serum StarvationPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 1 2008Yuko Ibuki Apoptosis is an important cell death system that deletes damaged and mutated cells to prevent cancer. We have previously reported that a certain dose of UVB irradiation inhibited the apoptosis induced by serum starvation and cell detachment, leading to cell transformation. This antiapoptotic effect was partially inhibited by phosphatidylinositol 3-kinase (PI3-kinase) inhibitors. UVB irradiation is known to cause the phosphorylation of Akt via the activation of PI3-kinase; however, the Akt isoform-specific relationship has not yet been clarified. Notably, the role in antiapoptotic effect of UVB has yet to be elucidated. In this study, the role of Akt1 in the UVB-induced inhibition of apoptosis was examined by Akt1 knockdown using small interfering RNA (siRNA). NIH3T3 cells showed typical apoptotic cell death by serum starvation and cell detachment, which was significantly inhibited by UVB irradiation. Akt1 knockdown decreased the antiapoptotic effect of UVB. Hydrogen peroxide-induced suppression of cell death was also decreased in Akt1 knockdown cells. An antioxidant, N -acetylcysteine, inhibited the antiapoptotic effect by UVB irradiation, whereas no inhibition was observed in Akt1 knockdown cells. Furthermore, UVB-induced intracellular peroxidation was not observed in the knockdown cells, indicating that Akt1 played an important role in mediating the intracellular redox status. Treatment with insulin had a similar antiapoptotic effect as UVB irradiation involving intracellular peroxidation, which was also attenuated in Akt1 knockdown cells. These findings suggest that appropriate intracellular oxidation after UVB irradiation prevented apoptosis, a process which might be partially regulated by the production of reactive oxygen species mediated by Akt1. [source] Extracts Of Actinobacillus Actinomycetemcomitans Induce Apoptotic Cell Death In Human Osteoblastic MG63 CellsAUSTRALIAN ENDODONTIC JOURNAL, Issue 1 2000Article first published online: 11 FEB 2010 No abstract is available for this article. [source] Geranylgeraniol, an Intermediate Product in Mevalonate Pathway, Induces Apoptotic Cell Death in Human Hepatoma Cells: Death Receptor-independent Activation of Caspase-8 with Down-regulation of Bcl-xL ExpressionCANCER SCIENCE, Issue 9 2001Yoshio Takeda Geranylgeraniol (GGOH), an intermediate of mevalonate metabolism, is known to induce apoptosis in various lines of cancer cells. The present study was undertaken to clarify the signaling pathways of apoptosis induced by GGOH in human hepatoma cells. HuH-7 human hepatoma cells were incubated in the absence or presence of GGOH. Activation of caspase-8/-9/-3 in HuH-7 cells was found after 8 h treatment with GGOH, at which tune DNA fragmentation and loss of mitochondrial transmembrane potential (,,m) occurred. HuH-7 cells do not express Bcl-2; however, down-regulation of Bcl-xL expression preceded activation of the caspase cascade in GGOH-treated HuH-7 cells, while Bax expression was not changed by GGOH treatment. Addition of caspase inhibitors restored the decreased cell viability of HuH-7 cells by GGOH, including ,,m, to the baseline level, which indicated that caspase triggers mitochondria-dependent apoptotic pathways in GGOH-treated HuH-7 cells. Similarly, GGOH-mediated apoptosis of HuH-7 cells was clearly prevented by coadministration of ursodeoxycholic acid (UDCA), which led to restoration of the level of Bcl-xL expression. Activation of caspase-8/-9/-3, as well as ,,m, by GGOH treatment was suppressed by addition of UDCA. Our results indicate that activation of the caspase cascade initiating from caspase-8, which could be accelerated by down-regulation of Bcl-xL expression, plays a key role in an apoptotic process induced by GGOH in human hepatoma cells. [source] Apoptosis in oral lichen planusEUROPEAN JOURNAL OF ORAL SCIENCES, Issue 5 2001Evelyn Neppelberg Apoptotic cell death may be a contributory cause of basal cell destruction in oral lichen planus (OLP). Therefore, the purpose of this study was to investigate the rate of apoptosis in OLP and the expression of two proteins (FasR and FasL) regulating this process. Biopsies from 18 patients with histologically diagnosed OLP were investigated, with comparison to normal oral mucosa of healthy persons. For visualisation of DNA fragmentation, the TUNEL method was used. In order to characterise the infiltrating cell population (CD3, CD4, CD8) and expression of FasR and FasL, we used an immunohistochemical technique. The results showed that T cells dominated in the subepithelial cell infiltrate. Within the epithelium the apoptotic cells were confined to the basal cell layer, and more apoptotic cells were seen in areas with basal cell degeneration and atrophic epithelium. There was a prominent expression of FasR/FasL in OLP, with a rather uniform distribution throughout the inflammatory cell infiltrate. In the epithelium, the FasR/FasL expression was more abundant in the basal cell area compared to the suprabasal cell layer. In conclusion, apoptosis within the epithelium is significantly increased in situ in OLP compared to normal oral mucosa, and seems to be related to the epithelial thickness. [source] Histamine induces neural stem cell proliferation and neuronal differentiation by activation of distinct histamine receptorsJOURNAL OF NEUROCHEMISTRY, Issue 2 2008Anayansi Molina-Hernández Abstract Histamine has neurotransmitter/neuromodulator functions in the adult brain, but its role during CNS development has been elusive. We studied histamine effects on proliferation, cell death and differentiation of neuroepithelial stem cells from rat cerebral cortex in vitro. RT-PCR and Western blot experiments showed that proliferating and differentiated cells express histamine H1, H2 and H3 receptors. Treatments with histamine concentrations (100 nM,1 mM) caused significant increases in cell numbers without affecting Nestin expression. Cell proliferation was evaluated by BrdU incorporation; histamine caused a significant increase dependent on H2 receptor activation. Apoptotic cell death during proliferation was significantly decreased at all histamine concentrations, and cell death was promoted in a concentration-dependent manner by histamine in differentiated cells. Immunocytochemistry studies showed that histamine increased 3-fold the number of neurons after differentiation, mainly by activation of H1 receptor, and also significantly decreased the glial (astrocytic) cell proportion, when compared to control conditions. In summary, histamine increases cell number during proliferative conditions, and has a neuronal-differentiating action on neural stem cells, suggesting that the elevated histamine concentration reported during development might play a role in cerebrocortical neurogenesis, by activation of H2 receptors to promote proliferation of neural precursors, and favoring neuronal fate by H1 -mediated stimulation. [source] Protective effect of melatonin against hippocampal injury of rats with intermittent hypoxiaJOURNAL OF PINEAL RESEARCH, Issue 2 2008Ming-Wai Hung Abstract:, Obstructive sleep apnea (OSA) patients suffer from intermittent hypoxia (IH) and neuropsychologic impairments. Oxidative stress is involved in the pathogenesis of OSA, so the application of an antioxidant may be useful. We evaluated the hypothesis that melatonin would reduce IH-induced hippocampal injury via an increased expression of antioxidant enzymes. Adult Sprague,Dawley rats that had received a daily injection of melatonin or vehicle were exposed to IH for 8 hr/day for 7 or 14 days. The serum and hippocampus were harvested for the measurement of malondialdehyde (MDA). Apoptotic cell death was studied histologically in hippocampal sections. The mRNA expression of inflammatory mediators including tumor necrosis factor-alpha, inducible nitric oxide synthase, cyclooxygenase-2 and antioxidant enzymes including glutathione peroxidase, catalase and copper/zinc superoxide dismutase were examined in the hippocampus by RT-PCR. The results show significant increases in levels of serum and hippocampal MDA, apoptotic cell death and mRNA levels of inflammatory mediators in hypoxic rats when compared with the normoxic controls. Also, mRNA levels of the antioxidant enzymes were decreased in hypoxic animals. In the melatonin-treated hypoxic rats, serum MDA levels were comparable with those in normoxic control rats. Also, melatonin treatment significantly reduced hippocampal MDA levels and totally prevented apoptosis. Moreover, there were a decreased expression of the inflammatory mediators and an elevated expression of antioxidant enzymes in the melatonin injected rats when compared with vehicle-treated animals. These results indicate that melatonin mitigates oxidative stress and the pathogenesis of IH-induced hippocampal injury via its antioxidant and anti-inflammatory properties which includes stimulation of transcriptional regulation of antioxidant enzymes. [source] Apoptotic cell death does not parallel other indicators of liver damage in chronic hepatitis C patientsJOURNAL OF VIRAL HEPATITIS, Issue 3 2000Rodrigues The mechanisms of hepatocyte damage and the events that lead to high rates of chronic liver disease in hepatitis C virus (HCV) infection remain unclear. Recent in vitro studies have suggested that the HCV core protein may disrupt specific signalling pathways of apoptosis. This prompted us to study patients with chronic HCV infection to: determine the extent of apoptosis in the liver; evaluate whether clinical and biochemical data are correlated with histological findings; and to investigate if apoptosis is related to the histological activity of the disease. Twelve patients with chronic hepatitis C were included in the study. Liver histology was scored by using the histological activity index (HAI) of Knodell et al. DNA fragmentation was assessed in liver tissue by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling (TUNEL) assay. Routine methods were used to determine serum markers of liver disease. Bile acids were measured in serum and liver by gas chromatography. Patients were placed, according to their HAI score, into group A (3.8 ± 0.3) or group B (7.8 ± 0.8) (P < 0.01). Liver enzymes tended to be higher in group B patients than in patients of group A. Levels of toxic bile acids in serum were greater in patients than in controls (P < 0.01). Chenodeoxycholic acid values were slightly higher in serum and liver of patients in group A. Liver biopsies with low HAI scores showed an increased rate of apoptosis (18.0 ± 4.0 apoptotic cells per field) compared to those with higher HAI scores (6.6 ± 2.1, P < 0.05) or to controls (3.5 ± 0.4, P < 0.01). Hence, less severe liver disease, associated with lower histological grades and biochemistries, as well as increased levels of chenodeoxycholic acid, induces an expanded apoptotic response. The lower apoptotic rate in advanced liver disease may be associated with the high incidence of hepatocellular dysplasia/neoplasia. [source] Antisense MDM2 oligonucleotides restore the apoptotic response of prostate cancer cells to androgen deprivation,THE PROSTATE, Issue 3 2004Zhaomei Mu Abstract BACKGROUND Early in the malignant transformation of prostate epithelial cells, the apoptotic response to androgen deprivation (AD) is lost and the principle response is a slowing of cell growth. In this study, we tested whether interruption of MDM2 function using antisense MDM2 oligonucleotide (AS) affects the apoptotic response of prostate cancer cells to AD. METHODS Wild type LNCaP cells and MDM2-overexpressing (LNCaP-MST) cells were treated with AS alone or in combination with AD. Protein levels of MDM2, p53, and p21 were determined by Western blotting. Cell viability was measure by trypan blue staining. Apoptotic cell death was confirmed by cell morphological changes, annexin V/propidium iodide staining and caspase-3,+,7 activity. Overall cell survival was quantified by clonogenic assay. RESULTS AS inhibited MDM2 expression to a greater extent in LNCaP cells, as compared to LNCaP-MST cells. AS enhanced the expression of p53 and p21 in both cell lines. The growth inhibitory and cell death effects of AS,+,AD were generally greater than AS alone in LNCaP cells. Treatment of LNCaP cells with AS,+,AD for 72 hr caused a significant increase in cell death (66%) over AD alone (13%), AS alone (33%), or AD,+,AS,+,R1881 (34% with synthetic androgen replacement) that was attributable mainly to apoptosis. Clonogenic survival reflected the same pattern. CONCLUSIONS Our results suggest that the apoptotic response of prostate cancer to AD is strongly influenced by MDM2 expression. Antisense MDM2 has broad potential as a therapeutic agent to sensitize prostate cancer cells to AD therapy by enhancing apoptotic cell death. © 2004 Wiley-Liss, Inc. [source] Modulation of tamoxifen sensitivity by antisense Bcl-2 and trastuzumab in breast carcinoma cellsCANCER, Issue 10 2005Ph.D., Ryungsa Kim M.D. Abstract BACKGROUND Because the overexpression of HER-2 and Bcl-2 is associated with resistance to tamoxifen (TAM), the authors examined the effect of antisense (AS) Bcl-2 on sensitivity to TAM compared with the effect of trastuzumab on sensitivity to TAM in breast carcinoma cell lines. METHODS Drug sensitivity was assessed in vitro using a [3-4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay with the breast carcinoma cell lines ZR-75-1, MDA-MB-453, and BT-474. AS Bcl-2 18-mer phosphorothioate oligonucleotide was applied. Apoptotic cell death was assessed with the terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling method, and gene expression was evaluated with Western blot analysis. RESULTS The expression of Bcl-2 was identified in ZR-75-1 and BT-474 cells and, to a lesser extent, in MDA-MB-453 cells. Overexpression of HER-2 was identified in BT-474 cells, and moderate expression was identified in MDA-MB-453 and ZR-75-1 cells. Combination treatment with trastuzumab or AS Bcl-2 enhanced TAM sensitivity in ZR-75-1 cells, which showed 50% inhibitory concentration (IC50) values of 0.9 ,M (7.2-fold increase) and 0.5 ,M (13.0-fold), respectively. Combination treatment with trastuzumab or AS Bcl-2 slightly enhanced TAM sensitivity of BT-474 cells, with IC50 values of 3.0 ,M (1.3-fold) and 1.5 ,M (2.6-fold), respectively. The sensitivity of MDA-MB-453 cells to TAM was not enhanced by combination with trastuzumab or AS Bcl-2. Modulation of TAM sensitivity by AS Bcl-2 was superior to modulation by trastuzumab in HER-2-expressing and Bcl-2 -expressing breast carcinoma cells. Enhanced sensitivity in combination with AS Bcl-2 was associated with down-regulation of Bcl-2 and pAkt, which was correlated with the induction of Bax and caspase-3, leading to apoptosis. CONCLUSIONS AS Bcl-2 appeared to be superior to trastuzumab with respect to regulating the signal-transduction pathways involved in breast carcinoma cells. Cancer 2005. © 2005 American Cancer Society. [source] Enhancement of In Vitro Hair Shaft Elongation in Follicles Stored in Buffers That Prevent Follicle Cell ApoptosisDERMATOLOGIC SURGERY, Issue 1 2004Walter Krugluger MD Background. Viability and survival of stored micrografts during hair follicle transplantation are important limitations of micrograft transplantation procedures. In this study, we investigated the effect of different storage solutions and inhibitors of apoptotic cell death (ACD) on hair follicle cell viability by measuring in vitro hair shaft elongation (HSE) for 5 days. Methods. Micrografts from informed patients undergoing routine micrograft transplantation were stored for 5 hours at room temperature in phosphate-buffered salt solution (PBS) or HEPES-buffered Dulbecco's modified Eagle's medium (DMEM), containing different concentrations of the ACD-inhibitors aminoguanidine (AMG), hormones (insulin, hydrocortisone), 14,15-epoxy-eicosatrienoic acid (14,15-EET), or combinations of these. Results. In vitro, HSE was significantly increased in micrografts stored in DMEM compared with PBS (2.3%±0.6% vs. 28.4%±3.9%, P<0.0001). DMEM supplemented with AMG (10 ,g/mL) or 14,15-EET (1 ng/mL) further increased in vitro HSE (33.9%±7.1%, p=0.01, and 32.8%±6.1%, P=0.02, respectively). Evaluation of ACD in stored micrografts, performed by determination of cytoplasmic histone-associated DNA fragments, confirmed the results found by HSE. ACD was detectable after a 36-hour culture in serum-containing medium and was higher in micrografts stored in PBS compared with micrografts stored in DMEM (A405nm/A492nm: 1.63±0.21 vs. 1.42±0.07, respectively; P<0.01). The addition of AMG further decreased serum-induced ACD in the micrografts (DMEM 1.42±0.07 vs. DMEM/AMG 0.90±0.11, P<0.0001). Conclusion. Our study demonstrated an important role of ACD in micrograft transplantation surgery. Preconditioning of micrografts with storage buffers containing inhibitors of ACD could prevent serum-induced ACD after transplantation and might increase the viability of micrografts and the clinical outcome in micrograft transplantation. [source] Is the Cell Death in Mesial Temporal Sclerosis Apoptotic?EPILEPSIA, Issue 6 2003Hilmi Uysal Summary: Purpose: Mesial temporal sclerosis (MTS) is characterized by neuronal loss in the hippocampus. Studies on experimental models and patients with intractable epilepsy suggest that apoptosis may be involved in neuronal death induced by recurrent seizures. Methods: We searched evidence for apoptotic cell death in temporal lobes resected from drug-resistant epilepsy patients with MTS by using the terminal deoxynucleotidyl transferase (TdT) and digoxigenin-11-dUTP (TUNEL) method and immunohistochemistry for Bcl-2, Bax, and caspase-cleaved actin fragment, fractin. The temporal lobe specimens were obtained from 15 patients (six women and nine men; mean age, 29 ± 8 years). Results: Unlike that in normal adult brain, we observed Bcl-2 immunoreactivity in some of the remaining neurons dispersed throughout the hippocampus proper as well as in most of the reactive astroglia. Bax immunopositivity was increased in almost all neurons. Fractin immunostaining, an indicator of caspase activity, was detected in ,10% of these neurons. Des pite increased Bax expression and activation of caspases, we could not find evidence for DNA fragmentation by TUNEL staining. We also could not detect typical apoptotic changes in nuclear morphology by Hoechst-33258 or hematoxylin counterstaining. Conclusions: These data suggest that either apoptosis is not involved in cell loss in MTS, or a very slow rate of cell demise may have precluded detecting TUNEL-positive neurons dying through apoptosis. Increased Bax expression and activation of caspases support the latter possibility. [source] How apoptosis got the immune system in shapeEUROPEAN JOURNAL OF IMMUNOLOGY, Issue S1 2007Christine Feig Abstract The discovery that apoptosis is an integral component of normal development has facilitated the widespread recognition that cell death is not at all inimical to life. For much of our lifetime the body maintains a cellular homeostasis persisting until, ultimately, it is broken during the aging process. However, unlike the body as a whole, fluctuations at any age in this cellular balance are frequent in the immune system, which responds to infections via massive clonal expansions and elimination of reactive T and B cells. Moreover, cell death also plays a key, and essential, role in the education of immune cells in the thymus and the bone marrow, where autoreactive cells are eliminated, thereby establishing tolerance to self tissues. Furthermore, the mechanism by which cytotoxic T and NK cells kill virus infected or transformed target cells is by inducing apoptotic cell death. Thus, cell death, and in particular apoptosis, is an integral facet of almost all aspects of immune function. Failure to execute apoptosis appropriately has dire consequences leading to the development of autoimmune disease and malignant growth. This narration provides a historical overview of the impact that the discovery of apoptosis had on the understanding of the function of the immune system. [source] Involvement of mitochondrial signaling pathways in the mechanism of Fas-mediated apoptosis after spinal cord injuryEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2009Wen Ru Yu Abstract Activation of the Fas receptor has been recently linked to apoptotic cell death after spinal cord injury (SCI). Although it is generally considered that Fas activation mediates apoptosis predominantly through the extrinsic pathway, we hypothesized that intrinsic mitochondrial signaling could be involved in the underlying mechanism of Fas-induced apoptosis after SCI. In the present study, we utilized the FejotaTM clip compression model of SCI at T5,6 in C57BL/6 Fas-deficient (lpr) and wild-type mice. Complementary studies were conducted using an in vitro model of trauma or a Fas-activating antibody to induce apoptosis in primary neuronal,glial mixed spinal cord cultures. After in vivo SCI, lpr mice, in comparison with wild-type mice, exhibited reduced numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells at the lesion, reduced expression of truncation of Bid (tBid), apoptosis-inducing factor, activated caspase-9 and activated caspase-3, and increased expression of the antiapoptotic proteins Bcl-2 and Bcl-xL. After in vitro neurotrauma or the induction of Fas signaling by the Jo2 activating antibody, lpr spinal cord cultures showed an increased proportion of cells retaining mitochondrial membrane integrity and a reduction of tBid expression, caspase-9 and caspase-3 activation, and TUNEL-positive cells as compared to wild-type spinal cord cultures. The neutralization of Fas ligand (FasL) protected against traumatically induced or Fas-mediated caspase-3 activation and the loss of mitochondrial membrane potential and tBid expression in wild-type spinal cord cultures. However, in lpr spinal cord cultures, FasL neutralization had no protective effects. In summary, these data provide direct evidence for the induction of intrinsic mitochondrial signaling pathways following Fas activation after SCI. [source] PACAP inhibits delayed rectifier potassium current via a cAMP/PKA transduction pathway: evidence for the involvement of IK in the anti-apoptotic action of PACAPEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2004Y. A. Mei Abstract Activation of potassium (K+) currents plays a critical role in the control of programmed cell death. Because pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to inhibit the apoptotic cascade in the cerebellar cortex during development, we have investigated the effect of PACAP on K+ currents in cultured cerebellar granule cells using the patch-clamp technique in the whole-cell configuration. Two types of outward K+ currents, a transient K+ current (IA) and a delayed rectifier K+ current (IK) were characterized using two different voltage protocols and specific inhibitors of K+ channels. Application of PACAP induced a reversible reduction of the IK amplitude, but did not affect IA, while the PACAP-related peptide vasoactive intestinal polypeptide had no effect on either types of K+ currents. Repeated applications of PACAP induced gradual attenuation of the electrophysiological response. In the presence of guanosine 5,-[,thio]triphosphate (GTP,S), PACAP provoked a marked and irreversible IK depression, whereas cell dialysis with guanosine 5,-[,thio]diphosphate GDP,S totally abolished the effect of PACAP. Pre-treatment of the cells with pertussis toxin did not modify the effect of PACAP on IK. In contrast, cholera toxin suppressed the PACAP-induced inhibition of IK. Exposure of granule cells to dibutyryl cyclic adenosine monophosphate (dbcAMP) mimicked the inhibitory effect of PACAP on IK. Addition of the specific protein kinase A inhibitor H89 in the patch pipette solution prevented the reduction of IK induced by both PACAP and dbcAMP. PACAP provoked a sustained increase of the resting membrane potential in cerebellar granule cells cultured either in high or low KCl-containing medium, and this long-term depolarizing effect of PACAP was mimicked by the IK specific blocker tetraethylammonium chloride (TEA). In addition, pre-incubation of granule cells with TEA suppressed the effect of PACAP on resting membrane potential. TEA mimicked the neuroprotective effect of PACAP against ethanol-induced apoptotic cell death, and the increase of caspase-3 activity observed after exposure of granule cells to ethanol was also significantly inhibited by TEA. Taken together, the present results demonstrate that, in rat cerebellar granule cells, PACAP reduces the delayed outward rectifier K+ current by activating a type 1 PACAP (PAC1) receptor coupled to the adenylyl cyclase/protein kinase A pathway through a cholera toxin-sensitive Gs protein. Our data also show that PACAP and TEA induce long-term depolarization of the resting membrane potential, promote cell survival and inhibit caspase-3 activity, suggesting that PACAP-evoked inhibition of IK contributes to the anti-apoptotic effect of the peptide on cerebellar granule cells. [source] Role of the IGF-II receptor in mediating acute, non-genomic effects of retinoids and IGF-II on keratinocyte cell deathEXPERIMENTAL DERMATOLOGY, Issue 4 2003F. Louafi Abstract:, In this study, we have examined the effects of retinoic acid (RA) on the human immortalized keratinocyte cell line (HaCaT). A significant twofold (P < 0.01) increase in apoptotic cell death compared with the control was found within 24 h of treatment with 10,5 M of RA. Apoptosis was confirmed by flow cytometry. Cycloheximide did not inhibit this acute RA-induced apoptosis. Interestingly, insulin-like growth factor-II (IGF-II, 50 ng/ml) was able to significantly (67.3%; P < 0.05) reduce RA effects, whereas IGF-I (50 ng/ml) and insulin (75 ng/ml) were without effect. Furthermore, analogues of IGF-II [leu27 IGF-II and Des(1-6) IGF-II], with altered affinities for the IGF-I receptor and IGF-binding proteins (IGFBPs), but retained affinities for the IGF-II receptor, also completely inhibited (100%; P < 0.01) RA-induced apoptosis, while an IGF-I receptor antagonist did not reduce the survival effects of IGF-II. Insulin pretreatment negates the survival effect of IGF-II. In contrast, mannose 6 phosphate (M6P) did not alter RA or IGF-II actions. These results indicate that rapid induction of cell death by RA is independent of production or secretion of new proteins. The inhibition of RA action by IGF-II was independent of its ability to signal through the IGF-I receptor or to interact with IGFBPs. [source] Pituitary adenylate cyclase-activating polypeptide attenuates streptozotocin-induced apoptotic death of RIN-m5F cells through regulation of Bcl-2 family protein mRNA expressionFEBS JOURNAL, Issue 22 2008Satomi Onoue Oxidative stress, followed by the apoptotic death of pancreatic , cells, is considered to be one of causative agents in the evolution of the type 2 diabetic state; therefore, the protection of , cells can comprise an efficacious strategy for preventing type 2 diabetes. In the present study, RIN-m5F cells (i.e. the rat insulinoma , cell line) were stimulated with streptozotocin, resulting in a time- and concentration-dependent release of lactate dehydrogenase. There appeared to be significant apoptotic cell death after 2 h of treatment with streptozotocin at 10 mm, as demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining and 2.6-fold activation of cellular caspase-3, an apoptotic enzyme. By contrast, some neuropeptides of the glucagon-secretin family and coenzyme Q10, an endogenous mitochondrial antioxidant, could attenuate streptozotocin cytotoxicity, and especially pituitary adenylate cyclase-activating polypeptide (PACAP), at a concentration of 10,7 m, exhibited 34% attenuation of lactate dehydrogenase release from streptozotocin-treated RIN-m5F cells. Quantitative RT-PCR experiments indicated the inhibitory effect of PACAP on streptozotocin-evoked up-regulation of pro-apoptotic factor (Noxa and Bax) and a 2.3-fold enhancement of Bcl-2 mRNA expression, a pro-survival protein, was also observed after addition of PACAP. The data obtained suggest the anti-apoptotic role of PACAP in streptozotocin-treated RIN-m5F cells through the regulation of pro-apoptotic and pro-survival factors. [source] D324N single-nucleotide polymorphism in the FLT3 gene is associated with higher risk of myeloid leukemiasGENES, CHROMOSOMES AND CANCER, Issue 4 2006Susanne Schnittger Mutations within the FLT3 gene are of growing importance for classification, risk assessment, and therapeutic targeting of acute myeloid leukemia (AML). We analyzed 656 AML patients for a recently described single-nucleotide polymorphism (SNP) in the third immunoglobulin-like domain of the extracellular region of FLT3. The FLT3 D324N variant was present in 42 cases (6.4%), but it was not associated with a specific AML subtype and did not show an elevated leukocyte count, as do other FLT3 mutations. In remission samples, a 50% ratio of the normal to the D324N variant was detectable. Stably expressed in IL-3 dependent Ba/F3 cells, the D324N variant did not confer receptor autophosphorylation, factor independent growth, or increased resistance to apoptotic cell death in response to varying doses of FLT3 ligand. In 400 healthy donors, the FLT3 D324N variant was detected in 6 cases (1.5%) and segregated in a family. Thus, it was shown to be a polymorphism with a lower frequency in healthy controls than in patients with AML (P < 0.001). In addition, 21 of 234 CML (9.0%) and 7 of 155 ALL (4.5%) cases carried the FLT3 D324N. Our data suggest that the FLT3 D324N variant might be associated with a predisposition to different subtypes of leukemia. © 2005 Wiley-Liss, Inc. [source] Silencing MAT2A gene by RNA interference inhibited cell growth and induced apoptosis in human hepatoma cellsHEPATOLOGY RESEARCH, Issue 5 2007Quanyan Liu Aims:, A switch in gene expression from MAT1A to MAT2A was found in liver cancer, suggesting that MAT2A plays an important role in facilitating cancer growth. MAT2A is an interesting target for antineoplastic therapy. The molecular mechanisms of silencing MAT2A by RNA interference inhibited cell growth and induced apoptosis in hepatoma cells was studied. Methods:, We investigated the effects of MAT2A on S-adenosyl-methionine (SAM) production, cell growth and apoptotic cell death in hepatoma cell lines (Bel-7402, HepG2, and Hep3B) using an RNA interference approach. Results:, The treatment of three hepatoma cell lines with small interfering RNA (siRNA) targeting to the MAT2A gene resulted in reducing the MAT II activity, facilitating SAM production, increasing SAM : SAH ratio, inhibiting cell growth and inducing cell apoptosis in hepatoma cells. In addition, silencing MAT2A gene resulted in the stimulation of MAT1A mRNA production, which was blocked by 3-deazaadenosine and l -ethionine, but not d -ethionine, suggesting that such effect was specific and mediated by upregulation of SAM level and SAM : S-adenosylethionine (SAH) ratio. Conclusion:, Silencing MAT2A by sequence-specific small interfering RNA caused a switch of MAT gene expression from MAT2A to MAT1A, which led the content of SAM to change to a higher steady-state level that resulted in the inhibition of cell growth and the induction of apoptotic cell death in human hepatoma cells. These results also suggested that MAT2A may hold potential as a new target for liver cancer gene therapy. [source] c-FLIP expression in colorectal carcinomas: association with Fas/FasL expression and prognostic implicationsHISTOPATHOLOGY, Issue 2 2007P Korkolopoulou Aims:, Disruption of apoptotic cell death has been implicated in tumour aggressiveness in colonic carcinogenesis. The Fas,Fas ligand (FasL) system is involved in the execution of apoptosis induced by the immune system. c-FLIP protein constitutes an inhibitor of Fas and other (TRAIL) death receptor-mediated apoptosis. The aim of this study was to investigate the simultaneous expression of Fas, FasL and c-FLIP in relation to standard clinicopathological parameters and patients' outcome in colorectal cancer. Methods and results:, Levels of Fas, FasL and c-FLIP protein expression were quantified immunohistochemically in paraffin-embedded tissues from 90 patients. Immunopositivity was detected for Fas, FasL and c-FLIP in 71%, 35.5% and 68.8% of cases, respectively. Concurrent expression of Fas/FasL was seen in 28 samples (31%), of which 24 (85.7%) also displayed c-FLIP positivity (P = 0.04). c-FLIP overexpression (> 10%) tended to prevail marginally in higher stage tumours (P = 0.09). Additionally, FasL and c-FLIP adversely affected survival on both univariate (P = 0.001 and P = 0.0024, respectively) and multivariate analysis [hazard ratio (HR) 3.491, P = 0.005 and HR 2.960, P = 0.036, respectively]. Conclusions:, The frequent expression and coexpression of Fas, FasL and c-FLIP in colorectal carcinoma implicates c-FLIP as an inhibitor of the Fas,FasL-induced death pathway in these tumours. Moreover, c-FLIP conveys independent prognostic information in the presence of classical prognosticators. [source] Inhibition of Fas-mediated apoptotic cell death of murine T lymphocytes in a mouse model of immunosenescence in linkage to deterioration in cell membrane raft functionIMMUNOLOGY, Issue 1 2004Toshihiro Yokoyama Summary We previously developed a transgenic mouse line into which a rabbit protein kinase C, (PKC,) gene fused to a human CD2 promoter/enhancer was introduced, and we found that immunosenescence was facilitated in these transgenic mice. In this study, we found that along with age-dependent increase in the level of protein expression of PKC, and its translocation to the membrane, activated T cells became less sensitive to apoptosis-inducing anti-Fas antibody. The capacity of T cells to express Fas antigen on their surfaces in response to anti-CD3 and interleukin-2 was impaired in PKC,-transgenic mice of relatively advanced age, although background Fas expression levels on T cells from those mice were high. We then found that out of proportion to a high level of cell surface Fas expression the density of cholera toxin B (CTx)-binding raft elements decreased in PKC,-transgenic mice of relatively advanced age and to a lesser extent in normal mice of advanced age. Correspondingly, the expression level of raft-associating Lck was decreased in these mice. These findings suggest for the first time that immunosenescence of T cells involves a decrease in density of cell surface CTx-binding raft elements, which might underlie a deterioration in T-cell signal pathway for either cell death or cell activation. [source] Biscoclaurine alkaloid cepharanthine inhibits the growth of primary effusion lymphoma in vitro and in vivo and induces apoptosis via suppression of the NF-,B pathwayINTERNATIONAL JOURNAL OF CANCER, Issue 6 2009Naoko Takahashi-Makise Abstract Primary effusion lymphoma (PEL) is a unique and recently identified non-Hodgkin's lymphoma that was originally identified in patients with AIDS. PEL is caused by the Kaposi sarcoma-associated herpes virus (KSHV/HHV-8) and shows a peculiar presentation involving liquid growth in the serous body cavity and a poor prognosis. As the nuclear factor (NF)- ,B pathway is activated in PEL and plays a central role in oncogenesis, we examined the effect of a biscoclaurine alkaloid, cepharanthine (CEP) on PEL derived cell lines (BCBL-1, TY-1 and RM-P1), in vitro and in vivo. An methylthiotetrazole assay revealed that the cell proliferation of PEL cell lines was significantly suppressed by the addition of CEP (1,10 ,g/ml). CEP also inhibited NF- ,B activation and induced apoptotic cell death in PEL cell lines. We established a PEL animal model by intraperitoneal injection of BCBL-1, which led to the development of ascites and diffuse infiltration of organs, without obvious solid lymphoma formation, which resembles the diffuse nature of human PEL. Intraperitoneal administration of CEP inhibited ascites formation and diffuse infiltration of BCBL-1 without significant systemic toxicity in this model. These results indicate that NF- ,B could be an ideal molecular target for treating PEL and that CEP is quite useful as a unique therapeutic agent for PEL. © 2009 UICC [source] EGFR tyrosine kinase inhibition radiosensitizes and induces apoptosis in malignant glioma and childhood ependymoma xenograftsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2008Birgit Geoerger Abstract Malignant gliomas and childhood ependymomas have a high rate of treatment failure. Epidermal growth factor receptor (EGFR) activation has been implicated in the tumorigenesis and radioresistance of many cancers, including brain tumors. Therefore, combining EGFR targeting with irradiation is a potentially attractive therapeutic option. We evaluated the tyrosine kinase inhibitor gefitinib for its antitumor activity and potential to radio-sensitize in vivo in two xenograft models: an EGFR amplified glioma and an EGFR expressing ependymoma, both derived from primary tumors. When administered at 100 mg/kg for 5 consecutive days, gefitinib-induced partial tumor regression in all treated EGFR amplified IGRG88 glioma xenografts. The addition of 1 Gy of irradiation prior to gefitinib administration resulted in 5 complete and 4 partial regressions for the 9 treated tumors as well as a significant tumor growth delay of 33 days for the combined treatment compared to 19 days for each therapy alone, suggesting additive antitumor activity. Tumor regression was associated with inhibition of AKT and MAPK pathways by gefitinib. In contrast, the ependymoma IGREP83 was sensitive to irradiation, but remained resistant to gefitinib. Combined treatment was associated with inhibition of radiation-induced MAPK phosphorylation and significant induction of apoptotic cell death though radiation-induced AKT phosphorylation was maintained. Depending on the scheduling of both therapies, a trend towards superior antitumor activity was observed with combined treatment. Thus, EGFR targeting through tyrosine kinase inhibition appears to be a promising new approach in the treatment of EGFR-driven glioma, particularly in combination with radiation therapy. © 2008 Wiley-Liss, Inc. [source] The increased expression of Y box-binding protein 1 in melanoma stimulates proliferation and tumor invasion, antagonizes apoptosis and enhances chemoresistanceINTERNATIONAL JOURNAL OF CANCER, Issue 10 2007Birgit Schittek Abstract In previous studies we identified the transcription/translation factor Y-box-binding protein (YB-1) as a gene that is upregulated in primary melanoma and melanoma metastases when compared to benign melanocytic nevi. To analyze whether YB-1 expression correlates with melanoma progression in vitro and in vivo, we performed expression analysis on melanoma cell lines representing different stages of melanoma progression and on tissues of melanocytic nevi, primary melanoma and melanoma metastases. Our data indicate that compared to benign melanocytes YB-1 expression is increased in melanoma cells in vitro and in vivo and that YB-1 is translocated into the nucleus in invasive and metastatic melanoma cells. To reveal the functional role of YB-1 in melanoma progression we achieved a stable downregulation of YB-1 using shRNA in metastatic melanoma cells. Interestingly, YB-1 downregulation resulted in a pronounced reduced rate of proliferation and an increased rate of apoptotic cell death. In addition, migration and invasion of melanoma cells in monolayer and in a three-dimensional skin reconstruct in vitro was significantly reduced. These effects were accompanied by downregulation of genes involved in proliferation, survival and migration/invasion of melanoma cells such as MMP-2, bcl-2, Cyclin D1, p53 and p16INK4A. Furthermore, melanoma cells with a reduced YB-1 expression showed a decreased resistance to the chemotherapeutic agents cisplatin and etoposide. These data suggest that YB-1 is involved in malignant transformation of melanocytes and contributes to the stimulation of proliferation, tumor invasion, survival and chemoresistance. Thus, YB-1 may be a promising molecular target in melanoma therapy. © 2007 Wiley-Liss, Inc. [source] Cell proliferation and death in the brain of active and hibernating frogsJOURNAL OF ANATOMY, Issue 2 2009Silvia Cerri Abstract ,Binomial' cell proliferation and cell death have been studied in only a few non-mammalian vertebrates, such as fish. We thought it of interest to map cell proliferation/apoptosis in the brain of the frog (Rana esculenta L.) as this animal species undergoes, during the annual cycle, physiological events that could be associated with central nervous system damage. Therefore, we compared the active period and the deep underground hibernation of the frog. Using western blot analysis for proliferating cell nuclear antigen (PCNA), we revealed a positive 36 kDa band in all samples and found higher optical density values in the hibernating frogs than in active frogs. In both active and hibernating frogs, we found regional differences in PCNA-immunoreactive cells and terminal transferase dUTP nick-end labelling apoptotic cells in the ventricular zones and parenchyma areas of the main encephalon subdivisions. During the active period of the frogs, the highest concentration of PCNA-immunoreactive cells was found in the ventricle dorsal zone of the cerebral hemispheres but only some of the cells were apoptotic. By contrast, the tectal and cerebellar ventricular zones had a small or medium amount of PCNA-immunoreactive cells, respectively, and a higher number of apoptotic cells. During hibernation, an increased PCNA-immunoreactive cell number was observed in both the brain ventricles and parenchyma compared with active frogs. This increase was primarily evident in the lateral ventricles, a region known to be a proliferation ,hot spot'. Although differences existed among the brain areas, a general increase of apoptotic cell death was found in hibernating frogs, with the highest number of apoptotic cells being detected in the parenchyma of the cerebral hemispheres and optic tectum. In particular, the increased number of apoptotic cells in the hibernating frogs compared with active frogs in the parenchyma of these brain areas occurred when cell proliferation was higher in the corresponding ventricular zones. We suggest that the high number of dying cells found in the parenchymal regions of hibernating frogs might provide the stimulus for the ventricular zones to proliferate. Hibernating frogs could utilize an increased cell proliferation in the brain areas as a neuroprotective strategy to face cell death and the onset of neurological damages. Therefore, the hibernator promises to be a valuable model for studying the mechanisms naturally carried out by the central nervous system in order to adapt itself or survive adverse conditions. [source] Exposure to mixtures of endosulfan and zineb induces apoptotic and necrotic cell death in SH-SY5Y neuroblastoma cells, in vitroJOURNAL OF APPLIED TOXICOLOGY, Issue 5 2007Zhenquan Jia Abstract A number of epidemiological studies have demonstrated a strong association between the incidence of Parkinson's disease and pesticide exposure. Earlier it was demonstrated that exposure to the pesticides endosulfan and zineb, alone and in combination, caused neurodegeneration in vivo. It was hypothesized that these pesticides cause neurotoxicity, in part, by enhancing apoptotic cell death. SH-SY5Y human neuroblastoma cells, which retain a catecholaminergic phenotype, were exposed to endosulfan, zineb or a combination of these chemicals, in vitro. For mixture studies, concentrations of pesticides (100 µm each) were chosen based on LC25 (lethal concentration) that would result in minimum cell death. Exposure to a mixture of pesticides exhibited significantly (P , 0.05) higher toxicity than each one alone. Both pesticides were found to cause apoptotic cell death that was concentration (50,400 µm) dependent. A flow cytometric (7-aminoactinomycin D) assay was used to distinguish live, early apoptotic and late apoptotic/necrotic populations. Exposure to mixtures of the pesticides enhanced both early apoptosis and late apoptosis/necrosis compared with either chemical alone. Visual evaluation using a DNA ladder assay and a fluorescence Annexin V/PI assay confirmed the contribution of both apoptotic and necrotic processes. These findings suggest that the cytotoxicity of endosulfan and zineb, both individually and in mixtures, is associated with the occurrence of early and late apoptotic/necrotic processes in SH-SY5Y human neuroblastoma cells and support the contention that pesticide-induced neuronal cell death leading to neurodegenerative disease may, at least in part, be associated with early and late apoptosis of dopaminergic neurons. Copyright © 2007 John Wiley & Sons, Ltd. [source] The role of calcium in apoptosis induced by 7,-hydroxycholesterol and cholesterol-5,,6,-epoxideJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 5 2009Sinéad Lordan Abstract Oxysterols, such as 7,-hydroxy-cholesterol (7,-OH) and cholesterol-5,,6,-epoxide (,-epoxide), may have a central role in promoting atherogenesis. This is thought to be predominantly due to their ability to induce apoptosis in cells of the vascular wall and in monocytes/macrophages. Although there has been extensive research regarding the mechanisms through which oxysterols induce apoptosis, much remains to be clarified. Given that experimental evidence has long associated alterations of calcium (Ca2+) homeostasis to apoptotic cell death, the aim of the present study was to determine the influence of intracellular Ca2+ changes on apoptosis induced by 7,-OH and ,-epoxide. Ca2+ responses in differentiated U937 cells were assessed by epifluorescence video microscopy, using the ratiometric dye fura-2. Over 15-min exposure of differentiated U937 cells to 30 ,M of 7,-OH induced a slow but significant rise in fura-2 ratio. The Ca2+ channel blocker nifedipine and the chelating agent EGTA blocked the increase in cytoplasmic Ca2+. Moreover, dihydropyridine (DHP) binding sites identified with BODIPY-FLX-DHP were blocked following pretreatment with nifedipine, indicating that the influx of Ca2+ occurred through L-type channels. However, following long-term incubation with 7,-OH, elevated levels of cytoplasmic Ca2+ were not maintained and nifedipine did not provide protection against apoptotic cell death. Our results indicate that the increase in Ca2+ may be an initial trigger of 7,-OH,induced apoptosis, but following chronic exposure to the oxysterol, the influence of Ca2+ on apoptotic cell death appears to be less significant. In contrast, Ca2+ did not appear to be involved in ,-epoxide,induced apoptosis. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:324,332, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20295 [source] 2,-Deoxyadenosine causes apoptotic cell death in a human colon carcinoma cell lineJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 6 2003Michela Giannecchini Abstract The combination of 2,-deoxyadenosine and 2,-deoxycoformycin is toxic for the human colon carcinoma cell line LoVo. In this study we investigated the mode of action of the two compounds and have found that they promote apoptosis. The examination by fluorescence microscopy of the cells treated with the combination revealed the characteristic morphology associated with apoptosis, such as chromatin condensation and nuclear fragmentation. The occurrence of apoptosis was also confirmed by the release of cytochrome c and the proteolytic processing of procaspase-3 in cells subjected to the treatment. To exert its triggering action on the apoptotic process, 2,-deoxyadenosine enters the cells through an equilibrative nitrobenzyl-thioinosine-insensitive carrier, and must be phosphorylated by intracellular kinases. Indeed, in the present work we demonstrate by analysis of the intracellular metabolic derivatives of 2,-deoxyadenosine that, as suggested by our previous findings, in the incubation performed with 2,-deoxyadenosine and 2,-deoxycoformycin, an appreciable amount of dATP was formed. Conversely, when also an inhibitor of adenosine kinase was added to the incubation mixture, dATP was not formed, and the toxic and apoptotic effect of the combination was completely reverted. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:329,337, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10095 [source] Translational regulation in cell stress and apoptosis.JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2001Roles of the eIF4E binding proteins Abstract Several mechanisms have been identified by which protein synthesis may be regulated during the response of mammalian cells to physiological stresses and conditions that induce apoptotic cell death (reviewed in Clemens et al., Cell Death and Differentiation 7, 603,615, 2000). Recent developments allow us to up-date this analysis and in this article I concentrate on one particular aspect of this regulation that has not previously been reviewed in depth in relation to apoptosis, viz. the control of the initiation of protein synthesis by eukaryotic initiation factor eIF4E and the eIF4E binding proteins (4E-BPs). Changes in the state of phosphorylation of the 4E-BPs and in the extent of their association with eIF4E occur at an early stage in the response of cells to apoptotic inducers. The review discusses the mechanisms by which these events are regulated and the significance of the changes for the control of protein synthesis, cell proliferation and cell survival. [source] | |||||||||||||||||||||||||||||||||||||