Nuclear Factor-κB Activation by the CXC Chemokine Melanoma Growth-stimulatory Activity/Growth-regulated Protein Involves the MEKK1/p38 Mitogen-activated Protein Kinase Pathway

Dingzhi Wang, Ann Richmond

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77 Citations (Scopus)

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/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.

Original languageEnglish (US)
Pages (from-to)3650-3659
Number of pages10
JournalJournal of Biological Chemistry
Volume276
Issue number5
DOIs
StatePublished - Feb 2 2001
Externally publishedYes

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MAP Kinase Kinase Kinase 1
CXC Chemokines
p38 Mitogen-Activated Protein Kinases
Melanoma
Chemical activation
Growth
Proteins
Nuclear Proteins
Melanocytes
MAP Kinase Kinase 6
MAP Kinase Kinase Kinase 3

ASJC Scopus subject areas

  • Biochemistry

Cite this

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title = "Nuclear Factor-κB Activation by the CXC Chemokine Melanoma Growth-stimulatory Activity/Growth-regulated Protein Involves the MEKK1/p38 Mitogen-activated Protein Kinase Pathway",
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/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.",
author = "Dingzhi Wang and Ann Richmond",
year = "2001",
month = "2",
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doi = "10.1074/jbc.M006115200",
language = "English (US)",
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T1 - Nuclear Factor-κB Activation by the CXC Chemokine Melanoma Growth-stimulatory Activity/Growth-regulated Protein Involves the MEKK1/p38 Mitogen-activated Protein Kinase Pathway

AU - Wang, Dingzhi

AU - Richmond, Ann

PY - 2001/2/2

Y1 - 2001/2/2

N2 - 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.

AB - 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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