Phosphatidylinositol 3-Kinase-dependent Suppression of the Human Inducible Nitric-oxide Synthase Promoter Is Mediated by FKHRL1

中华首席医学网    2008年08月15日 00:21:27 Friday  

 

作者：Arnold S. Kristof,Jill Fielhaber,Alexandra Triantafillopoulos,Shino Nemoto, Joel Moss

作者单位：Pulmonary-Critical Care Medicine Branch and Cardiovascular Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892 and the Critical Care and Respiratory Divisions, Royal Victoria Hospital and Meakins-Christie Laboratories, McGill University, Montreal, Quebec H3A 1A Canada

《生物物理学杂志》2006年8月281卷8期 文章精华

 

【摘要】  The synthesis of nitric oxide by inducible nitric-oxide synthase (iNOS) plays an important role in the innate immune response by promoting microbial killing and cell damage. In response to inflammatory cytokines and bacterial products, the human iNOS (hiNOS) gene undergoes rapid transcriptional activation via binding of stimulatory transcription factors (e.g. AP-1 and NF-B) to its 5 '-flanking region. However, maximal hiNOS promoter induction was suppressed via an unknown phosphatidylinositol 3-kinase (PI3K)-dependent mechanism. We hypothesized that inhibition of the transcription factor FKHRL1 by the PI3K/protein kinase B pathway attenuates hiNOS promoter induction by bacterial lipopolysaccharide and interferon-gamma (LPS/IFN-). Human lung epithelial adenocarcinoma (A549) cells were transiently transfected with an 8.3-kb hiNOS promoter luciferase reporter construct. Co-expression of dominant-negative protein kinase B potentiated LPS/IFN--stimulated hiNOS promoter activity. In response to LPS/IFN-, FKHRL1 was phosphorylated in a PI3K- and time-dependent fashion. Co-expression of constitutively active FKHRL1 increased hiNOS promoter activity and mRNA levels. Dominant-negative siRNA expression showed that FKHRL1 was necessary for the inhibitory effects of PI3K on hiNOS induction. The same effect was observed upon mutation of a consensus FKHRL1-binding site in the hiNOS promoter. By gel-shift analysis, the corresponding oligonucleotide probe bound endogenous FKHRL1 in an LPS/IFN-- and PI3K-sensitive fashion. Regulation of the hiNOS promoter by FKHRL1 represents a potentially important molecular mechanism by which the PI3K pathway might suppress pro-inflammatory and proapoptotic responses to cytokines and bacterial products.

【关键词】  Phosphatidylinositol Kinasedependent Suppression Inducible Nitricoxide Synthase Promoter Mediated

【参考文献】
  Stuehr, D. J., and Griffith, O. W. (1992) Adv. Enzymol. Relat. Areas. Mol. Biol. 65, 287-346

Michel, T., and Feron, O. (1997) J. Clin. Invest. 100, 2146-2152

Lowenstein, C. J., Dinerman, J. L., and Snyder, S. H. (1994) Ann. Intern. Med. 120, 227-237

Nathan, C., and Xie, Q. W. (1994) Cell 78, 915-918

Schmidt, H. H., and Walter, U. (1994) Cell 78, 919-925

Nathan, C. (1997) J. Clin. Invest. 100, 2417-2423

Murphy, M. P. (1999) Biochim. Biophys. Acta 1411, 401-414

Brune, B., von Knethen, A., and Sandau, K. B. (1999) Cell Death. Differ. 6, 969-975

Diaz-Guerra, M. J., Bodelon, O. G., Velasco, M., Whelan, R., Parker, P. J., and Bosca, L. (1996) J. Biol. Chem. 271, 32028-32033

Xu, W., Comhair, S. A., Zheng, S., Chu, S. C., Marks-Konczalik, J., Moss, J., Haque, S. J., and Erzurum, S. C. (2003) Am. J. Physiol. 285, L137-L148

Kleinert, H., Euchenhofer, C., Fritz, G., Ihrig-Biedert, I., and Forstermann, U. (1998) Br. J. Pharmacol. 123, 1716-1722

de Vera, M. E., Shapiro, R. A., Nussler, A. K., Mudgett, J. S., Simmons, R. L., Morris, S. M. J., Billiar, T. R., and Geller, D. A. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 1054-1059

Marks-Konczalik, J., Chu, S. C., and Moss, J. (1998) J. Biol. Chem. 273, 22201-22208

Kristof, A. S., Marks-Konczalik, J., and Moss, J. (2001) J. Biol. Chem. 276, 8445-8452

Ganster, R. W., Taylor, B. S., Shao, L., and Geller, D. A. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 8638-8643

Diaz-Guerra, M. J., Castrillo, A., Martin-Sanz, P., and Bosca, L. (1999) J. Immunol. 162, 6184-6190

Rameh, L. E., and Cantley, L. C. (1999) J. Biol. Chem. 274, 8347-8350

Duronio, V., Scheid, M. P., and Ettinger, S. (1998) Cell. Signal. 4, 233-239

Fruman, D. A., Meyers, R. E., and Cantley, L. C. (1998) Annu. Rev. Biochem. 67, 481-507

Cantley, L. C. (2002) Science 296, 1655-1657

Li, J., Chen, H., Tang, M. S., Shi, X., Amin, S., Desai, D., Costa, M., and Huang, C. (2004) J. Cell Biol. 165, 77-86

Nguyen, H., Ramana, C. V., Bayes, J., and Stark, G. R. (2001) J. Biol. Chem. 276, 33361-33368

Silverman, N., and Maniatis, T. (2001) Genes Dev. 15, 2321-2342

Pahan, K., Raymond, J. R., and Singh, I. (1999) J. Biol. Chem. 274, 7528-7536

Kristof, A. S., Marks-Konczalik, J., Billings, E., and Moss, J. (2003) J. Biol. Chem. 278, 33637-33644

Kops, G. J., and Burgering, B. M. (1999) J. Mol. Med. 77, 656-665

Dijkers, P. F., Medemadagger, R. H., Lammers, J. W., Koenderman, L., and Coffer, P. J. (2000) Curr. Biol. 10, 1201-1204

Cichy, S. B., Uddin, S., Danilkovich, A., Guo, S., Klippel, A., and Unterman, T. G. (1998) J. Biol. Chem. 273, 6482-6487

Dijkers, P. F., Medema, R. H., Pals, C., Banerji, L., Thomas, N. S., Lam, E. W., Burgering, B. M., Raaijmakers, J. A., Lammers, J. W., Koenderman, L., and Coffer, P. J. (2000) Mol. Cell. Biol. 20, 9138-9148

Ghaffari, S., Jagani, Z., Kitidis, C., Lodish, H. F., and Khosravi-Far, R. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 6523-6528

Brunet, A., Bonni, A., Zigmond, M. J., Lin, M. Z., Juo, P., Hu, L. S., Anderson, M. J., Arden, K. C., Blenis, J., and Greenberg, M. E. (1999) Cell 96, 857-868

Chu, S. C., Marks-Konczalik, J., Wu, H. P., Banks, T. C., and Moss, J. (1998) BBRC 248, 871-878

Livak, K. J., and Schmittgen, T. D. (2001) Methods 25, 402-408

Ackermann, K., Waxmann, A., Glover, C. V., and Pyerin, W. (2001) Mol. Cell Biochem. 227, 59-66

Salh, B., Wagey, R., Marotta, A., Tao, J. S., and Pelech, S. (1998) J. Immunol. 161, 6947-6954

Park, Y. C., Lee, C. H., Kang, H. S., Chung, H. T., and Kim, H. D. (1997) Biochem. Biophys. Res. Commun. 240, 692-696

Datta, S. R., Brunet, A., and Greenberg, M. E. (1999) Genes Dev. 13, 2905-2927

Hu, M. C., Lee, D. F., Xia, W., Golfman, L. S., Ou-Yang, F., Yang, J. Y., Zou, Y., Bao, S., Hanada, N., Saso, H., Kobayashi, R., and Hung, M. C. (2004) Cell 117, 225-237

Brunet, A., Park, J., Tran, H., Hu, L. S., Hemmings, B. A., and Greenberg, M. E. (2001) Mol. Cell. Biol. 21, 952-965

Trinchieri, G. (2003) Nat. Rev. Immunol. 3, 133-146

Beutler, B., Hoebe, K., Du, X., and Ulevitch, R. J. (2003) J. Leukocyte Biol. 74, 479-485

Nathan, C., and Shiloh, M. U. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 8841-8848

Dimmeler, S., Haendeler, J., Nehls, M., and Zeiher, A. M. (1997) J. Exp. Med. 185, 601-607

Taylor, B. S., de Vera, M. E., Ganster, R. W., Wang, Q., Shapiro, R. A., Morris, S. M., Jr., Billiar, T. R., and Geller, D. A. (1998) J. Biol. Chem. 273, 15148-15156

Foley, E., and O'Farrell, P. H. (2004) PLoS Biol. 2, E203

Feng, X., Guo, Z., Nourbakhsh, M., Hauser, H., Ganster, R., Shao, L., and Geller, D. A. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 14212-14217

Chen, C. W., Chang, Y. H., Tsi, C. J., and Lin, W. W. (2003) J. Immunol. 171, 979-988

Monick, M. M., Robeff, P. K., Butler, N. S., Flaherty, D. M., Carter, A. B., Peterson, M. W., and Hunninghake, G. W. (2002) J. Biol. Chem. 277, 32992-33000

Guha, M., and Mackman, N. (2002) J. Biol. Chem. 277, 32124-32132

Seoane, J., Le, H. V., Shen, L., Anderson, S. A., and Massague, J. (2004) Cell 117, 211-223

Forrester, K., Ambs, S., Lupold, S. E., Kapust, R. B., Spillare, E. A., Weinberg, W. C., Felley-Bosco, E., Wang, X. W., Geller, D. A., Tzeng, E., Billiar, T. R., and Harris, C. C. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 2442-2447

Hofseth, L. J., Saito, S., Hussain, S. P., Espey, M. G., Miranda, K. M., Araki, Y., Jhappan, C., Higashimoto, Y., He, P., Linke, S. P., Quezado, M. M., Zurer, I., Rotter, V., Wink, D. A., Appella, E., and Harris, C. C. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 143-148

Tran, H., Brunet, A., Grenier, J. M., Datta, S. R., Fornace, A. J., Jr., DiStefano, P. S., Chiang, L. W., and Greenberg, M. E. (2002) Science 296, 530-534

Nemoto, S., and Finkel, T. (2002) Science 295, 2450-2452

Motta, M. C., Divecha, N., Lemieux, M., Kamel, C., Chen, D., Gu, W., Bultsma, Y., McBurney, M., and Guarente, L. (2004) Cell 116, 551-563

 查看原文   加入收藏夹