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Review
. 2009 Jul;8(13):1197-203.
doi: 10.4161/cbt.8.13.8844. Epub 2009 Jul 27.

Functional targeting of the MUC1 oncogene in human cancers

Donald W Kufe  1
Affiliations
Review

Functional targeting of the MUC1 oncogene in human cancers

Donald W Kufe. Cancer Biol Ther. 2009 Jul.
No abstract available

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Figures

Figure 1
Figure 1
Schematic representation of the MUC1 heterodimer positioned at the cell membrane. MUC1-N is the mucin component of the heterodimer that contains the glycosylated variable numbers of tandem repeats. MUC1-N is tethered to the cell surface through binding to the transmembrane MUC1-C subunit (left). Shedding of MUC1-N leaves MUC1-C at the cell membrane as a putative receptor for signaling the presence of extracellular stress to the interior of the cell (right).
Figure 2
Figure 2
Structure of the MUC1-C subunit. (A) MUC1-C includes a 58 amino acid extracellular domain, a 28 amino acid transmembrane domain and a 72 amino acid cytoplasmic domain. Amino acid sequence of the MUC1-C extracellular domain is shown with highlighting of N-36 that undergoes glycosylation and functions as a galectin-3 binding site. (B) Schematic representation of the MUC1-C receptor with galectin-3 functioning as a bridge to EGFR and other cell surface molecules.
Figure 3
Figure 3
Amino acid sequence of the MUC1-C cytoplasmic domain. The kinases that interact with the cytoplasmic domain and their phosphorylation sites are highlighted. Effectors that interact with the cytoplasmic domain are also highlighted at their respective binding regions.
Figure 4
Figure 4
Intracellular targeting of MUC1-C to the nucleus and mitochondria. In transformed cells, MUC1 expression is upregulated and repositioned from the apical membrane to over the entire cell surface. In addition, MUC1-C accumulates in the cytosol and is transported to the nucleus by importin β, where it interacts with diverse transcription factors. Alternatively, MUC1-C is targeted to the mitochondrial outer membrane by HSP70/HSP90 complexes.
Figure 5
Figure 5
Mutants of the MUC1-C cytoplasmic domain that function as dominant-negatives for transformation. Stable expression of MUC1 with the indicated mutations in HCT116 colon cancer cells abrogates anchorage-independent growth and tumorigenicity, supporting their role as dominant-negatives. Expression of MUC1 with the AQA mutations blocks oligomerization and nuclear import of MUC1-C. Mutation of Tyr-46 to F blocks c-Src phosphorylation and thereby binding of the c-Src SH2 domain. Mutation of Tyr-60 to F blocks c-Abl phosphorylation, binding of the c-Abl SH2 domain and suppression of the ARF-MDM2-p53 pathway.
See this image and copyright information in PMC

References

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