title: A p38-p65 transcription complex induced by endothelin-1 mediates signal transduction in cancer cells.
abstract: Endothelin-1 is a powerful mitogen for various tumor and non-tumor cells. Its signaling cascade induces the inflammatory NF-kappaB complex, leading to expression of a number of target genes. In this context, MAPK p38 has been regarded as a potential phosphate donor for the p65 subunit of NF-kappaB. In the present study in HeLa cells, we have found that ET-1 induced signalling activates the NF-kappaB transcription complex (TC) in the nucleus at 6 h specifically via ET-A - but not ET-B receptor. The TC contains p65, p38 (alpha and beta) - binding to the NLS of p65 in the cytoplasm - as well as p50, but no IkappaBalpha. Specific p38 inhibition by SB203580 or by siRNA interferes markedly with gene expression of several target genes. Complex formation occurs in the cytoplasm, and both transcription factors transmigrate as a complex in the nucleus. Overexpression of p38, treatment with Chrysin, MG132, or dimethylformamide shows dependence of TC on p38 as partner. In other tumor cells lines studied, ET-1 activates TC, with p38 as an important complex partner of p65. TC-induction by ET-1 contains about twice the amount of p38 than by TNFalpha. Thus, p38 may be an additional therapeutic target to control inflammatory gene expression in tumor cells.
authors.affiliation: Institute of Pathology, University Hospital, Kerpernerstrasse, 50931 Koeln, Germany. melanie@vonbrandenstein.de
authors.forename: Melanie Gerstung
authors.initials: MG
authors.lastname: von Brandenstein
authors.forename: Anna
authors.initials: A
authors.lastname: Ngum Abety
authors.forename: Reinhard
authors.initials: R
authors.lastname: Depping
authors.forename: Tanja
authors.initials: T
authors.lastname: Roth
authors.forename: Matthias
authors.initials: M
authors.lastname: Koehler
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Dienes
authors.forename: Jochen W U
authors.initials: JW
authors.lastname: Fries
mesh_terms: D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D019332:Endothelin-1 / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D019913:Nuclear Localization Signals; D034622:RNA Interference; D044022:Receptor, Endothelin A / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D019913:Nuclear Localization Signals; D044022:Receptor, Endothelin A; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases