Chalick, Michael, Jacobi, Oded, Pichinuk, Edward, Garbar, Christian, Bensussan, Armand ORCID: 0000-0002-0409-2497, Meeker, Alan, Ziv, Ravit, Zehavi, Tania, Smorodinsky, Nechama I., Hilkens, John ORCID: 0000-0002-0932-7793, Hanisch, Franz-Georg, Rubinstein, Daniel B. and Wreschner, Daniel H. (2016). MUC1-ARF-A Novel MUC1 Protein That Resides in the Nucleus and Is Expressed by Alternate Reading Frame Translation of MUC1 mRNA. PLoS One, 11 (10). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Translation of mRNA in alternate reading frames (ARF) is a naturally occurring process heretofore underappreciated as a generator of protein diversity. The MUC1 gene encodes MUC1-TM, a signal-transducing trans-membrane protein highly expressed in human malignancies. Here we show that an AUG codon downstream to the MUC1-TM initiation codon initiates an alternate reading frame thereby generating a novel protein, MUC1-ARF. MUC1-ARF, like its MUC1-TM 'parent' protein, contains a tandem repeat (VNTR) domain. However, the amino acid sequence of the MUC1-ARF tandem repeat as well as N- and C-sequences flanking it differ entirely from those of MUC1-TM. In vitro protein synthesis assays and extensive immunohistochemical as well as western blot analyses with MUC1-ARF specific monoclonal antibodies confirmed MUC1-ARF expression. Rather than being expressed at the cell membrane like MUC1-TM, immunostaining showed that MUC1-ARF protein localizes mainly in the nucleus: Immunohistochemical analyses of MUC1-expressing tissues demonstrated MUC1-ARF expression in the nuclei of secretory luminal epithelial cells. MUC1-ARF expression varies in different malignancies. While the malignant epithelial cells of pancreatic cancer show limited expression, in breast cancer tissue MUC1-ARF demonstrates strong nuclear expression. Proinflammatory cytokines upregulate expression of MUC1-ARF protein and co-immunoprecipitation analyses demonstrate association of MUC1-ARF with SH3 domain-containing proteins. Mass spectrometry performed on proteins coprecipitating with MUC1-ARF demonstrated Glucose-6-phosphate 1-dehydrogenase (G6PD) and Dynamin 2 (DNM2). These studies not only reveal that the MUC1 gene generates a previously unidentified MUC1-ARF protein, they also show that just like its 'parent' MUC1-TM protein, MUC1-ARF is apparently linked to signaling and malignancy, yet a definitive link to these processes and the roles it plays awaits a precise identification of its molecular functions. Comprising at least 524 amino acids, MUC1-ARF is, furthermore, the longest ARF protein heretofore described.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Chalick, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jacobi, OdedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pichinuk, EdwardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garbar, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bensussan, ArmandUNSPECIFIEDorcid.org/0000-0002-0409-2497UNSPECIFIED
Meeker, AlanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ziv, RavitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zehavi, TaniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smorodinsky, Nechama I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hilkens, JohnUNSPECIFIEDorcid.org/0000-0002-0932-7793UNSPECIFIED
Hanisch, Franz-GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rubinstein, Daniel B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wreschner, Daniel H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-258228
DOI: 10.1371/journal.pone.0165031
Journal or Publication Title: PLoS One
Volume: 11
Number: 10
Date: 2016
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1932-6203
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
FIBROBLAST-GROWTH-FACTOR; HUMAN BREAST-CANCER; EPITHELIAL TUMOR-ANTIGEN; XL-ALPHA-S; MOLECULAR-CLONING; INTERFERON-GAMMA; CELL-LINES; SUBCELLULAR FATE; CYTOPLASMIC TAIL; BINDING-PROTEINMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/25822

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