title: Programmed cell death 4 protein (Pdcd4) and homeodomain-interacting protein kinase 2 (Hipk2) antagonistically control translation of Hipk2 mRNA.
abstract: The tumor suppressor protein programmed cell death 4 (Pdcd4) is a highly conserved RNA-binding protein that inhibits the translation of specific mRNAs. Here, we have identified the homeobox-interacting protein kinase-2 (Hipk2) mRNA as a novel translational target of Pdcd4. Unlike most other protein kinases Hipk2 is constitutively active after being synthesized by the ribosome and its expression and activity are thought to be mainly controlled by modulation of the half-life of the kinase. Our work provides the first evidence that Hipk2 expression is also controlled on the level of translation. We show that Hipk2 stimulates the translation of its own mRNA and that Pdcd4 suppresses the translation of Hipk2 mRNA by interfering with this auto-regulatory feedback mechanism. We also show that the translation of the related kinase Hipk1 is controlled by a similar feedback loop and that Hipk2 also stimulates the translation of Hipk1 mRNA. Taken together, our work describes a novel mechanism of translational suppression by Pdcd4 and shows for the first time that Hipk2 controls its own synthesis by an auto-regulatory feedback mechanism. Furthermore, the effect of Hipk2 on the translation of Hipk1 RNA suggests that Hipk2 and Pdcd4 can act in similar manner to control the translation of other mRNAs.
authors.affiliation: Institut für Biochemie, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ohnheiser
authors.affiliation: Institut für Biochemie, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Ferlemann
authors.affiliation: Institut für Biochemie, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Haas
authors.affiliation: Institut für Biochemie, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Müller
authors.affiliation: Institut für Biochemie, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany.
authors.forename: Eugen
authors.initials: E
authors.lastname: Werwein
authors.affiliation: Institut für Biochemie, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany.
authors.forename: Olesja
authors.initials: O
authors.lastname: Fehler
authors.affiliation: Institut für Biochemie, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany; Graduate School of Chemistry (GSC-MS), Westfälische-Wilhelms-Universität Münster, Germany.
authors.forename: Abhiruchi
authors.initials: A
authors.lastname: Biyanee
authors.affiliation: Institut für Biochemie, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany. Electronic address: klempna@uni-muenster.de.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Klempnauer
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002645:Chickens; D039601:Eukaryotic Initiation Factor-4A / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011784:Quail; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D050505:Mutant Proteins; C114487:PDCD4 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C115114:HIPK2 protein, human; C543644:HIPK1 protein, human; D017346:Protein Serine-Threonine Kinases; D039601:Eukaryotic Initiation Factor-4A
keywords: Autoregulation; HIPK1; Hipk2; Pdcd4; Translation