Journal of Biological Chemistry
Volume 276, Issue 5, 2 February 2001, Pages 3650-3659
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MECHANISMS OF SIGNAL TRANSDUCTION
Nuclear Factor-κB Activation by the CXC Chemokine Melanoma Growth-stimulatory Activity/Growth-regulated Protein Involves the MEKK1/p38 Mitogen-activated Protein Kinase Pathway*

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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/GROα in melanoma tumors is associated with constitutive nuclear factor (NF)-κB activity. We show here that either exogenous addition or continuous expression of MGSA/GROα in immortalized melanocytes enhances NF-κB 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/GROα-induced NF-κB transactivation, demonstrating that Ras, MEKK1, and p38 are involved in the signal pathways of MGSA/GROα activation of NF-κB. Expression of dominant active Ras or dominant active MEKK1 alone can also stimulate NF-κB activation. The expression of dominant negative MEKK1 inhibits the Ras-induced NF-κB activation, suggesting that MEKK1 is a downstream target of Ras. Moreover, MGSA/GROα induction of NF-κB is independent of the MEK1/ERK cascade, because MGSA/GROα failed to increase ERK and ELK activation, and specific chemical inhibitors for MEK1 (PD98059) had no effect on MGSA/GROα-enhanced NF-κB activation. These data demonstrate that NF-κB activation is required for MGSA/GROα-induced melanocyte transformation through a Ras/MEKK1/p38 cascade in melanocytes.

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Published, JBC Papers in Press, November 2, 2000, DOI 10.1074/jbc.M006115200

*

This work was supported by a Department of Veterans Affairs Merit Award and a Career Scientist Award (to A. R.), National Institutes of Health Grants CA56704 and CA34590 (to A. R.), Vanderbilt Vascular Biology Training Grant 2T32HL07751-06, and National Institutes of Health Grant CA68485 (to the Vanderbilt Cancer Center).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.