title: The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis.
abstract: Expression of the Myc oncoprotein is downregulated in response to stress signals to allow cells to cease proliferation and escape apoptosis, but the mechanisms involved in this process are poorly understood. Cell cycle arrest in response to DNA damage requires downregulation of Myc via a p53-independent signaling pathway. Here we have used siRNA screening of the human kinome to identify MAPKAPK5 (MK5, PRAK) as a negative regulator of Myc expression. MK5 regulates translation of Myc, since it is required for expression of miR-34b and miR-34c that bind to the 3'UTR of MYC. MK5 activates miR-34b/c expression via phosphorylation of FoxO3a, thereby promoting nuclear localization of FoxO3a and enabling it to induce miR-34b/c expression and arrest proliferation. Expression of MK5 in turn is directly activated by Myc, forming a negative feedback loop. MK5 is downregulated in colon carcinomas, arguing that this feedback loop is disrupted during colorectal tumorigenesis.
authors.affiliation: Theodor-Boveri-Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Theresia R
authors.initials: TR
authors.lastname: Kress
authors.forename: Ian G
authors.initials: IG
authors.lastname: Cannell
authors.forename: Arjan B
authors.initials: AB
authors.lastname: Brenkman
authors.forename: Birgit
authors.initials: B
authors.lastname: Samans
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.forename: Paul
authors.initials: P
authors.lastname: Roepman
authors.forename: Boudewijn M
authors.initials: BM
authors.lastname: Burgering
authors.forename: Martin
authors.initials: M
authors.lastname: Bushell
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics*; D015536:Down-Regulation; D025461:Feedback, Physiological; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C111049:MAP-kinase-activated kinase 5; D017346:Protein Serine-Threonine Kinases