Characterization of the MUC1-C Cytoplasmic Domain as a Cancer Target
McKnight, C. James
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CitationRaina, Deepak, Praveen Agarwal, James Lee, Ajit Bharti, C. James McKnight, Pankaj Sharma, Surender Kharbanda, and Donald Kufe. 2015. “Characterization of the MUC1-C Cytoplasmic Domain as a Cancer Target.” PLoS ONE 10 (8): e0135156. doi:10.1371/journal.pone.0135156. http://dx.doi.org/10.1371/journal.pone.0135156.
AbstractMucin 1 (MUC1) is a heterodimeric protein that is aberrantly expressed in diverse human carcinomas and certain hematologic malignancies. The oncogenic MUC1 transmembrane C-terminal subunit (MUC1-C) functions in part by transducing growth and survival signals from cell surface receptors. However, little is known about the structure of the MUC1-C cytoplasmic domain as a potential drug target. Using methods for structural predictions, our results indicate that a highly conserved CQCRRK sequence, which is adjacent to the cell membrane, forms a small pocket that exposes the two cysteine residues for forming disulfide bonds. By contrast, the remainder of the MUC1-C cytoplasmic domain has no apparent structure, consistent with an intrinsically disordered protein. Our studies thus focused on targeting the MUC1 CQCRRK region. The results show that L- and D-amino acid CQCRRK-containing peptides bind directly to the CQC motif. We further show that the D-amino acid peptide, designated GO-203, blocks homodimerization of the MUC1-C cytoplasmic domain in vitro and in transfected cells. Moreover, GO-203 binds directly to endogenous MUC1-C in breast and lung cancer cells. Colocalization studies further demonstrate that GO-203 predominantly binds to MUC1-C at the cell membrane. These findings support the further development of agents that target the MUC1-C cytoplasmic domain CQC motif and thereby MUC1-C function in cancer cells.
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