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Secretory group IIA phospholipase A₂ generates anti-apoptotic survival signals in kidney fibroblasts

JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第39期274卷 27726-27733页

作者： Zhang, YP Lemasters, J Herman, B Univ Texas Hlth Sci Ctr Dept Cellular & Struct Biol San Antonio TX 78284 USA Univ N Carolina Dept Cell Biol & Anat Chapel Hill NC 27599 USA

Mammalian group IIA phospholipase A(2) (PLA(2)) is believed to play important roles in inflammation, cell injury, and tumor resistance. However, the cellular site of action has not been clearly defined as it has long been recognized that group IIA PLA(2) is both a secretory and mitochondrial protein. The purpose of this study was to determine the subcellular target of the group IIA PLA(2) and its role in apoptosis stimulated by growth factor withdrawal. Cloning of the rat liver group IIA PLA(2) demonstrated a typical secretory signal and no alternative splicing of the primary transcript. When a sequence including the signal peptide and first 8 residues in the mature enzyme or the entire PLA(2) (including the signal peptide) was fused to enhanced green fluorescent protein, the fusion protein was directed to the secretory pathway rather than mitochondria in baby hamster kidney (BHK) cells. To examine the role of group IIA PLA(2) in cell injury, wild type (wt) rat group IIA PLA(2) and a mutant group IIA PLA(2) containing a His-47 --> Gln mutation (at the catalytic center) were transfected into BHK cells and cells stably expressing these constructs were isolated. After deprivation of growth factors, both normal BHK cells and BHK cells expressing mutant PLA(2) underwent massive apoptosis, while BHK cells expressing wt PLA(2) showed considerable resistance to growth factor withdrawal-induced apoptosis, The secretory PLA(2) inhibitors 12-epi-scalaradial and aristolochic acid abrogated resistance to apoptosis in the wt PLA(2) expressing cells. These two inhibitors did not induce cell death in the presence of fetal bovine serum, suggesting that they induce cell death by blocking PLA(2) generated survival signals. This study demonstrates that group IIA PLA(2) generates anti-apoptotic survival signals in BHK cells targeting the secretory pathway, and suggests that high levels of group HA PLA(2) accumulated at inflammatory sites may not only regulate inflammation, but also may

关键词：选择性剪接细胞凋亡/生理学碱基序列 CHO细胞细胞系细胞存活/生理学仓鼠亚科培养基成纤维细胞生长物质/生理学肾动力学肝/酶学分子序列数据磷脂酶A/遗传学磷脂酶A/代谢聚合酶链反应 RNA 信使/遗传学重组融合蛋白质类/代谢信号传导/生理学转染动物牛大鼠

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A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第12期275卷 8641-8649页

作者： Kainulainen, V Sundvall, M Määttä, JA Santiestevan, E Klagsbrun, M Elenius, K Univ Turku Medicity Res Labs FIN-20520 Turku Finland Univ Turku Dept Pediat FIN-20520 Turku Finland Univ Turku Dept Med Biochem & Mol Biol FIN-20520 Turku Finland Childrens Hosp Dept Surg Boston MA 02115 USA Childrens Hosp Dept Pathol Boston MA 02115 USA Harvard Univ Sch Med Boston MA 02115 USA

ErbB4 is a member of the epidermal growth factor receptor (ErbB) family that mediates cellular responses activated by neuregulins (NRG) and other epidermal growth factor-like growth factors. TWO naturally occurring ErbB4 isoforms, ErbB4 CYT-1 and ErbB4 CYT-2, have previously been identified. Unlike ErbB4 CYT-1, ErbB4 CYT-2 lacks a phosphoinositide 3-kinase (PIS-K)binding site and is incapable of activating PI3-K. We have now examined the consequences of the inability of this isoform to activate PI3-K on cell proliferation, survival, and chemotaxis in response to NRG-1 beta: (i) NRG-1 beta stimulated proliferation of cells expressing either ErbB4 CYT-1 or ErbB4 CYT-S, Consistent with the mitogenic responsiveness, analysis of downstream signaling showed that Shc and MAPK were phosphorylated after stimulating either isoform with NRG-1 beta. (ii) NRG-1 beta protected cells expressing ErbB4 CYT-1 but not cells expressing ErbB4 CYT-Q from starvation-induced apoptosis as measured by effects on cell number and 4',6-diamidino-2-phenylindole staining. Furthermore, in cells expressing ErbB4 CYT-2, Akt, a protein kinase that mediates cell survival, was not phosphorylated. (iii) NRG-1 beta stimulated chemotaxis and membrane ruffling in cells expressing ErbB4 CYT-1 but not in cells expressing ErbB4 CYT-8, In summary, ErbB4 CYT-8 can mediate proliferation but not chemotaxis or survival. These results suggest a novel mechanism by which cellular responses such as chemotaxis and survival may be regulated by the expression of alternative receptor-tyrosine kinase isoforms that differ in their coupling to PI3-K signaling.

关键词： 3T3细胞衔接蛋白质类信号转导衔接蛋白质类膜泡运输细胞凋亡细胞分裂/生理学细胞存活/生理学趋化作用/生理学培养基无血清酶激活丝裂原激活蛋白激酶类/代谢神经调节蛋白1/代谢磷酸肌醇3-激酶类/代谢磷酰化蛋白质亚型/代谢蛋白质丝氨酸苏氨酸激酶蛋白质类/代谢原癌基因蛋白质类/代谢原癌基因蛋白质c-akt Shc信号衔接蛋白质类信号传导动物小鼠

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Apoptosis signal-regulating kinase 1 (ASK1) induces neuronal differentiation and survival of PC12 cells

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第13期275卷 9805-9813页

作者： Takeda, K Hatai, T Hamazaki, TS Nishitoh, H Saitoh, M Ichijo, H Tokyo Med & Dent Univ Dept Biomat Sci Fac Dent Bunkyo Ku Tokyo 1138549 Japan

Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase kinase kinase that activates the c-dun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase signaling cascades, We report here that expression of constitutively active ASK1 (ASK1 Delta N) induces neurite outgrowth in the rat pheochromocytoma cell line PC12, We found that p38 and to a lesser extent JNK, but not ERK, were activated by the expression of ASK1 Delta N in PC12 cells. ASK1 Delta N-induced neurite outgrowth was strongly inhibited by treatment with the p38 inhibitor SB203580 but not with the MEK inhibitors, suggesting that activation of p38, rather than of ERK, is required for the neurite-inducing activity of ASK1 in PC12 cells. We also observed that ASK1 Delta N induced expression of several neuron-specific proteins and phosphorylation of neurofilament proteins, confirming that PC12 cells differentiated into mature neuronal cells by ASK1. Moreover, ASK1 Delta N-expressing PC12 cells survived in serum-starved condition. ASK1 thus appears to mediate signals leading to both differentiation and survival of PC12 cells. Together with previous reports indicating that ASI(1 functions as a pro-apoptotic signaling intermediate, these results suggest that ASK1 has a broad range of biological activities depending on cell types and/or cellular context.

关键词：拟南芥蛋白质类钙-钙调素依赖性蛋白激酶类/拮抗剂和抑制剂钙-钙调素依赖性蛋白激酶类/代谢细胞分化/生理学细胞存活/生理学培养基无血清酶激活酶抑制剂/药理学咪唑类/药理学丝裂原激活蛋白激酶类神经突神经元/细胞学 PC12细胞植物蛋白质类/生理学吡啶类/药理学 p38丝裂原活化蛋白激酶类动物大鼠

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Cross-talk between phosphatidylinositol 3-kinase and sphingomyelinase pathways as a mechanism for cell survival/death decisions

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第13期275卷 9628-9635页

作者： Burow, ME Weldon, CB Collins-Burow, BM Ramsey, N McKee, A Klippel, A McLachlan, JA Clejan, S Beckman, BS Tulane Univ Med Ctr Dept PharmacolSch Med Tulane Ctr Bioenvironm Res New Orleans LA 70112 USA Tulane Univ Sch Med Dept Pathol & Lab Med New Orleans LA 70112 USA Tulane Univ Sch Med Dept Surg New Orleans LA 70112 USA Tulane Univ Sch Med Tulane Canc Ctr New Orleans LA 70112 USA Tulane Univ Sch Med Dept Pharmacol New Orleans LA 70112 USA Tulane Univ Sch Med Mol & Cellular Biol Program New Orleans LA 70112 USA Chiron Corp Emeryville CA 94608 USA

Peptide hormones act to regulate apoptosis through activation of multiple pro- and anti-apoptotic signaling cascades of which lipid signaling events represent an important facet of the cellular rheostat that determines survival and death decisions. Activation of sphingomyelinase, which generates ceramide, is an intermediate in cellular stress responses and induction of apoptosis in many systems. Conversely, phosphatidylinositol 3-kinase (PI3K) is a critical signaling molecule involved in regulating cell survival and proliferation pathways. In the present study, we investigate cross-talk between the PI3K and sphingomyelinase pathways as a mechanism for regulation of cell survival/death decisions. We show that phorbol ester, insulin-like growth factor 1, and a constitutively active PI3K suppress both tumor necrosis factor-induced apoptosis and ceramide generation. Conversely, inhibition of the PI3K pathway with expression of a kinase-dead PI3K both prevented survival signaling and enhanced tumor necrosis factor-induced ceramide generation. The ability of exogenous sphingomyelinase to induce ceramide generation was partially suppressed by expression of constitutively active PI3K and enhanced by inhibition of PI3K suggesting that cross-talk between PI3K and ceramide generation within cells is regulated subsequent to activation of sphingomyelinase.

关键词：细胞凋亡/生理学细胞存活/生理学神经酰胺类/拮抗剂和抑制剂神经酰胺类/生理学酶激活成纤维细胞生长因子/药理学磷酸肌醇3-激酶类/代谢血小板源性生长因子/药理学信号传导鞘磷脂磷酸二酯酶/代谢十四酰佛波乙酯/药理学肿瘤细胞培养的肿瘤坏死因子α/生理学人类

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Pituitary tumor transforming gene (PTTG) regulates placental JEG-3 cell division and survival: Evidence from live cell imaging

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MOLECULAR ENDOCRINOLOGY 2000年第8期14卷 1137-1146页

作者： Yu, R Ren, SG Horwitz, GA Wang, ZY Melmed, S Univ Calif Los Angeles Sch Med Cedars Sinai Res Inst Div Endocrinol Los Angeles CA 90048 USA

The pituitary transforming gene, PTTG, is abundantly expressed in endocrine neoplasms. PTTG has recently been recognized as a mammalian securin based on its biochemical homology to Pds1 p. PTTG expression and intracellular localization were therefore studied during the cell cycle in human placental JEG-3 cells. PTTG mRNA and protein expressions were low at the G(1)/S border, gradually increased during S phase, and peaked at G(2)/M, but PTTG level were attenuated as cells entered G(1). In interphase cells, wild-type PTTG, an epitope-tagged PTTG, and a PTTG-EGFP conjugate all localized to both the nucleus and cytoplasm, but in mitotic cells, PTTG was not observed in the chromosome region. PTTG-EGFP colocalized with mitotic spindles in early mitosis and was degraded in anaphase. Intracellular fates of PTTG-EGFP and a conjugate of EGFP and a mutant inactivated PTTG devoid of an SH3-binding domain were observed by real-time visualization of the EGFP conjugates in live cells. The same cells were continuously observed as they progressed from G(1)/S border to S, G(2)/M, and G(1). Most cells (67%) expressing PTTG-EGFP died by apoptosis, and few cells (4%) expressing PTTG-EGFP divided, whereas those expressing mutant PTTG-EGFP divided. PTTG-EGFP, as well as the mutant PTTG-EGFP, disappeared after cells divided. The results show that PTTG expression and localization are cell cycle-dependent and demonstrate that PTTG regulates endocrine tumor cell division and survival.

关键词：氨基酸序列细胞周期/生理学细胞分裂/生理学细胞存活/生理学绿色荧光蛋白质类发光蛋白质类/分析发光蛋白质类/遗传学发光蛋白质类/代谢分子序列数据肿瘤蛋白质类/遗传学肿瘤蛋白质类/代谢胎盘/细胞学重组蛋白质类/遗传学重组蛋白质类/代谢肿瘤细胞培养的人类

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Withdrawal of life support, altruistic suicide, fratricidal killing and euthanasia by lymphocytes: different forms of drug-induced hepatic apoptosis

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JOURNAL OF HEPATOLOGY 1999年第4期31卷 760-770页

作者： Pessayre, D Haouzi, D Fau, D Robin, MA Mansouri, A Person, A Hop Beaujon INSERM U481 F-92118 Clichy France Hop Beaujon Ctr Claude Bernard Hepatites Virales F-92118 Clichy France

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Functional expression of exogenous proteins in mammalian sensory hair cells infected with adenoviral vectors

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JOURNAL OF NEUROPHYSIOLOGY 1999年第4期81卷 1881-1888页

作者： Holt, JR Johns, DC Wang, S Chen, ZY Dunn, RJ Marban, E Corey, DP Massachusetts Gen Hosp Dept Neurol Boston MA 02114 USA Harvard Univ Sch Med Dept Neurobiol Cambridge MA 02138 USA Howard Hughes Med Inst Boston MA 02114 USA Johns Hopkins Univ Sch Med Sect Mol & Cellular Cardiol Baltimore MD 21205 USA Montreal Gen Hosp Neurosci Res Ctr Montreal PQ H3G 1A4 Canada

To understand the function of specific proteins in sensory hair cells, it is necessary to add or inactivate those proteins in a system where their physiological effects can be studied. Unfortunately, the usefulness of heterologous expression systems for the study of many hair cell proteins is limited by the inherent difficulty of reconstituting the hair cell's exquisite cytoarchitecture. Expression of exogenous proteins within hair cells themselves may provide an alternative approach. Because recombinant viruses were efficient vectors for gene delivery in other systems, we screened three viral vectors for their ability to express exogenous genes in hair cells of organotypic cultures from mouse auditory and vestibular organs. We observed no expression of the genes for beta-galactosidase or green fluorescent protein (GFP) with either herpes simplex virus or adeno-associated virus. On the other hand, we found robust expression of GFP in hair cells exposed to a recombinant, replication-deficient adenovirus that carried the gene for GFP driven by a cytomegalovirus promoter. Titers of 4 x 10(7) pfu/ml were sufficient for expression in 50% of the similar to 1,000 hair cells in the utricular epithelium;< 1% of the nonhair cells in the epithelium were GFP positive. Expression of GFP was evident as early as 12 h postinfection, was maximal at 4 days, and continued for at least 10 days. Over the first 36 h there was no evidence of toxicity. We recorded normal voltage-dependent and transduction currents from infected cells identified by GFP fluorescence. At longer times hair bundle integrity was compromised despite a cell body that appeared healthy. To assess the ability of adenovirus-mediated gene transfer to alter hair cell function we introduced the gene for the ion channel Kir2.1. We used an adenovirus vector encoding Kir2.1 fused to GFP under the control of an ecdysone promoter. Unlike the diffuse distribution within the cell body we observed with Gm, the ion channel-GFP fu

关键词：腺病毒科腺病毒科感染/病理生理学细胞存活/生理学基因表达调控病毒基因转移技术基因检测绿色荧光蛋白质类毛细胞听觉/细胞学毛细胞听觉/生理学毛细胞听觉/病毒学指示剂和试剂发光蛋白质类膜电位/生理学小鼠近交系膜片钳术钾通道/遗传学钾通道内向整流球囊和椭圆囊/化学球囊和椭圆囊/细胞学动物小鼠

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Role of PI 3-kinase in angiopoietin-1-mediated migration and attachment-dependent survival of endothelial cells

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EXPERIMENTAL CELL RESEARCH 1999年第2期253卷 663-672页

作者： Fujikawa, K Scherpenseel, ID Jain, SK Presman, E Varticovski, L Tufts Univ Sch Med Dept Med St Elizabeths Med Ctr Boston MA 02135 USA

Angiopoietin-1 is a unique growth factor which induces Tie2 receptor autophosphorylation and interaction with signal transduction molecules, GRB2 and p85 subunit of PI 3-kinase, but no detectable mitogenic response. Here we show that PI 3-kinase-dependent activation of Akt and attachment to extracellular matrix are required for angiopoietin-1-mediated endothelial cell survival. Apoptosis of growth factor-deprived cells grown in monolayer was decreased by angiopoietin-1 and correlated with Akt activation. In contrast, angiopoietin-1, bFGF or VEGF failed to protect cells in suspension culture. Ceramide, an intermediate of several apoptotic pathways, interferes with growth factor-mediated Akt activation. Ceramide induced endothelial cell death and abolished angiopoietin-1-mediated activation of Akt and the effect on cell survival. In addition, we found that PI 3-kinase activity is necessary for migration of endothelial cells in response to Angiopoietin-1. A transient activation of MAPK/ERKs was also detected within 10 min after stimulation with angiopoietin-1. In contrast to VEGF-mediated biological effects, inhibition of MAPK/ERKs by PD98059 in endothelial cells did not affect angiopoietin-1 mediated survival or migration. These findings indicate significant differences in intracellular signaling between VEGF and angiopoietin-1 and that PI 3-kinase lipid products are key mediators of the biological effects of angiopoietin-1. (C) 1999 Academic Press.

关键词：血管生成素1 细胞凋亡/生理学细胞黏附/生理学细胞运动/生理学细胞存活/药物作用细胞存活/生理学色酮类/药理学内皮生长因子/药理学内皮血管/细胞学内皮血管/酶学酶激活/药物作用酶激活/生理学酶抑制剂/药理学成纤维细胞生长因子2/药理学淋巴因子/药理学膜糖蛋白类/代谢丝裂原激活蛋白激酶类/代谢吗啉类/药理学蛋白质丝氨酸苏氨酸激酶/代谢原癌基因蛋白质类原癌基因蛋白质c-akt 鞘氨醇/类似物和衍生物鞘氨醇/药理学脐静脉/细胞学血管内皮生长因子A 血管内皮生长因子类人类

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Enhanced secretion of cardiac hepatocyte growth factor from an infarct region is associated with less severe ventricular enlargement and improved cardiac function

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2000年第1期36卷 115-121页

作者： Yasuda, S Goto, Y Baba, T Satoh, T Sumida, H Miyazaki, S Nonogi, H Natl Cardiovasc Ctr Div Cardiol Dept Internal Med Suita Osaka 5658565 Japan

OBJECTIVES We hypothesized that the hepatocyte growth factor (HGF) may play a cardioprotective role in human myocardial infarction (MI). BACKGROUND The HGF is a novel, multifunctional growth factor implicated in wound healing, angiogenesis and promotion of cell survival. Recent animal studies have demonstrated the existence of an HGF system in the heart, where it is activated in response to myocardial ischemia and reperfusion. METHODS We studied 40 patients with acute myocardial infarction (AMI), who underwent coronary reperfusion therapy upon admission. Approximately four weeks later, left ventricular (LV) catheterization was repeated to determine the LV ejection fraction (EF), end-diastolic volume index (EDVI) and pressure (EDP). The levels of HGF and brain natriuretic peptide (BNP) were measured Ly collecting blood samples from cardiac veins draining the infarcted region (MI region) and those draining the noninfarcted region (non-MI region). The ratio of the HGF level in the MI region to that in the non-MI region (= MI/non-MI ratio) was calculated in each patient as an index of the MI-related HGF secretion. RESULTS The MI/non-MI ratio for BNP was also calculated. The MI/non-MI ratio for HGF correlated inversely with LVEDP (r = -0.633, p < 0.0001) and LVEDVI (r = -0.843, p < 0.0001) and positively with LVEF (r = 0.763, p < 0.0001). These correlations were completely opposite in direction from those for BNP and LVEDP (r = 0.678, p < 0.0001), LVEDVI (r = 0.783, p < 0.0001) and LVEF (r = -0.805, p < 0.0001). These findings indicate that cardiac HGF acts in contrast to BNP, a biochemical marker for the development of LV remodeling. CONCLUSION Enhanced secretion of cardiac HGF from the MI region is associated with an attenuation of ventricular enlargement and an improvement in cardiac function. The HGF system may modulate the process of ventricular remodeling and thus have important clinical implications. (J Am Cell Cardiol 2000;36:115-21) (C) 2000 by the American Coll

关键词：心排血量细胞存活/生理学冠状血管造影术酶联免疫吸附测定心室/诊断显像心室/代谢心室/病理生理学肝细胞生长因子/血液肝细胞生长因子/代谢心肌梗死/血液心肌梗死/诊断显像心肌梗死/病理生理学心肌梗死/治疗心肌再灌注/方法心肌/代谢利钠肽脑/血液预后功能恢复回顾性研究心室压心室重构/生理学人类男(雄)性中年人

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CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex

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NATURE NEUROSCIENCE 2000年第9期3卷 867-872页

作者： Elson, GCA Lelièvre, E Guillet, C Chevalier, S Plun-Favreau, H Froger, J Suard, I de Coignac, AB Delneste, Y Bonnefoy, JY Gauchat, JF Gascan, H Ctr Immunol Pierre Fabre F-74164 St Julien Genevois France CHU Angers INSERM E9928 F-49033 Angers France

Ciliary neurotrophic factor (CNTF) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, CNTFR, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (LIFR). Striking phenotypic differences between CNTF- and CNTFR-deficient mice suggest that CNTFR serves as a receptor for a second, developmentally important ligand. We have identified this factor as a stable secreted complex of cardiotrophin-like cytokine (CLC) and the soluble receptor cytokine-like factor-1 (CLF). CLF expression was required for CLC secretion, and the complex acted only on cells expressing functional CNTF receptors. The CLF/CLC complex activated gp130, LIFR and signal transducer and activator of transcription 3 (STAT3) and supported motor neuron survival. Our results indicate that the CLF/CLC complex is a second ligand for CNTFR with potentially important implications in nervous system development.

关键词： COS细胞细胞分化/生理学细胞存活/生理学细胞因子类/代谢细胞因子类/分泌配体运动神经元/细胞学运动神经元/代谢神经变性/病理生理学放射配体测定受体睫状神经营养因子/代谢受体细胞因子/代谢肿瘤细胞培养的动物

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