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J. Biol. Chem., Vol. 276, Issue 46, 42737-42743, November 16, 2001

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Induction of cPLA₂ in Lung Epithelial Cells and Non-small Cell Lung Cancer Is Mediated by Sp1 and c-Jun^*

Stacy A. Blaine, Marilee Wick^§, Christina Dessev^§, and Raphael A. Nemenoff^§¶

From the Departments of ^§ Medicine and  Pharmacology, University of Colorado Health Science Center, Denver, Colorado 80262

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 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.

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