MUC1及其C端活性片段突变体具有抑制肿瘤的活性

MUC1 C-terminal Heterodimer and Its Tumorigenicity

MUC1蛋白翻译后成为一条多肽链,它很快在内质网被切割成2个亚基,形成稳定的异源二聚体.Cys-Gln-Cys(CQC)3个氨基酸位于MUC1C端亚基跨膜结构域与胞内结构域的连接处.研究发现,MUC1C端的CQCRRK结构域突变成AQARRK或使其缺失,突变体的致瘤性明显降低.表明:通过突变CQC→AQA来阻碍与C端亚基相关的二聚体化,可能成为肿瘤治疗的新途径.

The MUC1 protein is expressed as a stable heterodimer from a single polypeptide, which was cleaved into two subunits in endoplasmic reticuhun. It localizes at the cell membrane as an α/β-complex, tethered by the β-subunit transmembrane domain. Previous studies implicated that the three amino acids of the transmembrane domain adjacent to the cytoplasmic domain in MUC1 β-subunit are the residues Cys-Gln-Cys （CQC）. Therein, site-directed mutagenesis of the CQC motif was performed and the cell lines were established. These cell lines include HCT116/MUC1, HCT116/MUC1 （CQC→AQA）, HCT116/MUC1 （ACQCRRK）, HCT116/MUC1C-ter （CQC→AQA）, which can express wild type or mutant MUC1 on the cell surface, or its cytoplasmic domain. The effects of CQC→AQA mutation or CQCRRK deletion were investigated in vitro and in vivo. Compared with wild type MUC1, the mutants depressed soft agar colony formation and showed abrogated tumorigenicity in nude mice. These findings implicate that CQCRRK motif mediate the formation of MUC1 protein complex. As a result of this research, disruption of MUC1-C-terminal subunit-associated dimerization by mutation of CQC →AQA might represent a novel therapeutic approach for tumor.