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. 1997 Mar;17(3):1118–1128. doi: 10.1128/mcb.17.3.1118

Lipopolysaccharide and Raf-1 kinase regulate secretory interleukin-1 receptor antagonist gene expression by mutually antagonistic mechanisms.

C J Guthridge 1, D Eidlen 1, W P Arend 1, A Gutierrez-Hartmann 1, M F Smith Jr 1
PMCID: PMC231837  PMID: 9032239

Abstract

Lipopolysaccharide (LPS) treatment of monocytic cells has been shown to activate the Raf-1/mitogen-activated protein kinase (MAPK) signaling pathway and to increase secretory interleukin-1 receptor antagonist (sIL-1Ra) gene expression. The significance of the activation of the Raf-1/MAPK signaling pathway to LPS regulation of sIL-1Ra gene expression, however, has not been determined. This study addresses the role of the Raf-1/MAPK signaling pathway in regulation of sIL-1Ra gene expression by LPS. Cotransfection of the murine macrophage cell line RAW 264.7 with a 294-bp sIL-1Ra promoter/luciferase construct (pRA-294-luc) and a constitutively active Raf-1 kinase expression vector (pRSV-Raf-BXB) resulted in induction of sIL-1Ra promoter activity, indicating that Raf-1, like LPS, can regulate sIL-1Ra promoter activity. An in vitro MAPK analysis indicated that both LPS treatment and pRSV-Raf-BXB transfection of RAW 264.7 cells increases p42 MAPK activity. An in vitro Raf-1 kinase assay, however, failed to detect LPS-induced Raf-1 kinase activity in RAW 264.7 cells, suggesting that in RAW 264.7 cells, Raf-1 kinase is not an activating component of the LPS signaling pathway regulating MAPK activity or sIL-1Ra promoter activity. This observation was supported by results from transfection studies which demonstrated that expression of a dominant-inhibitory Raf-1 mutant in RAW 264.7 cells does not inhibit LPS-induced MAPK activity or sIL-1Ra promoter activity, indicating that LPS-induced sIL-1Ra promoter activation occurs independent of the Raf-1/MAPK signaling pathway. In additional studies, cotransfection of RAW 264.7 cells with pRA-294-luc and increasing amounts of pRSV-Raf-BXB caused a dose-dependent inhibition of LPS-induced sIL-1Ra promoter activity, indicating that the role of the Raf-1 pathway in the regulation of sIL-1Ra promoter activity by LPS is as an antagonizer. Interestingly, LPS treatment of RAW 264.7 cells, cotransfected with pRA-294-luc and pRSV-Raf-BXB, also inhibited pRSV-Raf-BXB-induced sIL-1Ra promoter activity, suggesting that inductions of sIL-1Ra promoter activity by LPS and Raf-1 actually occur by mutually antagonistic mechanisms. In support of this conclusion, sIL-1Ra promoter mapping studies indicated that LPS and Raf-1 responses localized to different regions of the sIL-1Ra promoter. Further studies demonstrated that mutual antagonism between the LPS and Raf-1 kinase pathways is not promoter specific, as the same phenomenon is observed in assays using a c-fos enhancer/thymidine kinase promoter/luciferase construct (pc-fos-TK81-luc). Additionally, mutual antagonism with regard to sIL-1Ra promoter activity also was observed between the LPS and MEK kinase pathways, indicating that mutual antagonism can occur in more than one MAPK activation pathway.

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Selected References

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  1. Adams D. O., Hamilton T. A. The cell biology of macrophage activation. Annu Rev Immunol. 1984;2:283–318. doi: 10.1146/annurev.iy.02.040184.001435. [DOI] [PubMed] [Google Scholar]
  2. Agarwal S., Corbley M. J., Roberts T. M. Reconstitution of signal transduction from the membrane to the nucleus in a baculovirus expression system: activation of Raf-1 leads to hypermodification of c-jun and c-fos via multiple pathways. Oncogene. 1995 Aug 3;11(3):427–438. [PubMed] [Google Scholar]
  3. Arend W. P. Interleukin-1 receptor antagonist. Adv Immunol. 1993;54:167–227. doi: 10.1016/s0065-2776(08)60535-0. [DOI] [PubMed] [Google Scholar]
  4. Arend W. P., Smith M. F., Jr, Janson R. W., Joslin F. G. IL-1 receptor antagonist and IL-1 beta production in human monocytes are regulated differently. J Immunol. 1991 Sep 1;147(5):1530–1536. [PubMed] [Google Scholar]
  5. Atfi A., Drobetsky E., Boissonneault M., Chapdelaine A., Chevalier S. Transforming growth factor beta down-regulates Src family protein tyrosine kinase signaling pathways. J Biol Chem. 1994 Dec 2;269(48):30688–30693. [PubMed] [Google Scholar]
  6. Baccarini M., Sabatini D. M., App H., Rapp U. R., Stanley E. R. Colony stimulating factor-1 (CSF-1) stimulates temperature dependent phosphorylation and activation of the RAF-1 proto-oncogene product. EMBO J. 1990 Nov;9(11):3649–3657. doi: 10.1002/j.1460-2075.1990.tb07576.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Blenis J. Signal transduction via the MAP kinases: proceed at your own RSK. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5889–5892. doi: 10.1073/pnas.90.13.5889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Blumer K. J., Johnson G. L. Diversity in function and regulation of MAP kinase pathways. Trends Biochem Sci. 1994 Jun;19(6):236–240. doi: 10.1016/0968-0004(94)90147-3. [DOI] [PubMed] [Google Scholar]
  9. Bruder J. T., Heidecker G., Rapp U. R. Serum-, TPA-, and Ras-induced expression from Ap-1/Ets-driven promoters requires Raf-1 kinase. Genes Dev. 1992 Apr;6(4):545–556. doi: 10.1101/gad.6.4.545. [DOI] [PubMed] [Google Scholar]
  10. Butcher C., Steinkasserer A., Tejura S., Lennard A. C. Comparison of two promoters controlling expression of secreted or intracellular IL-1 receptor antagonist. J Immunol. 1994 Jul 15;153(2):701–711. [PubMed] [Google Scholar]
  11. Büscher D., Hipskind R. A., Krautwald S., Reimann T., Baccarini M. Ras-dependent and -independent pathways target the mitogen-activated protein kinase network in macrophages. Mol Cell Biol. 1995 Jan;15(1):466–475. doi: 10.1128/mcb.15.1.466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Carroll M. P., Clark-Lewis I., Rapp U. R., May W. S. Interleukin-3 and granulocyte-macrophage colony-stimulating factor mediate rapid phosphorylation and activation of cytosolic c-raf. J Biol Chem. 1990 Nov 15;265(32):19812–19817. [PubMed] [Google Scholar]
  13. Chandra G., Cogswell J. P., Miller L. R., Godlevski M. M., Stinnett S. W., Noel S. L., Kadwell S. H., Kost T. A., Gray J. G. Cyclic AMP signaling pathways are important in IL-1 beta transcriptional regulation. J Immunol. 1995 Nov 15;155(10):4535–4543. [PubMed] [Google Scholar]
  14. Chen B. D., Chou T. H., Sensenbrenner L. Downregulation of M-CSF receptors by lipopolysaccharide in murine peritoneal exudate macrophages is mediated through a phospholipase C dependent pathway. Exp Hematol. 1993 May;21(5):623–628. [PubMed] [Google Scholar]
  15. Chen W. S., Lazar C. S., Poenie M., Tsien R. Y., Gill G. N., Rosenfeld M. G. Requirement for intrinsic protein tyrosine kinase in the immediate and late actions of the EGF receptor. 1987 Aug 27-Sep 2Nature. 328(6133):820–823. doi: 10.1038/328820a0. [DOI] [PubMed] [Google Scholar]
  16. Chu A. J. Bacterial lipopolysaccharide stimulates phospholipid synthesis and phosphatidylcholine breakdown in cultured human leukemia monocytic THP-1 cells. Int J Biochem. 1992 Feb;24(2):317–323. doi: 10.1016/0020-711x(92)90264-2. [DOI] [PubMed] [Google Scholar]
  17. Chu A. J., Moore J. Bacterial lipopolysaccharide induces phosphatidylcholine breakdown in human leukaemia monocytic U937 cells. Blood Coagul Fibrinolysis. 1992 Feb;3(1):19–23. doi: 10.1097/00001721-199202000-00004. [DOI] [PubMed] [Google Scholar]
  18. Cobb M. H., Boulton T. G., Robbins D. J. Extracellular signal-regulated kinases: ERKs in progress. Cell Regul. 1991 Dec;2(12):965–978. doi: 10.1091/mbc.2.12.965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Conrad K. E., Gutierrez-Hartmann A. The ras and protein kinase A pathways are mutually antagonistic in regulating rat prolactin promoter activity. Oncogene. 1992 Jul;7(7):1279–1286. [PubMed] [Google Scholar]
  20. Cook S. J., McCormick F. Inhibition by cAMP of Ras-dependent activation of Raf. Science. 1993 Nov 12;262(5136):1069–1072. doi: 10.1126/science.7694367. [DOI] [PubMed] [Google Scholar]
  21. Davis R. J. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993 Jul 15;268(20):14553–14556. [PubMed] [Google Scholar]
  22. Dent P., Haser W., Haystead T. A., Vincent L. A., Roberts T. M., Sturgill T. W. Activation of mitogen-activated protein kinase kinase by v-Raf in NIH 3T3 cells and in vitro. Science. 1992 Sep 4;257(5075):1404–1407. doi: 10.1126/science.1326789. [DOI] [PubMed] [Google Scholar]
  23. Dérijard B., Raingeaud J., Barrett T., Wu I. H., Han J., Ulevitch R. J., Davis R. J. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995 Feb 3;267(5198):682–685. doi: 10.1126/science.7839144. [DOI] [PubMed] [Google Scholar]
  24. Fenton M. J., Buras J. A., Donnelly R. P. IL-4 reciprocally regulates IL-1 and IL-1 receptor antagonist expression in human monocytes. J Immunol. 1992 Aug 15;149(4):1283–1288. [PubMed] [Google Scholar]
  25. Fujihara M., Muroi M., Muroi Y., Ito N., Suzuki T. Mechanism of lipopolysaccharide-triggered junB activation in a mouse macrophage-like cell line (J774). J Biol Chem. 1993 Jul 15;268(20):14898–14905. [PubMed] [Google Scholar]
  26. Gardner A. M., Lange-Carter C. A., Vaillancourt R. R., Johnson G. L. Measuring activation of kinases in mitogen-activated protein kinase regulatory network. Methods Enzymol. 1994;238:258–270. doi: 10.1016/0076-6879(94)38024-4. [DOI] [PubMed] [Google Scholar]
  27. Geng Y., Zhang B., Lotz M. Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. J Immunol. 1993 Dec 15;151(12):6692–6700. [PubMed] [Google Scholar]
  28. Geppert T. D., Whitehurst C. E., Thompson P., Beutler B. Lipopolysaccharide signals activation of tumor necrosis factor biosynthesis through the ras/raf-1/MEK/MAPK pathway. Mol Med. 1994 Nov;1(1):93–103. [PMC free article] [PubMed] [Google Scholar]
  29. Gotoh Y., Nishida E., Yamashita T., Hoshi M., Kawakami M., Sakai H. Microtubule-associated-protein (MAP) kinase activated by nerve growth factor and epidermal growth factor in PC12 cells. Identity with the mitogen-activated MAP kinase of fibroblastic cells. Eur J Biochem. 1990 Nov 13;193(3):661–669. doi: 10.1111/j.1432-1033.1990.tb19384.x. [DOI] [PubMed] [Google Scholar]
  30. Graves L. M., Bornfeldt K. E., Raines E. W., Potts B. C., Macdonald S. G., Ross R., Krebs E. G. Protein kinase A antagonizes platelet-derived growth factor-induced signaling by mitogen-activated protein kinase in human arterial smooth muscle cells. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10300–10304. doi: 10.1073/pnas.90.21.10300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Gutman A., Wasylyk C., Wasylyk B. Cell-specific regulation of oncogene-responsive sequences of the c-fos promoter. Mol Cell Biol. 1991 Oct;11(10):5381–5387. doi: 10.1128/mcb.11.10.5381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Heidecker G., Kölch W., Morrison D. K., Rapp U. R. The role of Raf-1 phosphorylation in signal transduction. Adv Cancer Res. 1992;58:53–73. doi: 10.1016/s0065-230x(08)60290-0. [DOI] [PubMed] [Google Scholar]
  33. Her J. H., Lakhani S., Zu K., Vila J., Dent P., Sturgill T. W., Weber M. J. Dual phosphorylation and autophosphorylation in mitogen-activated protein (MAP) kinase activation. Biochem J. 1993 Nov 15;296(Pt 1):25–31. doi: 10.1042/bj2960025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Häfner S., Adler H. S., Mischak H., Janosch P., Heidecker G., Wolfman A., Pippig S., Lohse M., Ueffing M., Kolch W. Mechanism of inhibition of Raf-1 by protein kinase A. Mol Cell Biol. 1994 Oct;14(10):6696–6703. doi: 10.1128/mcb.14.10.6696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Høgåsen A. K., Hestdal K., Abrahamsen T. G. Granulocyte-macrophage colony-stimulating factor, but not macrophage colony-stimulating factor, suppresses basal and lipopolysaccharide-stimulated complement factor production in human monocytes. J Immunol. 1993 Sep 15;151(6):3215–3224. [PubMed] [Google Scholar]
  36. Johnson G. L., Vaillancourt R. R. Sequential protein kinase reactions controlling cell growth and differentiation. Curr Opin Cell Biol. 1994 Apr;6(2):230–238. doi: 10.1016/0955-0674(94)90141-4. [DOI] [PubMed] [Google Scholar]
  37. Kamińska B., Kaczmarek L., Malaguarnera L., Arcidiacono A., Messina L., Spampinato G., Messina A. Transcription factor activation and functional stimulation of human monocytes. Cell Biol Int Rep. 1992 Jan;16(1):37–45. doi: 10.1016/s0309-1651(06)80154-2. [DOI] [PubMed] [Google Scholar]
  38. Kharbanda S., Saleem A., Emoto Y., Stone R., Rapp U., Kufe D. Activation of Raf-1 and mitogen-activated protein kinases during monocytic differentiation of human myeloid leukemia cells. J Biol Chem. 1994 Jan 14;269(2):872–878. [PubMed] [Google Scholar]
  39. Kyriakis J. M., App H., Zhang X. F., Banerjee P., Brautigan D. L., Rapp U. R., Avruch J. Raf-1 activates MAP kinase-kinase. Nature. 1992 Jul 30;358(6385):417–421. doi: 10.1038/358417a0. [DOI] [PubMed] [Google Scholar]
  40. Lange-Carter C. A., Johnson G. L. Ras-dependent growth factor regulation of MEK kinase in PC12 cells. Science. 1994 Sep 2;265(5177):1458–1461. doi: 10.1126/science.8073291. [DOI] [PubMed] [Google Scholar]
  41. Lange-Carter C. A., Pleiman C. M., Gardner A. M., Blumer K. J., Johnson G. L. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science. 1993 Apr 16;260(5106):315–319. doi: 10.1126/science.8385802. [DOI] [PubMed] [Google Scholar]
  42. Levin D. E., Errede B. The proliferation of MAP kinase signaling pathways in yeast. Curr Opin Cell Biol. 1995 Apr;7(2):197–202. doi: 10.1016/0955-0674(95)80028-x. [DOI] [PubMed] [Google Scholar]
  43. Li S., Sedivy J. M. Raf-1 protein kinase activates the NF-kappa B transcription factor by dissociating the cytoplasmic NF-kappa B-I kappa B complex. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9247–9251. doi: 10.1073/pnas.90.20.9247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Lin A., Minden A., Martinetto H., Claret F. X., Lange-Carter C., Mercurio F., Johnson G. L., Karin M. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science. 1995 Apr 14;268(5208):286–290. doi: 10.1126/science.7716521. [DOI] [PubMed] [Google Scholar]
  45. Liu M. K., Herrera-Velit P., Brownsey R. W., Reiner N. E. CD14-dependent activation of protein kinase C and mitogen-activated protein kinases (p42 and p44) in human monocytes treated with bacterial lipopolysaccharide. J Immunol. 1994 Sep 15;153(6):2642–2652. [PubMed] [Google Scholar]
  46. Magnuson N. S., Beck T., Vahidi H., Hahn H., Smola U., Rapp U. R. The Raf-1 serine/threonine protein kinase. Semin Cancer Biol. 1994 Aug;5(4):247–253. [PubMed] [Google Scholar]
  47. Marshall M. Interactions between Ras and Raf: key regulatory proteins in cellular transformation. Mol Reprod Dev. 1995 Dec;42(4):493–499. doi: 10.1002/mrd.1080420418. [DOI] [PubMed] [Google Scholar]
  48. Minden A., Lin A., McMahon M., Lange-Carter C., Dérijard B., Davis R. J., Johnson G. L., Karin M. Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science. 1994 Dec 9;266(5191):1719–1723. doi: 10.1126/science.7992057. [DOI] [PubMed] [Google Scholar]
  49. Morrison D. C., Ryan J. L. Bacterial endotoxins and host immune responses. Adv Immunol. 1979;28:293–450. doi: 10.1016/s0065-2776(08)60802-0. [DOI] [PubMed] [Google Scholar]
  50. Muroi M., Suzuki T. Role of protein kinase A in LPS-induced activation of NF-kappa B proteins of a mouse macrophage-like cell line, J774. Cell Signal. 1993 May;5(3):289–298. doi: 10.1016/0898-6568(93)90019-i. [DOI] [PubMed] [Google Scholar]
  51. Myers M. J., Ghildyal N., Schook L. B. Endotoxin and interferon-gamma differentially regulate the transcriptional levels of proto-oncogenes and cytokine genes during the differentiation of colony-stimulating factor type-1-derived macrophages. Immunology. 1995 Jun;85(2):318–324. [PMC free article] [PubMed] [Google Scholar]
  52. Nordeen S. K. Luciferase reporter gene vectors for analysis of promoters and enhancers. Biotechniques. 1988 May;6(5):454–458. [PubMed] [Google Scholar]
  53. Oberwetter J. M., Conrad K. E., Gutierrez-Hartmann A. The Ras and protein kinase C signaling pathways are functionally antagonistic in GH4 neuroendocrine cells. Mol Endocrinol. 1993 Jul;7(7):915–923. doi: 10.1210/mend.7.7.8413316. [DOI] [PubMed] [Google Scholar]
  54. Payne D. M., Rossomando A. J., Martino P., Erickson A. K., Her J. H., Shabanowitz J., Hunt D. F., Weber M. J., Sturgill T. W. Identification of the regulatory phosphorylation sites in pp42/mitogen-activated protein kinase (MAP kinase). EMBO J. 1991 Apr;10(4):885–892. doi: 10.1002/j.1460-2075.1991.tb08021.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Pelech S. L., Charest D. L., Mordret G. P., Siow Y. L., Palaty C., Campbell D., Charlton L., Samiei M., Sanghera J. S. Networking with mitogen-activated protein kinases. Mol Cell Biochem. 1993 Nov;127-128:157–169. doi: 10.1007/BF01076767. [DOI] [PubMed] [Google Scholar]
  56. Phillips W. A., Hamilton J. A. Colony stimulating factor-1 is a negative regulator of the macrophage respiratory burst. J Cell Physiol. 1990 Aug;144(2):190–196. doi: 10.1002/jcp.1041440203. [DOI] [PubMed] [Google Scholar]
  57. Pickett C. A., Gutierrez-Hartmann A. Epidermal growth factor and Ras regulate gene expression in GH4 pituitary cells by separate, antagonistic signal transduction pathways. Mol Cell Biol. 1995 Dec;15(12):6777–6784. doi: 10.1128/mcb.15.12.6777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Poutsiaka D. D., Clark B. D., Vannier E., Dinarello C. A. Production of interleukin-1 receptor antagonist and interleukin-1 beta by peripheral blood mononuclear cells is differentially regulated. Blood. 1991 Sep 1;78(5):1275–1281. [PubMed] [Google Scholar]
  59. Ray L. B., Sturgill T. W. Insulin-stimulated microtubule-associated protein kinase is phosphorylated on tyrosine and threonine in vivo. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3753–3757. doi: 10.1073/pnas.85.11.3753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Reimann T., Büscher D., Hipskind R. A., Krautwald S., Lohmann-Matthes M. L., Baccarini M. Lipopolysaccharide induces activation of the Raf-1/MAP kinase pathway. A putative role for Raf-1 in the induction of the IL-1 beta and the TNF-alpha genes. J Immunol. 1994 Dec 15;153(12):5740–5749. [PubMed] [Google Scholar]
  61. Russell M., Lange-Carter C. A., Johnson G. L. Regulation of recombinant MEK1 and MEK2b expressed in Escherichia coli. Biochemistry. 1995 May 23;34(20):6611–6615. doi: 10.1021/bi00020a005. [DOI] [PubMed] [Google Scholar]
  62. Russell M., Winitz S., Johnson G. L. Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity. Mol Cell Biol. 1994 Apr;14(4):2343–2351. doi: 10.1128/mcb.14.4.2343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Sanghera J. S., Weinstein S. L., Aluwalia M., Girn J., Pelech S. L. Activation of multiple proline-directed kinases by bacterial lipopolysaccharide in murine macrophages. J Immunol. 1996 Jun 1;156(11):4457–4465. [PubMed] [Google Scholar]
  64. Sauma S., Huang F., Winawer S., Friedman E. Colon goblet cells lose proliferative response to TGF alpha as they differentiate. Int J Cancer. 1995 Jun 9;61(6):848–853. doi: 10.1002/ijc.2910610617. [DOI] [PubMed] [Google Scholar]
  65. Seger R., Krebs E. G. The MAPK signaling cascade. FASEB J. 1995 Jun;9(9):726–735. [PubMed] [Google Scholar]
  66. Smith M. F., Jr, Eidlen D., Arend W. P., Gutierrez-Hartmann A. LPS-induced expression of the human IL-1 receptor antagonist gene is controlled by multiple interacting promoter elements. J Immunol. 1994 Oct 15;153(8):3584–3593. [PubMed] [Google Scholar]
  67. Smith M. F., Jr, Eidlen D., Brewer M. T., Eisenberg S. P., Arend W. P., Gutierrez-Hartmann A. Human IL-1 receptor antagonist promoter. Cell type-specific activity and identification of regulatory regions. J Immunol. 1992 Sep 15;149(6):2000–2007. [PubMed] [Google Scholar]
  68. Stefanová I., Corcoran M. L., Horak E. M., Wahl L. M., Bolen J. B., Horak I. D. Lipopolysaccharide induces activation of CD14-associated protein tyrosine kinase p53/56lyn. J Biol Chem. 1993 Oct 5;268(28):20725–20728. [PubMed] [Google Scholar]
  69. Stephens R. M., Sithanandam G., Copeland T. D., Kaplan D. R., Rapp U. R., Morrison D. K. 95-kilodalton B-Raf serine/threonine kinase: identification of the protein and its major autophosphorylation site. Mol Cell Biol. 1992 Sep;12(9):3733–3742. doi: 10.1128/mcb.12.9.3733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Vaillancourt R. R., Gardner A. M., Johnson G. L. B-Raf-dependent regulation of the MEK-1/mitogen-activated protein kinase pathway in PC12 cells and regulation by cyclic AMP. Mol Cell Biol. 1994 Oct;14(10):6522–6530. doi: 10.1128/mcb.14.10.6522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Vairo G., Argyriou S., Knight K. R., Hamilton J. A. Inhibition of colony-stimulating factor-stimulated macrophage proliferation by tumor necrosis factor-alpha, IFN-gamma, and lipopolysaccharide is not due to a general loss of responsiveness to growth factor. J Immunol. 1991 May 15;146(10):3469–3477. [PubMed] [Google Scholar]
  72. Vairo G., Royston A. K., Hamilton J. A. Biochemical events accompanying macrophage activation and the inhibition of colony-stimulating factor-1-induced macrophage proliferation by tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide. J Cell Physiol. 1992 Jun;151(3):630–641. doi: 10.1002/jcp.1041510324. [DOI] [PubMed] [Google Scholar]
  73. Vannier E., Miller L. C., Dinarello C. A. Coordinated antiinflammatory effects of interleukin 4: interleukin 4 suppresses interleukin 1 production but up-regulates gene expression and synthesis of interleukin 1 receptor antagonist. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4076–4080. doi: 10.1073/pnas.89.9.4076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Weinstein S. L., Gold M. R., DeFranco A. L. Bacterial lipopolysaccharide stimulates protein tyrosine phosphorylation in macrophages. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4148–4152. doi: 10.1073/pnas.88.10.4148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Weinstein S. L., Sanghera J. S., Lemke K., DeFranco A. L., Pelech S. L. Bacterial lipopolysaccharide induces tyrosine phosphorylation and activation of mitogen-activated protein kinases in macrophages. J Biol Chem. 1992 Jul 25;267(21):14955–14962. [PubMed] [Google Scholar]
  76. Wright S. D., Ramos R. A., Tobias P. S., Ulevitch R. J., Mathison J. C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science. 1990 Sep 21;249(4975):1431–1433. doi: 10.1126/science.1698311. [DOI] [PubMed] [Google Scholar]
  77. Wu J., Dent P., Jelinek T., Wolfman A., Weber M. J., Sturgill T. W. Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3',5'-monophosphate. Science. 1993 Nov 12;262(5136):1065–1069. doi: 10.1126/science.7694366. [DOI] [PubMed] [Google Scholar]
  78. Wu J., Rossomando A. J., Her J. H., Del Vecchio R., Weber M. J., Sturgill T. W. Autophosphorylation in vitro of recombinant 42-kilodalton mitogen-activated protein kinase on tyrosine. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9508–9512. doi: 10.1073/pnas.88.21.9508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Xu J., Rockow S., Kim S., Xiong W., Li W. Interferons block protein kinase C-dependent but not-independent activation of Raf-1 and mitogen-activated protein kinases and mitogenesis in NIH 3T3 cells. Mol Cell Biol. 1994 Dec;14(12):8018–8027. doi: 10.1128/mcb.14.12.8018. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  80. Xu S., Robbins D., Frost J., Dang A., Lange-Carter C., Cobb M. H. MEKK1 phosphorylates MEK1 and MEK2 but does not cause activation of mitogen-activated protein kinase. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6808–6812. doi: 10.1073/pnas.92.15.6808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Zheng C. F., Guan K. L. Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal-regulated kinases. J Biol Chem. 1993 Nov 15;268(32):23933–23939. [PubMed] [Google Scholar]

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