title: Differential cyclooxygenase-2 transcriptional control in proliferating versus quiescent fibroblasts.
abstract: Cyclooxygenase-2 (COX-2) overexpression is associated with cancer. One potential mechanism is DNA damage caused by COX-2 derived oxidants. Since DNA in proliferating cells is highly vulnerable to oxidative damage and mutation, we propose that COX-2 transactivation by exogenous stimuli is suppressed in proliferating cells compared to quiescent cells. In this review, we provide evidence for reduced COX-2 transcriptional expression in response to phorbol esters (PMA), lipopolysaccharide (LPS), interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha). Our results show that COX-2 transcription in proliferating fibroblasts is suppressed by a small molecular weight compound produced by proliferating cells. By contrast, COX-2 expression in response to exogenous stimuli is robust in quiescent cells. The quiescent cells in human body may play a primary role in mounting response to exogenous stimuli. Salicylate inhibits COX-2 transcriptional activation in quiescent cells but not in serum-driven proliferating cells by blocking C/EBPbeta DNA binding. These studies suggest that COX-2 expressions in quiescent and proliferating cells are regulated by different mechanisms. Further investigations into their transcriptional control mechanisms will have great impact on the fundamental understanding of the division of cell functions between quiescent and proliferating cells and the design of novel therapeutic strategies.
authors.affiliation: Vascular Biology Research Center at Institute of Molecular Medicine, University of Texas Health Science Center at Houston, TX, USA. kenneth.k.wu@uth.tmc.edu
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D012980:Sodium Salicylate / Q000378:metabolism / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D017077:Culture Media, Conditioned; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C016658:phorbolol myristate acetate; D051546:Cyclooxygenase 2; D013755:Tetradecanoylphorbol Acetate; D012980:Sodium Salicylate