title: Activation of NF-kappa B and p38 MAP kinase is not sufficient for triggering efficient HIV gene expression in response to stress.
abstract: Recent studies have established an essential role for p38 MAP kinase in UV activation of human immunodeficiency virus (HIV) gene expression. However, p38 MAP kinase is not involved in activation of NF-kappa B, a key transcriptional activator of HIV gene expression, in response to UV, suggesting that NF-kappa B acts independently of p38 MAP kinase. In this study, we have investigated whether activation of HIV gene expression occurs when p38 MAP kinase and NF-kappa B are activated by separate stress-causing treatments, each relatively specific for activating only one of the factors. Treatment of cells with sorbitol (hyperosmotic shock) strongly activates p38 MAP kinase, whereas the cytokine TNF-alpha is a poor activator of p38 MAP kinase. On the other hand, TNF-alpha is a strong activator of NF-kappa B whereas sorbitol is not. Sorbitol, however, activates AP-1 DNA binding activity in a manner similar to that of UV. Most importantly, both sorbitol and TNF-alpha are poor activators of HIV gene expression in HeLa cells stably transfected with an HIVcat reporter gene, whereas UV elicits a strong response. The combined treatment with UV and hyperosmotic shock produces an additive effect on HIV gene expression, suggesting that these agents activate at least in part by different mechanisms. The combined treatment with sorbitol and TNF-alpha activates p38 and NF-kappa B to levels similar to those with UV, yet only results in 25-30% of the CAT levels elicited by UV. Inhibition of NF-kappa B activation by the protease inhibitor N-alpha-tosyl-L-phenylalanine chloromethyl ketone (TPCK) prevents UV activation of HIV gene expression, but does not inhibit p38 MAP kinase activation. We conclude that whereas both p38 MAP kinase and NF-kappa B are important for UV activation of HIV gene expression they act independently from each other and activation of both factors is not sufficient for triggering a full HIV gene expression response. Activation of HIV gene expression by UV must therefore involve additional cellular processes, such as those triggered by DNA damage, for generation of a full gene expression response.
authors.affiliation: Department of Radiation Oncology and Massey Cancer Center, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0058, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Taher
authors.forename: J D
authors.initials: JD
authors.lastname: Oakley
authors.forename: C
authors.initials: C
authors.lastname: Hershey
authors.forename: K
authors.initials: K
authors.lastname: Valerie
mesh_terms: D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000528:radiation effects; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000528:radiation effects*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000528:radiation effects*; D006678:HIV / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D006367:HeLa Cells; D006801:Humans; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000528:radiation effects; D009997:Osmotic Pressure; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D012965:Sodium Chloride / Q000494:pharmacology; D013012:Sorbitol / Q000494:pharmacology; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016328:NF-kappa B; D011500:Protein Synthesis Inhibitors; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D014108:Tosylphenylalanyl Chloromethyl Ketone; D012965:Sodium Chloride; D013012:Sorbitol; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases