Home LiteratureArticle Details
PMID: 11062239 Published · ppublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Nuclear factor-kappa B activation by the CXC chemokine melanoma growth-stimulatory activity/growth-regulated protein involves the MEKK1/p38 mitogen-activated protein kinase pathway.

The Journal of biological chemistry ·Vol. 276 ·No. 5 ·2001-02-02 ·Pages 3650-9

Wang D, Richmond A

Abstract

Melanoma growth stimulatory activity/growth-regulated protein (MGSA/GRO), a CXC chemokine, plays an important role in inflammation, wound healing, growth regulation, angiogenesis, and tumorigenesis. Constitutive expression of MGSA/GROalpha in melanoma tumors is associated with constitutive nuclear factor (NF)-kappaB activity. We show here that either exogenous addition or continuous expression of MGSA/GROalpha in immortalized melanocytes enhances NF-kappaB activation, as well as mitogen-activated protein (MAP) kinase kinase kinase (MEKK) 1, MAP kinase kinase (MEK) 3/6, and p38 MAP kinase activation. Expression of dominant negative M-Ras (S27N), dominant negative MEKK1 (K432M), or specific chemical inhibitors for p38 MAP kinase (SB202190 and SB203580) block MGSA/GROalpha-induced NF-kappaB transactivation, demonstrating that Ras, MEKK1, and p38 are involved in the signal pathways of MGSA/GROalpha activation of NF-kappaB. Expression of dominant active Ras or dominant active MEKK1 alone can also stimulate NF-kappaB activation. The expression of dominant negative MEKK1 inhibits the Ras-induced NF-kappaB activation, suggesting that MEKK1 is a downstream target of Ras. Moreover, MGSA/GROalpha induction of NF-kappaB is independent of the MEK1/ERK cascade, because MGSA/GROalpha failed to increase ERK and ELK activation, and specific chemical inhibitors for MEK1 (PD98059) had no effect on MGSA/GROalpha-enhanced NF-kappaB activation. These data demonstrate that NF-kappaB activation is required for MGSA/GROalpha-induced melanocyte transformation through a Ras/MEKK1/p38 cascade in melanocytes.

MeSH Terms
Animals Cell Transformation, Neoplastic/drug effects,metabolism Cells, Cultured Chemokine CXCL1 Chemokines, CXC/pharmacology Chemotactic Factors/pharmacology Enzyme Activation/drug effects Growth Substances/pharmacology Intercellular Signaling Peptides and Proteins MAP Kinase Kinase 1 MAP Kinase Kinase Kinase 1 Melanocytes/drug effects,physiology Mice Mitogen-Activated Protein Kinase Kinases/metabolism Mitogen-Activated Protein Kinases/metabolism NF-kappa B/metabolism Protein Serine-Threonine Kinases/metabolism p38 Mitogen-Activated Protein Kinases ras Proteins/metabolism
Chemicals
Chemokine CXCL1 Chemokines, CXC Chemotactic Factors Cxcl1 protein, mouse Growth Substances Intercellular Signaling Peptides and Proteins NF-kappa B Protein Serine-Threonine Kinases Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases MAP Kinase Kinase Kinase 1 Map3k1 protein, mouse MAP Kinase Kinase 1 Map2k1 protein, mouse Mitogen-Activated Protein Kinase Kinases ras Proteins
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Wang D
Department of Veterans Affairs, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Richmond A
References (72)
72 references, click to expand
  1. A novel SAPK/JNK kinase, MKK7, stimulated by TNFalpha and cellular stresses.
    EMBO J. 1997 Dec 1;16(23):7045-53 PMID: 9384583
  2. Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras.
    Science. 1997 Dec 5;278(5344):1812-5 PMID: 9388187
  3. p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways are required for nuclear factor-kappaB p65 transactivation mediated by tumor necrosis factor.
    J Biol Chem. 1998 Feb 6;273(6):3285-90 PMID: 9452444
  4. Identification and characterization of an MGSA/GRO pseudogene.
    DNA Seq. 1997;7(6):379-86 PMID: 9524820
  5. Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration.
    J Biol Chem. 1998 Apr 24;273(17):10095-8 PMID: 9553055
  6. Constitutive activation of NF-kappaB causes resistance to apoptosis in human cutaneous T cell lymphoma HuT-78 cells. Autocrine role of tumor necrosis factor and reactive oxygen intermediates.
    J Biol Chem. 1998 May 29;273(22):14008-14 PMID: 9593751
  7. Signaling pathways in Ras-mediated tumorigenicity and metastasis.
    Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8773-8 PMID: 9671754
  8. The alpha-chemokine, stromal cell-derived factor-1alpha, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways.
    J Biol Chem. 1998 Sep 4;273(36):23169-75 PMID: 9722546
  9. Interleukin-8 receptors R1 and R2 activate mitogen-activated protein kinases and induce c-fos, independent of Ras and Raf-1 in Chinese hamster ovary cells.
    Biochemistry. 1998 Nov 10;37(45):15918-24 PMID: 9843397
  10. Cooperation of p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways during granulocyte colony-stimulating factor-induced hemopoietic cell proliferation.
    J Biol Chem. 1999 Feb 12;274(7):4096-105 PMID: 9933603
  11. Extracellular-regulated kinase 1/2, Jun N-terminal kinase, and c-Jun are involved in NF-kappa B-dependent IL-6 expression in human monocytes.
    J Immunol. 1999 Apr 15;162(8):4893-902 PMID: 10202034
  12. Oncogenic Ras enhances NF-kappaB transcriptional activity through Raf-dependent and Raf-independent mitogen-activated protein kinase signaling pathways.
    J Biol Chem. 1999 May 14;274(20):13841-6 PMID: 10318790
  13. The host environment promotes the constitutive activation of nuclear factor-kappaB and proinflammatory cytokine expression during metastatic tumor progression of murine squamous cell carcinoma.
    Cancer Res. 1999 Jul 15;59(14):3495-504 PMID: 10416616
  14. Essential role for oncogenic Ras in tumour maintenance.
    Nature. 1999 Jul 29;400(6743):468-72 PMID: 10440378
  15. Induction of melanoma in TPras transgenic mice.
    Carcinogenesis. 1999 Sep;20(9):1747-53 PMID: 10469620
  16. Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression.
    J Biol Chem. 1999 Sep 17;274(38):27161-7 PMID: 10480932
  17. ERK MAP kinase links cytokine signals to activation of latent HIV-1 infection by stimulating a cooperative interaction of AP-1 and NF-kappaB.
    J Biol Chem. 1999 Sep 24;274(39):27981-8 PMID: 10488148
  18. Constitutive activation of transcription factors NF-(kappa)B, AP-1, and NF-IL6 in human head and neck squamous cell carcinoma cell lines that express pro-inflammatory and pro-angiogenic cytokines.
    Mol Carcinog. 1999 Oct;26(2):119-29 PMID: 10506755
  19. Engagement of tumor necrosis factor (TNF) receptor 1 leads to ATF-2- and p38 mitogen-activated protein kinase-dependent TNF-alpha gene expression.
    J Biol Chem. 1999 Oct 22;274(43):30882-6 PMID: 10521481
  20. Novel Ras antagonist blocks human melanoma growth.
    Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):14019-24 PMID: 10570191
  21. MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway.
    J Biol Chem. 1999 Dec 17;274(51):36035-8 PMID: 10593883
  22. Activation of nuclear factor kappaB in single living cells. Dependence of nuclear translocation and anti-apoptotic function on EGFPRELA concentration.
    J Biol Chem. 1999 Dec 31;274(53):37941-9 PMID: 10608861
  23. The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma.
    J Leukoc Biol. 2000 Jan;67(1):53-62 PMID: 10647998
  24. The IKK complex: an integrator of all signals that activate NF-kappaB?
    Trends Cell Biol. 2000 Apr;10(4):129-33 PMID: 10740266
  25. Transfection of constitutively active mitogen-activated protein/extracellular signal-regulated kinase kinase confers tumorigenic and metastatic potentials to NIH3T3 cells.
    Cancer Res. 2000 Mar 15;60(6):1552-6 PMID: 10749122
  26. Raf induces NF-kappaB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation.
    Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4615-20 PMID: 10758165
  27. MGSA/GRO-mediated melanocyte transformation involves induction of Ras expression.
    Oncogene. 2000 Sep 21;19(40):4647-59 PMID: 11030154
  28. Purification of melanoma growth stimulatory activity.
    J Cell Physiol. 1986 Dec;129(3):375-84 PMID: 3465735
  29. A line of non-tumorigenic mouse melanocytes, syngeneic with the B16 melanoma and requiring a tumour promoter for growth.
    Int J Cancer. 1987 Mar 15;39(3):414-8 PMID: 3102392
  30. Cloning and characterization of cDNAs for murine macrophage inflammatory protein 2 and its human homologues.
    J Exp Med. 1990 Sep 1;172(3):911-9 PMID: 2201751
  31. Cloning and sequencing of a new gro transcript from activated human monocytes: expression in leukocytes and wound tissue.
    Mol Cell Biol. 1990 Oct;10(10):5596-9 PMID: 2078213
  32. Identification of three related human GRO genes encoding cytokine functions.
    Proc Natl Acad Sci U S A. 1990 Oct;87(19):7732-6 PMID: 2217207
  33. Effects of MGSA/GRO alpha on melanocyte transformation.
    Oncogene. 1991 Jul;6(7):1115-24 PMID: 1861861
  34. Scanning mutagenesis of interleukin-8 identifies a cluster of residues required for receptor binding.
    J Biol Chem. 1991 Oct 5;266(28):18989-94 PMID: 1918013
  35. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling.
    Cell. 1992 Aug 7;70(3):401-10 PMID: 1643658
  36. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf.
    Science. 1993 Apr 16;260(5106):315-9 PMID: 8385802
  37. Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2.
    J Biol Chem. 1993 May 25;268(15):11435-9 PMID: 8388392
  38. The interleukin-8-related chemotactic cytokines GRO alpha, GRO beta, and GRO gamma activate human neutrophil and basophil leukocytes.
    J Biol Chem. 1993 Jul 25;268(21):15419-24 PMID: 8340371
  39. Mechanisms of transcriptional synergism between distinct virus-inducible enhancer elements.
    Cell. 1993 Sep 10;74(5):887-98 PMID: 8374955
  40. Cyclic AMP-independent ATF family members interact with NF-kappa B and function in the activation of the E-selectin promoter in response to cytokines.
    Mol Cell Biol. 1993 Nov;13(11):7180-90 PMID: 7692236
  41. Antisense inhibition of the p65 subunit of NF-kappa B blocks tumorigenicity and causes tumor regression.
    Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9901-5 PMID: 8234333
  42. Expression of cytokine/growth factors and their receptors in human melanoma and melanocytes.
    Int J Cancer. 1994 Mar 15;56(6):853-7 PMID: 7509778
  43. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells.
    Science. 1994 Aug 5;265(5173):808-11 PMID: 7914033
  44. Activation of NF-kappa B in vivo is regulated by multiple phosphorylations.
    EMBO J. 1994 Oct 3;13(19):4597-607 PMID: 7925300
  45. Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK.
    Science. 1994 Dec 9;266(5191):1719-23 PMID: 7992057
  46. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis.
    Nature. 1994 Dec 22-29;372(6508):739-46 PMID: 7997261
  47. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms.
    Science. 1995 Feb 3;267(5198):682-5 PMID: 7839144
  48. Structure, regulation and function of NF-kappa B.
    Annu Rev Cell Biol. 1994;10:405-55 PMID: 7888182
  49. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2.
    Science. 1995 Apr 14;268(5208):286-90 PMID: 7716521
  50. Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation.
    Mol Cell Biol. 1995 May;15(5):2809-18 PMID: 7739562
  51. Direct interaction between Ras and the kinase domain of mitogen-activated protein kinase kinase kinase (MEKK1).
    J Biol Chem. 1995 May 19;270(20):11757-60 PMID: 7744823
  52. A synthetic inhibitor of the mitogen-activated protein kinase cascade.
    Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686-9 PMID: 7644477
  53. Expression and growth-promoting function of the IL-8 receptor beta in human melanoma cells.
    J Immunol. 1996 Feb 1;156(3):1132-37 PMID: 8557989
  54. MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway.
    Mol Cell Biol. 1996 Mar;16(3):1247-55 PMID: 8622669
  55. Characterization of the structure and function of a novel MAP kinase kinase (MKK6).
    J Biol Chem. 1996 Feb 9;271(6):2886-91 PMID: 8621675
  56. Phosphatidylinositol 3-kinase is an early intermediate in the G beta gamma-mediated mitogen-activated protein kinase signaling pathway.
    J Biol Chem. 1996 May 24;271(21):12133-6 PMID: 8647803
  57. Physical association of Gi2alpha with interleukin-8 receptors.
    J Biol Chem. 1996 May 31;271(22):12783-9 PMID: 8662698
  58. Rel/NF-kappaB/IkappaB proteins and cancer.
    Oncogene. 1996 Oct 3;13(7):1367-78 PMID: 8875974
  59. Linkage of G protein-coupled receptors to the MAPK signaling pathway through PI 3-kinase gamma.
    Science. 1997 Jan 17;275(5298):394-7 PMID: 8994038
  60. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases.
    N Engl J Med. 1997 Apr 10;336(15):1066-71 PMID: 9091804
  61. CREB-binding protein/p300 are transcriptional coactivators of p65.
    Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):2927-32 PMID: 9096323
  62. Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils independent of extracellular signal-regulated kinase and p38 mitogen-activated protein kinases.
    Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3052-7 PMID: 9096344
  63. Stimulation of NF-kappa B activation and gene expression by platelet-activating factor.
    Adv Exp Med Biol. 1996;416:143-51 PMID: 9131140
  64. The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism.
    Cell. 1997 May 2;89(3):413-24 PMID: 9150141
  65. Enhanced degradation of I-kappaB alpha contributes to endogenous activation of NF-kappaB in Hs294T melanoma cells.
    Cancer Res. 1997 Jul 15;57(14):3032-9 PMID: 9230219
  66. Ras-dependent mitogen-activated protein kinase activation by G protein-coupled receptors. Convergence of Gi- and Gq-mediated pathways on calcium/calmodulin, Pyk2, and Src kinase.
    J Biol Chem. 1997 Aug 1;272(31):19125-32 PMID: 9235901
  67. MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42.
    EMBO J. 1997 Aug 15;16(16):4961-72 PMID: 9305638
  68. Oncogenic Ha-Ras-induced signaling activates NF-kappaB transcriptional activity, which is required for cellular transformation.
    J Biol Chem. 1997 Sep 26;272(39):24113-6 PMID: 9305854
  69. Enhanced tumor-forming capacity for immortalized melanocytes expressing melanoma growth stimulatory activity/growth-regulated cytokine beta and gamma proteins.
    Int J Cancer. 1997 Sep 26;73(1):94-103 PMID: 9334815
  70. Mechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression.
    J Leukoc Biol. 1997 Nov;62(5):588-97 PMID: 9365113
  71. Expression of the neoplastic phenotype by human thyroid carcinoma cell lines requires NFkappaB p65 protein expression.
    Oncogene. 1997 Oct 16;15(16):1987-94 PMID: 9365245
  72. Fas induces cytoplasmic apoptotic responses and activation of the MKK7-JNK/SAPK and MKK6-p38 pathways independent of CPP32-like proteases.
    J Cell Biol. 1997 Nov 17;139(4):1005-15 PMID: 9362518
Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M006115200
Published
2001-02-02
Epub
2000-00-02
Pages
3650-9
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2676351
Subset
IM
Grants
NCI NIH HHS · R01 CA056704-07 · United States
NHLBI NIH HHS · T32 HL007751 · United States
NCI NIH HHS · CA34590 · United States
NHLBI NIH HHS · 2T32HL07751-06 · United States
NCI NIH HHS · R01 CA034590 · United States
NCI NIH HHS · P30 CA068485 · United States
NCI NIH HHS · CA56704 · United States
NCI NIH HHS · R01 CA056704-09 · United States
NCI NIH HHS · R01 CA056704-08 · United States
External Links
PubMed source DOI: 10.1074/jbc.M006115200 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2