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ATF6 as a transcription activator of the endoplasmic reticulum stress element: Thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1

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MOLECULAR AND CELLULAR BIOLOGY 2000年第14期20卷 5096-5106页

作者： Li, MQ Baumeister, P Roy, B Phan, T Foti, D Luo, SZ Lee, AS Univ So Calif Keck Sch Med Dept Biochem & Mol Biol USC Norris Comprehens Canc Ctr Los Angeles CA 90089 USA

ATF6, a member of the leucine zipper protein family, can constitutively induce the promoter of glucose-regulated protein (grp) genes through activation of the endoplasmic reticulum (ER) stress element (ERSE). To understand the mechanism of grp78 induction by ATF6 in cells subjected to ER calcium depletion stress mediated by thapsigargin (Tg) treatment, we discovered that ATF6 itself undergoes Tg stress induced changes. In nonstressed cells, ATF6, which contains a putative short transmembrane domain, is primarily associated with the perinuclear region. Upon Tg stress, the ATF6 protein level dropped initially but quickly recovered with the additional appearance of a faster-migrating form. This ne cv form of ATF6 was recovered as soluble nuclear protein by biochemical fractionation, correlating with enhanced nuclear localization of ATF6 as revealed by immunofluorescence. Optimal ATF6 stimulation requires at least two copies of the ERSE and the integrity of the tripartite structure of the ERSE. Of primary importance is a functional NF-Y complex and a high-affinity NF-Y binding site that confers selectivity among different ERSEs for ATF6 inducibility. In addition, we showed that YY1 interacts with ATF6 and in Tg-treated cells can enhance ATF6 activity. The ERSE stimulatory activity of ATF6 exhibits properties distinct from those of human Ire1p, an upstream regulator of the mammalian unfolded protein response. The requirement for a high-affinity NF-Y site for ATF6 but not human Ire1p activity suggests that they stimulate the ERSE through diverse pathways.

关键词： 3T3细胞/药物作用 3T3细胞/代谢激活转录因子6 碱性亮氨酸拉链转录因子类 CCAAT增强子结合蛋白类 COS细胞/药物作用 COS细胞/代谢载体蛋白质类/遗传学载体蛋白质类/代谢 dna结合蛋白质类/药物作用 dna结合蛋白质类/遗传学 dna结合蛋白质类/代谢内质网/药物作用内质网/生理学内切核糖核酸酶类酶抑制剂/药理学红系细胞特异性dna结合因子类热休克蛋白质类膜糖蛋白类/代谢膜蛋白质类分子伴侣/遗传学分子伴侣/代谢启动区遗传蛋白质丝氨酸苏氨酸激酶/代谢阻遏蛋白质类/代谢反应元件酿酒酵母蛋白质类应激生理学毒胡萝卜内酯/药理学转录因子/药物作用转录因子/遗传学转录因子/代谢 YY1转录因子动物人类小鼠

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The mechanism of taurine chloramine inhibition of cytokine (interleukin-6, interleukin-8) production by rheumatoid arthritis fibroblast-like synoviocytes

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ARTHRITIS AND RHEUMATISM 2000年第10期43卷 2169-2177页

作者： Kontny, E Szczepanska, K Kowalczewski, J Kurowska, M Janicka, I Marcinkiewicz, J Maslinski, W Inst Rheumatol Dept Pathophysiol & Immunol PL-02637 Warsaw Poland Jagiellonian Univ Coll Med Krakow Poland Med Univ Warsaw Warsaw Poland

Objective, Taurine chloramine (Tau-Cl) has been shown to inhibit the production of proinflammatory cytokines (interleukin-6 [IL-6] and IL-8) by fibroblastlike synoviocytes (FLS) isolated from rheumatoid arthritis (RA) patients, The present study was conducted to elucidate the mechanism of inhibitory action exerted by Tau-Cl, Methods. The effects of Tau-Cl on 1) the transcription of genes coding for IL-6 and IL-8, and 2) the activity of nuclear factor kappa B (NF-kappa B) and activator protein 1 (AP-1) transcription factors, which are crucial for the transcription of these cytokine genes, were investigated in FLS isolated from the synovial tissue of RA patients. FLS were cultured in vitro for 3-6 passages and stimulated with recombinant human IL-1 beta (1 ng/ mi) in the presence of either Tau or Tau-Cl, which were added simultaneously with the stimulus at concentrations of 250 mu M or 500 mu M. The relative expression of IL-6 and IL-8 messenger RNA (mRNA) was evaluated after 4 hours of stimulation, using competitive reverse transcriptase-polymerase chain reaction. The dna binding activity of NF-kappa B and AP-1 was examined 30 minutes and 2 hours after cell stimulation, respectively, using electromobility gel shift assay. Results. IL-1 beta triggered a significant rise in the activity of transcription factors NF-kappa B and AP-1, followed by an elevation of cytokine IL-6 and IL-8 mRNA expression. Tau-Cl, but not Tau, reduced IL-1 beta-triggered cytokine mRNA expression, exerting stronger inhibitory activity on the levels of IL-6 than on those of IL-8, Importantly, Tau-Cl also diminished the activity of NF-kappa B and, to a lesser extent, that of AP-1 transcription factor. Neither IL-1 beta nor Tau-Cl affected the activity of octamer transcription factor 1, Conclusion. Tau-Cl inhibition of IL-6 and IL-8 synthesis in FLS from RA patients results from the ability of this compound to diminish the activity of the major transcriptional regulators (NF-kappa B and AP-1), whi

关键词：关节炎类风湿/代谢关节炎类风湿/病理学 dna结合蛋白质类/药物作用成纤维细胞/细胞学宿主细胞因子C1 炎症介导素类/药理学白细胞介素6/拮抗剂和抑制剂白细胞介素6/生物合成白细胞介素6/遗传学白细胞介素8/拮抗剂和抑制剂白细胞介素8/生物合成白细胞介素8/遗传学 NF-κB/药物作用八聚体转录因子1 滑膜/代谢滑膜/病理学牛磺酸/类似物和衍生物牛磺酸/药理学转录因子AP-1/药物作用转录因子/药物作用转录遗传/药物作用老年人女(雌)性人类男(雄)性中年人

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Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第9期97卷 4790-4795页

作者： Strick, R Strissel, PL Borgers, S Smith, SL Rowley, JD Univ Chicago Dept Med Hematol Oncol Sect Chicago IL 60637 USA

Chromosomal translocations involving the MLL gene occur in about 80% of infant leukemia. In the search for possible agents inducing infant leukemia, we identified bioflavonoids. natural substances in food as well as in dietary supplements, that cause site-specific dna cleavage in the MLL breakpoint cluster region (BCR) in vivo. The MLL BCR dna cleavage was shown in primary progenitor hematopoietic cells from healthy newborns and adults as well as in cell lines;it colocalized with the MLL BCR cleavage site induced by chemotherapeutic agents, such as etoposide (VP16) and doxorubicin (Dox), Both in vivo and additional in vitro experiments demonstrated topoisomerase II (topo II) as the target of bioflavonoids similar to VP16 and Dox, Based on 20 bioflavonoids tested, we identified a common structure essential for topo II-induced dna cleavage. Reversibility experiments demonstrated a religation of the bioflavonoid as well as the VP16-induced MLL cleavage site. Our observations support a two-stage model of cellular processing of topo II inhibitors: The first and reversible stage of topo II-induced dna cleavage results in dna repair, but also rarely in chromosome translocations;whereas the second, nonreversible stage leads to cell death because of an accumulation of dna damage. These results suggest that maternal ingestion of bioflavonoids may induce MLL breaks and potentially translocations in utero leading to infant and early childhood leukemia.

关键词：细胞分化细胞培养的 dna拓扑异构酶类 Ⅱ型/代谢 dna结合蛋白质类/药物作用 dna结合蛋白质类/遗传学膳食外显子胎血/细胞学类黄酮物质/副作用类黄酮物质/药理学造血干细胞/细胞学组蛋白赖氨酸N-甲基转移酶白血病髓样急性/流行病学白血病髓样急性/遗传学髓淋巴细胞性白血病蛋白质前体细胞淋巴母细胞白血病淋巴瘤/流行病学前体细胞淋巴母细胞白血病淋巴瘤/遗传学原癌基因转录因子易位遗传成年人人类婴儿婴儿新生

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Stimulation of 92-kd gelatinase (matrix metalloproteinase 9) production by interleukin-17 in human monocyte/macrophages - A possible role in rheumatoid arthritis

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ARTHRITIS AND RHEUMATISM 2000年第5期43卷 1134-1144页

作者： Jovanovic, DV Martel-Pelletier, J Di Battista, JA Mineau, F Jolicoeur, FC Benderdour, M Pelletier, JP Univ Montreal Notre Dame Hosp Ctr Hosp Osteoarthrit Res Unit Montreal PQ H2L 4M1 Canada

Objective, To examine the cellular mechanisms by which the proinflammatory cytokine interleukin-17 (IL-17) induces the synthesis of 92-kd gelatinase (matrix metalloproteinase 9 [MMP-9]) by human monocyte/macrophages in primary culture. Methods, IL-17-stimulated human monocytes isolated from the peripheral blood of healthy donors were cultured in the presence of antiinflammatory cytokines, neutralizing antibodies against IL-1 beta, tumor necrosis factor alpha (TNF alpha), or IL-1 receptor antagonist, and with protein kinase inhibitors of diverse specificity. MMP measurements were performed using specific enzyme-linked immunosorbent assays, while the expression of specific messenger RNA was determined by Northern blotting. Detection of phosphorylated proteins and specific transcriptional factors was performed by Western blotting and by gel retardation experiments, respectively. Results. Biologically active IL-17 was detected in the synovial fluid of patients with rheumatoid arthritis. IL-17-induced MMP-9 production in human monocyte/macrophages was dependent on endogenous prostaglandin E-2 synthesis and related to autocrine stimulation by TNF alpha, but was IL-1 beta independent. This activation involves both p42/44 and p38 kinases and nuclear factor kappa B. IL-17-inducible activator protein 1 and signal transducer and activator of transcription 1/3 may transactivate the MMP-9 promoter. Conclusion. IL-17 may contribute to an unbalanced production of proinflammatory cytokines and MMP-9 in diseased articular joint tissues by interacting with the macrophages in the rheumatoid synovium.

关键词：关节炎类风湿/血液关节炎类风湿/病理生理学环氧化酶2 dna结合蛋白质类/药物作用地诺前列酮/分泌酶抑制剂/药理学白细胞介素1/拮抗剂和抑制剂白细胞介素17/分析白细胞介素17/药理学同工酶类/生物合成同工酶类/药物作用巨噬细胞/药物作用巨噬细胞/酶学巨噬细胞/代谢基质金属蛋白酶9/生物合成膜蛋白质类单核细胞/药物作用单核细胞/代谢前列腺素内过氧化物合酶类/生物合成前列腺素内过氧化物合酶类/药物作用蛋白激酶抑制剂 STAT1转录因子 STAT3转录因子信号传导/生理学滑液/化学反式激活因子类/药物作用转录因子AP-1/药物作用肿瘤坏死因子α/拮抗剂和抑制剂成年人老年人女(雌)性人类男(雄)性中年人

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Post-translational regulation of AP-1 transcription factor dna-binding activity in the rat conceptus

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MOLECULAR PHARMACOLOGY 1999年第3期56卷 537-544页

作者： Ozolins, TRS Hales, BF McGill Univ Dept Pharmacol & Therapeut Montreal PQ H3G 1Y6 Canada

Activator protein-1 (AP-I) transcription factor dna binding is induced during transient oxidative stress in the midorganogenesis rat conceptus in culture. L-2-Oxothiazolidine-4-carboxylate (OTC)I a cysteine prodrug, prevented oxidative stress and the induction of AP-I binding activity in the embryo but not in the yolk sac. Because AP-I activity may be a significant determinant of developmental outcome after insult, we investigated the regulation of AP-1 activity in the conceptus. Supershift assays indicated that basal AP-I binding in the embryo was due primarily to JunD, whereas in the yolk sac c-Jun and JunD were important. Under oxidative stress, c-Fos and c-Jun contributed to the AP-1 binding in the embryo;in the yolk sac, a c-fos-shifted complex emerged. OTC protection from oxidative stress did not change the AP-I composition, suggesting that increased AP-I activity was due to post-translational modifications, Changes in AP-I activity in embryos under oxidative stress or with OTC protection were not the result of alterations in the net phosphorylation state of Fos or Jun proteins or of changes in activities of the extracellular signal-regulated kinases 1 and 2 or stress-activated protein kinases. However, immunodepletion of redox factor 1 (Ref-l), a nuclear factor that promotes AP-I binding, eliminated AP-1 activity from embryonic nuclear extracts under both basal and oxidative stress conditions. Therefore, Ref-l plays a critical role in regulating AP-1 activity in the conceptus;it is plausible that Ref-l-mediated modulation of the AP-I stress response is a determinant of embryonic fate.

关键词：钙-钙调素依赖性蛋白激酶类/代谢碳氧裂合酶类/代谢 dna-(无嘌呤或无嘧啶位点)裂合酶 dna结合蛋白质类/药物作用 dna结合蛋白质类/代谢胚胎哺乳动物/代谢基因 jun HeLa细胞 JNK丝裂原活化蛋白激酶类 MAP激酶激酶4 丝裂原激活蛋白激酶激酶类氧化性应激/药物作用磷酰化蛋白质生物合成蛋白激酶类/代谢吡咯烷酮羧酸大鼠 Sprague-Dawley 噻唑类/药理学噻唑烷类转录因子AP-1/代谢肿瘤细胞培养的动物女(雌)性人类小鼠妊娠大鼠

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Egr-1 gene is induced by the systemic administration of the vascular endothelial growth factor and the epidermal growth factor

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BLOOD 2000年第5期96卷 1772-1781页

作者： Liu, LX Tsai, JC Aird, WC Beth Israel Deaconess Med Ctr Dept Mol Med Boston MA 02215 USA

Egr-1 is a transcription factor that couples short-term changes in the extracellular milieu to long-term changes in gene expression. In cultured endothelial cells, the Egr-1 gene has been shown to respond to a variety of extracellular signals. However, the physiological relevance of these findings remains unclear. To address this question, the growth factor-mediated response of the Egr-1 gene under in vivo conditions was analyzed. To that end, either vascular endothelial growth factor (VEGF) or epidermal growth factor (EGF) was injected into the intraperitoneal cavity of mice. Growth factors were delivered to all tissues examined, as evidenced by the widespread distribution of I-125-labeled growth factors and the phosphorylation of their respective receptors. In Western blot analyses of whole-tissue extracts, Egr-1 protein levels were shown to be induced in the heart, brain, liver, and spleen of VEGF-treated mice, and in the heart, lung, brain, liver and skeletal muscle of EGF treated animals. Changes in Egr-1 levels did not correlate with changes in receptor phosphorylation or ERK1/2 phosphorylation. In Northern blot analyses, VEGF induced Egr-1 mRNA levels in all tissues examined except lung and kidney, whereas EGF led to increased transcripts in all tissues except kidney. In immunofluorescence studies, VEGF induced Egr-1 in microvascular endothelial cells of the heart and liver, and EGF induced Egr-1 in the microvascular bed of skeletal muscle. Taken together, these re suits suggest that the Egr-1 gene is differentially regulated in response to systemically administered VEGF and EGF, (C) 2000 by The American Society of Hematology.

关键词：脑/药物作用脑/代谢 dna结合蛋白质类/药物作用 dna结合蛋白质类/遗传学 dna结合蛋白质类/代谢早期生长反应蛋白质1 内皮生长因子/药理学内皮血管/细胞学内皮血管/药物作用内皮血管/代谢表皮生长因子/药理学心脏/药物作用即早蛋白质类注射腹腔内肝/药物作用肝/代谢肺/药物作用肺/代谢淋巴因子/药理学显微镜检查共焦丝裂原活化蛋白激酶1/代谢丝裂原活化蛋白激酶3 丝裂原激活蛋白激酶类/代谢肌骨骼/药物作用肌骨骼/代谢心肌/代谢磷酰化/药物作用 RNA 信使/药物作用 RNA 信使/遗传学 RNA 信使/代谢受体蛋白质酪氨酸激酶类/代谢受体表皮生长因子/代谢受体生长因子/代谢受体血管内皮生长因子脾/药物作用脾/代谢转录因子/药物作用转录因子/遗传学转录因子/代谢血管内皮生长因子A 血管内皮生长因子类动物女(雌)性小鼠

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N^G-monomethyl-L-arginine inhibits erythropoietin gene expression by stimulating GATA-2

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BLOOD 2000年第5期96卷 1716-1722页

作者： Tarumoto, T Imagawa, S Ohmine, K Nagai, T Higuchi, M Imai, N Suzuki, N Yamamoto, M Ozawa, K Univ Tsukuba Inst Clin Med Div Hematol Tsukuba Ibaraki 3058575 Japan Jichi Med Sch Dept Hematol Minami Kawachi Tochigi 32904 Japan Univ Tsukuba Ctr Tsukuba Adv Res Alliance Tsukuba Ibaraki 305 Japan Univ Tsukuba Inst Basic Med Sci Tsukuba Ibaraki 305 Japan Chugai Pharmaceut Co Ltd Tokyo Japan

N-G-monomethyl-L-arginine (L-NMMA) has been reported to be elevated in uremic patients. Based on the hypothesis that the pathogenesis of the anemia of renal disease might be due to the perturbation of transcription factors of the erythropoietin (Epo) gene by L-NMMA, the present study was designed to investigate the effect of L-NMMA on Epo gene expression through the GATA transcription factor. L-NMMA caused decreased levels of Nc, cyclic guanosine monophosphate (cGMP), and Epo protein in Hep3B cells. L-NAME (analogue of L-NMMA) also inhibited Epo production in anemic mice. Transfection of the Epo promoter-luciferase gene into Hep3B cells revealed that L-NMMA inhibited the Epo promoter activity. However, L-NMMA did not inhibit the Epo promoter activity when mutated Epo promoter (GATA to TATA) was transfected, and L-NMMA did not affect the enhancer activity. Electrophoretic mobility shift assays demonstrated the stimulation of GATA binding activity by L-NMMA. However, L-NMMA had no effect on the binding activity of hepatic nuclear factor-4, COUP-TF1, hypoxia-inducing factor-1,or NF-kappa B, Furthermore, cGMP inhibited the L-NMMA-induced GATA binding activity. L-NMMA also increased GATA-2 messenger RNA expression. These results demonstrate that L-NMMA suppresses Epo gene expression by upregulation of the GATA transcription factor and support the hypothesis that L-NMMA is one of the candidate substances that underlie the pathogenesis of renal anemia. (C) 2000 by The American Society of Hematology.

关键词：缺氧碱基序列结合部位/遗传学环GMP/代谢 dna/遗传学 dna/代谢 dna结合蛋白质类/药物作用 dna结合蛋白质类/代谢酶抑制剂/药理学红细胞生成素/血液红细胞生成素/遗传学红细胞生成素/代谢 GATA2转录因子基因表达调控/药物作用萤光素酶类/药物作用萤光素酶类/遗传学萤光素酶类/代谢分子序列数据突变 NG-硝基精氨酸甲酯/药理学一氧化氮/代谢启动区(遗传学)/遗传学蛋白质结合重组融合蛋白质类/药物作用重组融合蛋白质类/遗传学重组融合蛋白质类/代谢转录因子/药物作用转录因子/代谢肿瘤细胞培养的/细胞学肿瘤细胞培养的/药物作用肿瘤细胞培养的/代谢 ωN-甲基精氨酸/药理学动物人类小鼠

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Disruption of mouse SNM1 causes increased sensitivity to the dna interstrand cross-linking agent mitomycin C

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MOLECULAR AND CELLULAR BIOLOGY 2000年第13期20卷 4553-4561页

作者： Dronkert, MLG de Wit, J Boeve, M Vasconcelos, ML van Steeg, H Tan, TLR Hoeijmakers, JHJ Kanaar, R Erasmus Univ Dept Cell Biol & Genet Ctr Biomed Genet NL-3000 DR Rotterdam Netherlands Daniel den Hoed Canc Ctr Dept Radiat Oncol NL-3000 DR Rotterdam Netherlands Natl Inst Publ Hlth & Environm Hlth Effects Res Lab NL-3720 BA Bilthoven Netherlands

dna interstrand cross-links (ICLs) represent lethal dna damage, because they block transcription, replication, and segregation of dna. Because of their genotoxicity, agents inducing ICLs are often used in antitumor therapy. The repair of ICLs is complex and involves proteins belonging to nucleotide excision, recombination, and translesion dna repair pathways in Escherichia coli, Saccharomyces cerevisiae, and mammals. We cloned and analyzed mammalian homologs of the S. cerevisiae gene SNM1 (PSO2), which is specifically involved in ICL repair. Human Snm1, a nuclear protein, was ubiquitously expressed at a very low level. We generated mouse SNM1(-/-) embryonic stem cells and showed that these cells were sensitive to mitomycin C. In contrast to S. cerevisiae snm1 mutants, they were not significantly sensitive to other ICL agents, probably due to redundancy in mammalian ICL repair and the existence of other SNM1 homologs. The sensitivity to mitomycin C was complemented by transfection of the human SNM1 cdna and by targeting of a genomic cdna-murine SNM1 fusion construct to the disrupted locus. We also generated mice deficient for murine SNM1. They were viable and fertile and showed no major abnormalities. However, they were sensitive to mitomycin C. The ICL sensitivity of the mammalian SNM1 mutant suggests that SNM1 function and, by implication, ICL repair are at least partially conserved between S. cerevisiae and mammals.

关键词：氨基酸序列交联试剂/药理学 dna修复/药物作用 dna结合蛋白质类/药物作用 dna结合蛋白质类/遗传学 dna结合蛋白质类/代谢药物过敏/遗传学内切脱氧核糖核酸酶类成纤维细胞小鼠近交C57BL 小鼠基因敲除丝裂霉素/药理学分子序列数据核蛋白质类/药物作用核蛋白质类/遗传学核蛋白质类/代谢酿酒酵母蛋白质类序列同源性氨基酸干细胞/生理学亚细胞部分动物女(雌)性人类男(雄)性小鼠

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Prolactin enhances CCAAT enhancer-binding protein-β (C/EBPβ) and peroxisome proliferator-activated receptor γ (PPARγ) messenger RNA expression and stimulates adipogenic conversion of NIH-3T3 cells

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MOLECULAR ENDOCRINOLOGY 2000年第2期14卷 307-316页

作者： Nanbu-Wakao, R Fujitani, Y Masuho, Y Muramatu, M Wakao, H Helix Res Inst Chiba 2920812 Japan Osaka Univ Sch Med Dept Internal Med 1 Suita Osaka 565 Japan

Extracellular stimuli trigger adipocyte differentiation by inducing the complex cascades of transcription. Transcription factors CCAAT enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPAR gamma) play crucial roles in this process. Although ectopic expression of these factors in NIH-3T3 cells, a multipotential mesenchymal stem cell line, results in adipogenic conversion, little is known as to hormonal factors that regulate adipogenesis in these cells. In this report we demonstrate that PRL, a lactogenic hormone, enhances C/EBP beta and PPAR gamma mRNA expression and augments adipogenic conversion of NIH-3T3 cells. Moreover, we show that ectopic expression of the PRL receptor in NIH-3T3 cells results in efficient adipocyte conversion when stimulated with PRL and a PPAR gamma ligand, as evidenced by expression of the adipocyte differentiation-specific genes as well as the presence of fat-laden cells. We further demonstrate that signal transducer and activator of transcription 5 (Stat5), a PRL signal transducer, activates aP2 promoter in a PRL-dependent manner. These results suggest that PRL acts as an adipogenesis-enhancing hormone in NIH-3T3 cells.

关键词： 3T3细胞/药物作用 3T3细胞/病理学脂细胞/药物作用脂细胞/代谢 CCAAT增强子结合蛋白类 dna结合蛋白质类/药物作用 dna结合蛋白质类/遗传学 dna结合蛋白质类/代谢地塞米松/药理学基因表达调控乳蛋白质类核蛋白质类/药物作用核蛋白质类/遗传学核蛋白质类/代谢催乳素/代谢催乳素/药理学 RNA 信使受体胞质和核/药物作用受体胞质和核/遗传学受体胞质和核/代谢受体催乳素/代谢 STAT5转录因子反式激活因子类/药物作用反式激活因子类/代谢转录因子AP-2 转录因子/药物作用转录因子/遗传学转录因子/代谢转录遗传黄嘌呤类/药理学动物小鼠

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Activation of surfactant protein-B transcription: Signaling through the SP-A receptor utilizing the PI3 kinase pathway

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JOURNAL OF CELLULAR PHYSIOLOGY 2000年第2期184卷 229-238页

作者： Strayer, DS Korutla, L Thomas Jefferson Univ Jefferson Med Coll Dept Pathol & Cell Biol Philadelphia PA 19107 USA

This study describes receptor-activated signaling initiated by surfactant protein-A (SP-A), and the means by which it activates transcription of surfactant protein-B. Pulmonary surfactant is a mixture of lipids and associated proteins produced by type II pneumocytes. Interaction of SP-A with its cognate receptor (SPAR) on type II cells is involved in regulating surfactant secretion. This interaction also increases transcription of surfactant proteins and several other genes. To study SP-A cytokine activity, we used as a model surfactant-protein (SP-B) transcription, the activators of which have been characterized. HNF-3 and TTF-1 transcription factors are known to stimulate SP-B transcription. SP-A caused increased phosphorylation and nuclear localization of both. Corresponding increases in protein binding to the SP-B promoter were demonstrated by gel shift analysis. SP-A increased protein binding to HNF-3 and TTF-1 consensus recognition elements. Footprinting analysis indicated that SP-A-induced protein binding to SP-B promoter was greater in amount, but not different in location, from that seen in control cells, which normally transcribe SP-B. SP-A caused transient increases in PI3 kinase localization at the plasma membrane, and SP-A signaling to elicit increased SP-B transcription was blocked by LY294002, an inhibitor of PI3 kinase. Therefore, SP-A signals through PI3 kinase to increase SP-B transcription in type II pneumocytes by enhancing TTF-1 and HNF-3 activation of the SP-B promoter. SP-A activation of this signaling pathway, which affects many cellular functions and has not previously been implicated in type II cell transcriptional activity, has profound import for understanding type II cell biology. J. Cell. Physiol. 184:229-238, 2000. (C) 2000 Wiley-Liss, Inc.

关键词： 1-磷脂酰肌醇3-激酶/药物作用 1-磷脂酰肌醇3-激酶/生理学细胞培养的 dna结合蛋白质类/药物作用 dna结合蛋白质类/生理学糖蛋白类/药理学肝细胞核因子3α 肺/细胞学肺/药物作用肺/生理学核蛋白质类/药物作用核蛋白质类/生理学启动区(遗传学) 蛋白质亚型/药物作用蛋白脂质类/药物作用蛋白脂质类/遗传学蛋白脂质类/药理学蛋白脂质类/生理学肺表面活性物质相关蛋白质A 肺表面活性物质相关蛋白质类肺表面活性剂/药物作用肺表面活性剂/遗传学肺表面活性剂/药理学肺表面活性剂/生理学受体细胞表面/药物作用受体细胞表面/生理学转录因子/药物作用转录因子/生理学转录遗传/药物作用转录遗传/生理学动物女(雌)性大鼠

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