Differential regulation of COX-2 transcription by Ras- and Rho-family of GTPases

Cyclooxygenase-2 (Cox-2) gene expression which is rapidly induced by cytoki nes, growth factors and tumor promoters, is important for inflammation, ang iogenesis, and is markedly enhanced in various cancer cells. Many of these factors initiate signaling through Ras- and Rho-family small GTPases. Here, we investigated the ability of Has, Rac, Rho, and Cdc42Hs to differentiall y regulate transcription from the murine COX-2 promoter in NIH 3T3 cells. O ver-expression of constitutively active mutants of Ras, Rac, Rho, but not C dc42Hs induced transcription from the COX-2 promoter. Transactivation by Ra c and Rho required cis-acting elements located between -80 and -40 of the C OX-2 promoter whereas deletion of this region enhanced transactivation by R as. A CRE/ATF element located at -56 was critical for Ras- and Rac-induced transactivation of the COX-2 promoter, but was not required for transactiva tion by Rho. This demonstrates Rho-dependent transactivation of the COX-2 p romoter through novel trans-acting elements and suggests that, in NM 3T3 ce lls, signaling by small GTPases that result in COX-2 expression is not thro ugh a sequential pathway from Cdc42 to Rac to Rho, but rather through indep endent, parallel signaling pathways. (C) 2000 Academic Press.