title: NRAS isoforms differentially affect downstream pathways, cell growth, and cell transformation.
abstract: Neuroblastoma rat sarcoma (RAS) viral oncogene homolog (NRAS), a small GTPase, is one of the most thoroughly studied oncogenes that controls cell growth, differentiation, and survival by facilitating signal transduction. Here, we identify four novel naturally occurring NRAS isoforms (isoforms 2-5) in addition to the canonical isoform (isoform 1). Expression analyses performed on a panel of several different human malignancies and matching normal tissue revealed distinct isoform expression patterns. Two of the novel isoforms were found in the nucleus and cytoplasm, whereas the others were exclusively cytoplasmic. The isoforms varied in their binding affinities to known downstream targets and differentially regulated the RAS signaling pathway. Strikingly, forced expression of isoform 5, which encodes only a 20-aa peptide, led to increased cell proliferation and to transformation by activation of known NRAS targets. These discoveries open new avenues in the study of NRAS.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Eisfeld
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schwind
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Hoag
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Walker
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.forename: Ravi
authors.initials: R
authors.lastname: Patel
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Huang
authors.forename: Joseph
authors.initials: J
authors.lastname: Markowitz
authors.forename: Wenrui
authors.initials: W
authors.lastname: Duan
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Otterson
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D019556:COS Cells; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D020033:Protein Isoforms / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*; D018709:Statistics, Nonparametric
chemical_list: D017931:DNA Primers; D008565:Membrane Proteins; D020033:Protein Isoforms; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human