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Published ahead of print on January 31, 2003, doi:10.1165/rcmb.2002-0261OC

Am. J. Respir. Cell Mol. Biol., Volume 28, Number 6, June 2003, 762-769

A more recent version of this article appeared on June 1, 2003
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Submitted on November 20, 2002
Revised on January 29, 2003

RAS AND MEKK1 CO-REGULATE AP-1 AND NF-{kappa}B-MEDIATED GENE EXPRESSION IN AIRWAY EPITHELIAL CELLS

Limei Zhou1, Alan Tan, Svetlana Iasvovskaia, Jing Li, Anning Lin2, and Marc B Hershenson1*

1 Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA, 2 Ben May Institute for Cancer Research, University of Chicago, Chicago, IL, USA

* To whom correspondence should be addressed. E-mail: mhershen{at}umich.edu.

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)-{kappa}B. 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-{kappa}B 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-{kappa}B transcriptional activities, but not for activation of I{kappa}B kinase (IKK)-{beta}, an upstream activator of NF-{kappa}B. MEKK1 was required for maximal activation of ERK, JNK and IKK, as well as for maximal AP-1 and NF-{kappa}B transcriptional activities. We conclude that Ras regulates TNF{alpha}-induced chemokine expression by activating the AP-1 pathway and enhancing transcriptional function of NF-{kappa}B, whereas MEKK1 activates both the AP-1 and NF-{kappa}B pathways.




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