title: Dickkopf homolog 1, a Wnt signaling antagonist, is transcriptionally up-regulated via an ATF4-independent and MAPK/ERK-dependent pathway following amino acid deprivation.
abstract: Amino acid response (AAR) pathway is activated when cells are deprived of amino acids. In the present study, using the human colon cancer cell line SW480, we observed that DKK1, an antagonist of the Wnt pathway, was significantly induced at the mRNA level after the removal of amino acids from the medium. Addition of the amino alcohol histidinol, which prevents the formation of histidinyl-tRNA(His), also increased DKK1 mRNA to a level similar to that observed when cells were deprived of all amino acids. Transcriptional activity and stability of DKK1 mRNA were both increased in the amino acid-deprived condition. The induction of DKK1 gene expression was confirmed by the increased immunofluorescent staining of the DKK1 protein in the amino acid deprived condition. Although chromatin immunoprecipitation assays showed increased RNA Polymerase II binding at the DKK1 promoter in amino acid-limited conditions, ATF4 binding to the promoter is absent. Luciferase reporter assays did not detect any functional AARE within the DKK1 gene structure. Knockdown of ATF4 by siRNA did not affect the increase of DKK1 mRNA during amino acid limitation. Inhibition of ERK phosphorylation abolished the induction of DKK1. Our study revealed that DKK1 is a novel target gene in the response to amino acid deficiency and that the expression of DKK1 is up-regulated through an ATF4-independent and an ERK-dependent pathway.
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.forename: Yukun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yuan-Xiang
authors.initials: YX
authors.lastname: Pan
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C497109:ATF4 protein, human; D000596:Amino Acids; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D051701:Activating Transcription Factor 4; D048049:Extracellular Signal-Regulated MAP Kinases; D012319:RNA Polymerase II