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Papers In Press, published online ahead of print September 14, 2001
Dept. of Medicine, Division of Renal Diseases and Hypertens, University of Colorado Health Sciences Center, Denver, CO 80262
Corresponding Author: Raphael.Nemenoff{at}uchsc.edu
Activating mutations in ras genes are frequently associated with non-small cell lung cancer cells (NSCLC) and contribute to tranformed 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 –58 to –12 that is required for H-Ras mediated induction. To further characterize the cis-regulatory elements within this region involved in this reponse, 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 H-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 H-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.
J. Biol. Chem, 10.1074/jbc.M107773200
Submitted on August 13, 2001
Revised on September 14, 2001
Accepted on September 14, 2001
Induction of cPLA2 in lung Epithelial cells and non-small cell lung cancer is mediated by Sp1 and c-Jun
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