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

Abstract

Cyclooxygenase-2 (Cox-2) gene expression which is rapidly induced by cytokines, growth factors and tumor promoters, is important for inflammation, angiogenesis, 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 Ras, Rac, Rho, and Cdc42Hs to differentially regulate transcription from the murine COX-2 promoter in NIH 3T3 cells. Over-expression of constitutively active mutants of Ras, Rac, Rho, but not Cdc42Hs induced transcription from the COX-2 promoter. Transactivation by Rac and Rho required cis-acting elements located between -80 and -40 of the COX-2 promoter whereas deletion of this region enhanced transactivation by Ras. 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 transactivation by Rho. This demonstrates Rho-dependent transactivation of the COX-2 promoter through novel trans-acting elements and suggests that, in NIH 3T3 cells, signaling by small GTPases that result in COX-2 expression is not through a sequential pathway from Cdc42 to Rac to Rho, but rather through independent, parallel signaling pathways.