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J. Biol. Chem., Vol. 276, Issue 46, 42737-42743, November 16, 2001
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From the Departments of § Medicine and
Activating mutations in ras
genes are frequently associated with non-small cell lung cancer cells
(NSCLC) and contribute to transformed growth in these cells. Expression
of oncogenic forms of Ras in these cells is associated with increased
expression and activity of cytosolic phospholipase A2
(cPLA2) and cyclooxygenase-2 (COX-2), leading to
constitutively elevated levels of prostaglandin production. Expression
of oncogenic Ras is sufficient to induce these enzymes in normal lung
epithelial cells. We have previously reported that the JNK and ERK
pathways are necessary for induction of cPLA2 and have
defined a minimal region of the cPLA2 promoter from
Induction of cPLA2 in Lung Epithelial Cells and
Non-small Cell Lung Cancer Is Mediated by Sp1 and c-Jun*
,§¶
Pharmacology, University of Colorado Health Science
Center, Denver, Colorado 80262
58 to
12 that is required for Ha-Ras-mediated induction. To further
characterize the cis-regulatory elements within this region
involved in this response, site-directed mutagenesis was used to make
mutations at various sites. Three cis-regulatory elements
were identified: regions 21/18, 37/30, and 55/53. Mutations
in any of these elements decreased basal and Ha-Ras-induced cPLA2 promoter activity in both normal lung epithelial
cells, as well as steady state promoter activity in A549 cells, with a
mutation in element 21/18 completely eliminating all promoter activity. Overexpression studies and gel shift assays indicated that
Sp1 may serve as a transcription factor functionally regulating promoter activity by directly interacting with two of the
cis-regulatory elements, 21/18 and 37/30.
Expression of Ha-Ras led to induction of c-Jun protein, which showed
functional cooperation with Sp1 in driving promoter activity.
Additional unidentified transcription factors bound to the
regions from 55/53 and 37/34.
*
This work was supported by National Institutes of Health NCI
SPORE Grant CA 58187 and National Institutes of Health Grants DK 19928 and DK 39902.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.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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