title: Separate cis-trans pathways post-transcriptionally regulate murine CD154 (CD40 ligand) expression: a novel function for CA repeats in the 3'-untranslated region.
abstract: We report a role for CA repeats in the 3'-untranslated region (3'-UTR) in regulating CD154 expression. Human CD154 is encoded by an unstable mRNA; this instability is conferred in cis by a portion of its 3'-UTR that includes a polypyrimidine-rich region and CA dinucleotide repeat. We demonstrate similar instability activity with the murine CD154 3'-UTR. This instability element mapped solely to a conserved 100-base CU-rich region alone, which we call a CU-rich response element. Surprisingly, the CA dinucleotide-rich region also regulated reporter expression but at the level of translation. This activity was associated with poly(A) tail shortening and regulated by heterogeneous nuclear ribonucleoprotein L levels. We conclude that the CD154 3'-UTR contains dual cis-acting elements, one of which defines a novel function for exonic CA dinucleotide repeats. These findings suggest a mechanism for the association of 3'-UTR CA-rich response element polymorphisms with CD154 overexpression and the subsequent risk of autoimmune disease.
authors.affiliation: Department of Medicine, Lebanon, New Hampshire 03756.
authors.forename: B JoNell
authors.initials: BJ
authors.lastname: Hamilton
authors.affiliation: Department of Medicine, Lebanon, New Hampshire 03756.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Wang
authors.affiliation: Department of Medicine, Lebanon, New Hampshire 03756.
authors.forename: Jane
authors.initials: J
authors.lastname: Collins
authors.affiliation: Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Donald
authors.initials: D
authors.lastname: Bloch
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756.
authors.forename: Alan
authors.initials: A
authors.lastname: Bergeron
authors.affiliation: Department of Medicine, Lebanon, New Hampshire 03756.
authors.forename: Brian
authors.initials: B
authors.lastname: Henry
authors.affiliation: New York Medical College, Valhalla, New York 10595.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Terry
authors.affiliation: Department of Medicine, Lebanon, New Hampshire 03756.
authors.forename: Moe
authors.initials: M
authors.lastname: Zan
authors.affiliation: Lady Davis Institute for Medical Research and McGill University, Montreal, Quebec H3T 1E2, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mouland
authors.affiliation: Department of Medicine, Lebanon, New Hampshire 03756; Department of Microbiology and Immunology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756. Electronic address: William.Rigby@Dartmouth.edu.
authors.forename: William F C
authors.initials: WFC
authors.lastname: Rigby
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001327:Autoimmune Diseases; D001483:Base Sequence; D023201:CD40 Ligand / Q000235:genetics*; D002417:Cattle; D005786:Gene Expression Regulation; D034664:Heterogeneous-Nuclear Ribonucleoprotein L / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011061:Poly A / Q000378:metabolism; D011110:Polymorphism, Genetic; D012323:RNA Processing, Post-Transcriptional; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: D020413:3' Untranslated Regions; D034664:Heterogeneous-Nuclear Ribonucleoprotein L; D023201:CD40 Ligand; D011061:Poly A