title: A novel function of Tis11b/BRF1 as a regulator of Dll4 mRNA 3'-end processing.
abstract: Tis11b/BRF1 belongs to the tristetraprolin family, the members of which are involved in AU-rich-dependent regulation of mRNA stability/degradation. Mouse inactivation of the Tis11b gene has revealed disorganization of the vascular network and up-regulation of the proangiogenic factor VEGF. However, the VEGF deregulation alone cannot explain the phenotype of Tis11b knockouts. Therefore we investigated the role of Tis11b in expression of Dll4, another angiogenic gene for which haploinsufficiency is lethal. In this paper, we show that Tis11b silencing in endothelial cells leads to up-regulation of Dll4 protein and mRNA expressions, indicating that Dll4 is a physiological target of Tis11b. Tis11b protein binds to endogenous Dll4 mRNA, and represses mRNA expression without affecting its stability. In the Dll4 mRNA 3' untranslated region, we identified one particular AUUUA motif embedded in a weak noncanonical polyadenylation (poly(A)) signal as the major Tis11b-binding site. Moreover, we observed that inhibition of Tis11b expression changes the ratio between mRNAs that are cleaved or read through at the poly(A) signal position, suggesting that Tis11b can interfere with mRNA cleavage and poly(A) efficiency. Last, we report that this Tis11b-mediated mechanism is used by endothelial cells under hypoxia for controlling Dll4 mRNA levels. This work constitutes the first description of a new function for Tis11b in mammalian cell mRNA 3'-end maturation.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1036, Biologie du Cancer et de l'Infection, Grenoble F-38054, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Desroches-Castan
authors.forename: Nadia
authors.initials: N
authors.lastname: Cherradi
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Feige
authors.forename: Delphine
authors.initials: D
authors.lastname: Ciais
mesh_terms: D016475:3T3 Cells; D000818:Animals; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation; D020868:Gene Silencing; D057895:Haploinsufficiency / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D000860:Hypoxia; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D026721:RNA 3' End Processing / Q000235:genetics; D039104:RNA 3' Polyadenylation Signals / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: C441028:BRF1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D035381:TATA-Binding Protein Associated Factors; C064045:delta protein