title: Far upstream element binding protein 1 activates translation of p27Kip1 mRNA through its internal ribosomal entry site.
abstract: The cyclin dependent kinase inhibitor p27 plays an important role in controlling the eukaryotic cell cycle by regulating progression through G1 and entry into S phase. It is often elevated during differentiation and under conditions of cellular stress. In contrast, it is commonly downregulated in cancer cells and its levels are generally inversely correlated with favorable prognosis. The cellular levels of p27 are regulated, in part, by translational control mechanisms. The 5'-untranslated region (5'-UTR) of the p27 mRNA harbors an internal ribosome entry site (IRES) which may facilitate synthesis of p27 in certain conditions. In this study, Far Upstream Element (FUSE) Binding Protein 1 (FBP1) was shown to directly bind to the human p27 5'-UTR and to promote IRES activity. An eight-nucleotide element downstream of a U-rich region within the 5'-UTR was important for FBP1 binding and p27 IRES activity. Overexpression of FBP1 enhanced endogenous p27 levels and stimulated translation initiation. In contrast, repression of FBP1 by siRNA transfection downregulated endogenous p27 protein levels. Using rabbit reticulocyte lysates, FBP1 stimulated p27 mRNA translation in vitro. The central domain of FBP1, containing four K homology motifs, was required for p27 5'-UTR RNA binding and the N terminal domain was important for translational activation. These findings indicate that FBP1 is a novel activator of p27 translation upon binding to the 5'-UTR.
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD 57001, USA. yuzheng@mdanderson.org
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Zheng
authors.forename: W Keith
authors.initials: WK
authors.lastname: Miskimins
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D001665:Binding Sites; D002453:Cell Cycle / Q000235:genetics*; D002454:Cell Differentiation; D002457:Cell Extracts; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D011485:Protein Binding; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D011817:Rabbits; D012156:Reticulocytes / Q000737:chemistry / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D020121:5' Untranslated Regions; C436291:CDKN1B protein, human; D002457:Cell Extracts; D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004265:DNA Helicases