Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Chalick, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Jacobi, Oded UNSPECIFIED UNSPECIFIED UNSPECIFIED Pichinuk, Edward UNSPECIFIED UNSPECIFIED UNSPECIFIED Garbar, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Bensussan, Armand UNSPECIFIED orcid.org/0000-0002-0409-2497 UNSPECIFIED Meeker, Alan UNSPECIFIED UNSPECIFIED UNSPECIFIED Ziv, Ravit UNSPECIFIED UNSPECIFIED UNSPECIFIED Zehavi, Tania UNSPECIFIED UNSPECIFIED UNSPECIFIED Smorodinsky, Nechama I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hilkens, John UNSPECIFIED orcid.org/0000-0002-0932-7793 UNSPECIFIED Hanisch, Franz-Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Rubinstein, Daniel B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wreschner, Daniel H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language FIBROBLAST-GROWTH-FACTOR; HUMAN BREAST-CANCER; EPITHELIAL TUMOR-ANTIGEN; XL-ALPHA-S; MOLECULAR-CLONING; INTERFERON-GAMMA; CELL-LINES; SUBCELLULAR FATE; CYTOPLASMIC TAIL; BINDING-PROTEIN Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25822