Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells

  • Authors:
    • Deepak Raina
    • Rehan Ahmad
    • Hasan Rajabi
    • Govind Panchamoorthy
    • Surender Kharbanda
    • Donald Kufe
  • View Affiliations

  • Published online on: December 20, 2011     https://doi.org/10.3892/ijo.2011.1308
  • Pages: 1643-1649
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Abstract

The MUC1 heterodimeric protein is aberrantly overexpressed in diverse human carcinomas and contributes to the malignant phenotype. The MUC1-C transmembrane subunit contains a CQC motif in the cytoplasmic domain that has been implicated in the formation of dimers and in its oncogenic function. The present study demonstrates that MUC1-C forms dimers in human breast and lung cancer cells. MUC1-C dimerization was detectable in the cytoplasm and was independent of MUC1-N, the N-terminal mucin subunit that extends outside the cell. We show that the MUC1-C cytoplasmic domain forms dimers in vitro that are disrupted by reducing agents. Moreover, dimerization of the MUC1-C subunit in cancer cells was blocked by reducing agents and increased by oxidative stress, supporting involvement of the CQC motif in forming disulfide bonds. In support of these observations, mutation of the MUC1-C CQC motif to AQA completely blocked MUC1-C dimerization. Importantly, this study was performed with MUC1-C devoid of fluorescent proteins, such as GFP, CFP and YFP. In this regard, we show that GFP, CFP and YFP themselves form dimers that are readily detectable with cross-linking agents. The present results further demonstrate that a cell-penetrating peptide that targets the MUC1-C CQC cysteines blocks MUC1-C dimerization in cancer cells. These findings provide definitive evidence that: i) the MUC1-C cytoplasmic domain cysteines are necessary and sufficient for MUC1-C dimerization, and ii) these CQC motif cysteines represent an Achilles' heel for targeting MUC1-C function.

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May 2012
Volume 40 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Raina D, Ahmad R, Rajabi H, Panchamoorthy G, Kharbanda S and Kufe D: Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells. Int J Oncol 40: 1643-1649, 2012
APA
Raina, D., Ahmad, R., Rajabi, H., Panchamoorthy, G., Kharbanda, S., & Kufe, D. (2012). Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells. International Journal of Oncology, 40, 1643-1649. https://doi.org/10.3892/ijo.2011.1308
MLA
Raina, D., Ahmad, R., Rajabi, H., Panchamoorthy, G., Kharbanda, S., Kufe, D."Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells". International Journal of Oncology 40.5 (2012): 1643-1649.
Chicago
Raina, D., Ahmad, R., Rajabi, H., Panchamoorthy, G., Kharbanda, S., Kufe, D."Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells". International Journal of Oncology 40, no. 5 (2012): 1643-1649. https://doi.org/10.3892/ijo.2011.1308