title: Radicicol suppresses transformation and restores tropomyosin-2 expression in both ras- and MEK-transformed cells without inhibiting the Raf/MEK/ERK signaling cascade.
abstract: The antibiotic radicicol suppresses transformation in a variety of transformed cells. The antineoplastic effects of the drug have been attributed to the degradation of Raf and the inactivation of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling cascade. Here we demonstrate that radicicol induces cell spreading, suppresses anchorage-independent cell growth, and increases the expression of the high-molecular weight tropomyosin isoform TM-2 in cells stably expressing a constitutively active form of MEK-1 as well as in ras-transformed cells. Furthermore, the reverting effects of the drug are achieved at concentrations below those required to deplete Raf from the cell or to inhibit the phosphorylation of ERK or its substrates Elk and pp90(RSK). In contrast, low concentrations of radicicol significantly inhibited activator protein (AP-1) and serum response factor (SRF)-mediated transcription. The lack of correlation between the effects of radicicol on cell phenotype and on the signaling activities of the Raf/MEK/ERK pathway indicate that Raf depletion or disruption of proximal signaling events in the mitogen-activated protein kinase pathway are not the predominant mechanisms by which the drug suppresses the transformed phenotype. Our observation that low concentrations of radicicol block transcriptional activities mediated by AP-1 and SRF suggests that interference with signaling upstream of these transcription factors may contribute to the reverting effects of the drug.
authors.affiliation: Laboratory of Immunobiology, Division of Monoclonal Antibodies, Center for Biologics Evaluation & Research, Bethesda, Maryland 20892-4555, USA.
authors.forename: P N
authors.initials: PN
authors.lastname: Kim
authors.forename: E
authors.initials: E
authors.lastname: Jonasch
authors.forename: B C
authors.initials: BC
authors.lastname: Mosterman
authors.forename: J W
authors.initials: JW
authors.lastname: Mier
authors.forename: R A
authors.initials: RA
authors.lastname: Janssen
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D048429:Cell Size / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007783:Lactones / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D018942:Macrolides; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism*; D050807:ets-Domain Protein Elk-1
chemical_list: D004268:DNA-Binding Proteins; D007783:Lactones; D018942:Macrolides; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014335:Tropomyosin; D050807:ets-Domain Protein Elk-1; D011494:Protein Kinases; C405628:serum response factor kinase; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D019893:Ribosomal Protein S6 Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D015689:Oncogene Protein p21(ras); C035359:monorden