PMID- 12600818
OWN - NLM
STAT- MEDLINE
DCOM- 20030710
LR  - 20211203
IS  - 1044-1549 (Print)
IS  - 1044-1549 (Linking)
VI  - 28
IP  - 6
DP  - 2003 Jun
TI  - Ras and mitogen-activated protein kinase kinase kinase-1 coregulate activator 
      protein-1- and nuclear factor-kappaB-mediated gene expression in airway 
      epithelial cells.
PG  - 762-9
AB  - In 16HBE14o- human bronchial epithelial cells, maximal tumor necrosis factor 
      (TNF)-alpha-induced interleukin (IL)-8 expression depends on the activation of 
      two distinct signaling pathways, one constituted in part by activator protein 
      (AP)-1 and the other by nuclear factor (NF)-kappaB. We examined the upstream 
      signaling intermediates responsible for IL-8 and granulocyte-macrophage 
      colony-stimulating factor (GM-CSF) expression in this system, hypothesizing that 
      p21 Ras and mitogen-activated protein kinase/extracellular signal-regulated 
      kinase kinase kinase (MEKK)-1 function as common upstream activators of both the 
      AP-1 and NF-kappaB pathways. TNF-alpha treatment induced both Ras and MEKK1 
      activation. Dominant-negative forms of Ras (N17Ras) and MEKK1 (MEKK1-KM) each 
      inhibited TNF-alpha-induced transcription from IL-8 and GM-CSF promoters. Ras was 
      required for maximal activation of extracellular signal-regulated kinase (ERK) 
      and Jun amino terminal kinase (JNK) as well as AP-1 and NF-kappaB transcriptional 
      activities, but not for activation of IkappaB kinase (IKK)-beta, an upstream 
      activator of NF-kappaB. MEKK1 was required for maximal activation of ERK, JNK, 
      and IKK, as well as for maximal AP-1 and NF-kappaB transcriptional activities. We 
      conclude that Ras regulates TNF-alpha-induced chemokine expression by activating 
      the AP-1 pathway and enhancing transcriptional function of NF-kappaB, whereas 
      MEKK1 activates both the AP-1 and NF-kappaB pathways.
FAU - Zhou, Limei
AU  - Zhou L
AD  - Department of Pediatrics and Communicable Diseases, University of Michigan, Ann 
      Arbor, MI 48109-0212, USA.
FAU - Tan, Alan
AU  - Tan A
FAU - Iasvovskaia, Svetlana
AU  - Iasvovskaia S
FAU - Li, Jing
AU  - Li J
FAU - Lin, Anning
AU  - Lin A
FAU - Hershenson, Marc B
AU  - Hershenson MB
LA  - eng
GR  - HL56399/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20030131
PL  - United States
TA  - Am J Respir Cell Mol Biol
JT  - American journal of respiratory cell and molecular biology
JID - 8917225
RN  - 0 (Interleukin-8)
RN  - 0 (NF-kappa B)
RN  - 0 (Transcription Factor AP-1)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinase 1)
RN  - EC 2.7.11.25 (MAP3K1 protein, human)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Bronchi/cytology
MH  - Cells, Cultured
MH  - Epithelial Cells/drug effects/*metabolism
MH  - Gene Expression Regulation/drug effects/*physiology
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/genetics
MH  - Humans
MH  - Interleukin-8/genetics
MH  - JNK Mitogen-Activated Protein Kinases
MH  - *MAP Kinase Kinase Kinase 1
MH  - Mitogen-Activated Protein Kinases/drug effects/genetics/metabolism
MH  - Mutation
MH  - NF-kappa B/genetics/*metabolism
MH  - Promoter Regions, Genetic
MH  - Protein Kinases/genetics/metabolism
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Signal Transduction/physiology
MH  - Transcription Factor AP-1/genetics/*metabolism
MH  - Transcription, Genetic
MH  - Transcriptional Activation
MH  - Tumor Necrosis Factor-alpha/metabolism/pharmacology
MH  - ras Proteins/genetics/*metabolism
EDAT- 2003/02/26 04:00
MHDA- 2003/07/11 05:00
CRDT- 2003/02/26 04:00
PHST- 2003/02/26 04:00 [pubmed]
PHST- 2003/07/11 05:00 [medline]
PHST- 2003/02/26 04:00 [entrez]
AID - 2002-0261OC [pii]
AID - 10.1165/rcmb.2002-0261OC [doi]
PST - ppublish
SO  - Am J Respir Cell Mol Biol. 2003 Jun;28(6):762-9. doi: 10.1165/rcmb.2002-0261OC. 
      Epub 2003 Jan 31.