6533b82afe1ef96bd128b7bf

RESEARCH PRODUCT

p38 MAPK Controls Prothrombin Expression by Regulated RNA 3′ End Processing

Stephan Macher-goeppingerAnne Susan GantzertAnne Susan GantzertHans Christian ProbstSven DanckwardtMatthias WilmMatthias WilmMarc GentzelMarc GentzelHermann Josef GröneMatthias W. HentzeMatthias W. HentzePeter SchirmacherAndreas E. KulozikAndreas E. Kulozik

subject

MaleAdenosinePolymersp38 mitogen-activated protein kinasesInflammationPlasma protein bindingBiologyp38 Mitogen-Activated Protein KinasesGene Expression Regulation EnzymologicMiceThrombinCell Line TumormedicineAnimalsHumansNeoplasm InvasivenessRNA MessengerMolecular BiologyRegulation of gene expressionMessenger RNARNACell BiologyXenograft Model Antitumor AssaysCell biologyRibonucleoproteinsImmunologyPhosphorylationRNAProthrombinmedicine.symptomRNA 3' End Processingmedicine.drugProtein Binding

description

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.

yearjournalcountryeditionlanguage
2011-02-01Molecular Cell
10.1016/j.molcel.2010.12.032http://dx.doi.org/10.1016/j.molcel.2010.12.032