title: p38 MAPK controls prothrombin expression by regulated RNA 3' end processing.
abstract: Thrombin is a key protease involved in blood coagulation, complement activation, inflammation, angiogenesis, and tumor invasion. Although induced in many (patho-)physiological conditions, the underlying mechanisms controlling prothrombin expression remained enigmatic. We have now discovered that prothrombin expression is regulated by a posttranscriptional regulatory mechanism responding to stress and inflammation. This mechanism is triggered by external stimuli that activate p38 MAPK. In turn, p38 MAPK upmodulates canonical 3' end processing components and phosphorylates the RNA-binding proteins FBP2 and FBP3, which inhibit 3' end processing of mRNAs, such as prothrombin mRNA, that bear a defined upstream sequence element (USE) in their 3'UTRs. Upon phosphorylation, FBP2 and FBP3 dissociate from the USE, making it accessible to proteins that stimulate 3' end processing. We provide in vivo evidence suggesting the importance of this mechanism in inflammatory hypercoagulation and tumor invasion. Regulated 3' end processing thus emerges as a key mechanism of gene regulation with broad biological and medical implications.
authors.affiliation: Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Danckwardt
authors.forename: Anne-Susan
authors.initials: AS
authors.lastname: Gantzert
authors.forename: Stephan
authors.initials: S
authors.lastname: Macher-Goeppinger
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Probst
authors.forename: Marc
authors.initials: M
authors.lastname: Gentzel
authors.forename: Matthias
authors.initials: M
authors.lastname: Wilm
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Hentze
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D011108:Polymers / Q000378:metabolism; D011485:Protein Binding; D011516:Prothrombin / Q000235:genetics / Q000378:metabolism*; D012313:RNA; D026721:RNA 3' End Processing; D012333:RNA, Messenger / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D011108:Polymers; D012333:RNA, Messenger; D012261:Ribonucleoproteins; C069424:polyadenosine; D012313:RNA; D011516:Prothrombin; D048051:p38 Mitogen-Activated Protein Kinases; D000241:Adenosine