1. NRAS isoforms differentially affect downstream pathways, cell growth, and cell transformation
- Author
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Sebastian Schwind, Xiaomeng Huang, Sandya Liyanarachchi, Wenrui Duan, Albert de la Chapelle, William E. Carson, Ann-Kathrin Eisfeld, Kevin W. Hoag, Clara D. Bloomfield, Ravi Patel, Christopher J. Walker, Guido Marcucci, Joseph Markowitz, and Gregory A. Otterson
- Subjects
Neuroblastoma RAS viral oncogene homolog ,Gene isoform ,viruses ,Blotting, Western ,Molecular Sequence Data ,Biology ,Statistics, Nonparametric ,GTP Phosphohydrolases ,Mice ,Carcinoma, Non-Small-Cell Lung ,Chlorocebus aethiops ,Animals ,Humans ,Immunoprecipitation ,Protein Isoforms ,Small GTPase ,Cloning, Molecular ,DNA Primers ,Regulation of gene expression ,Microscopy, Confocal ,Multidisciplinary ,Base Sequence ,Cell growth ,Membrane Proteins ,Sequence Analysis, DNA ,Biological Sciences ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,Ras Signaling Pathway ,Cytoplasm ,COS Cells ,NIH 3T3 Cells ,Signal transduction ,Signal Transduction - 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.
- Published
- 2014
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