Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells.
Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells.
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DOI：
10.3892/ijo.2011.1308
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发表时间：
2012-05
影响因子：
5.2
通讯作者：
Kufe D
中科院分区：
文献类型：
--
作者：
Raina D;Ahmad R;Rajabi H;Panchamoorthy G;Kharbanda S;Kufe D
MUC1异源二聚体蛋白在多种人类肿瘤中异常过表达，并与恶性表型有关。MUC1-C跨膜亚单位在细胞质结构域中含有一个CQC基序，参与二聚体的形成及其致癌功能。目前的研究表明，MUC1-C在人乳腺和肺癌细胞中形成二聚体。MUC1-C二聚化在细胞质中可检测到，并且不依赖于延伸到细胞外的N端粘蛋白亚基MUC1-N。我们发现，MUC1-C细胞质结构域在体外形成二聚体，并被还原剂破坏。此外，癌细胞中MUC1-C亚单位的二聚化被还原剂阻断，并被氧化应激增加，支持CQC基序参与形成二硫键。为了支持这些观察，MUC1-C CQC基序突变为AQA完全阻止了MUC1-C的二聚化。重要的是，这项研究是用不含荧光蛋白的MUC1-C进行的，如GFP、CFP和YFP。在这方面，我们证明了GFP、CFP和YFP本身形成的二聚体很容易被交联剂检测到。目前的结果进一步证明，靶向MUC1-C CQC半胱氨酸的穿透性多肽可以阻止癌细胞中的MUC1-C二聚化。这些发现提供了确凿的证据：i)MUC1-C胞质结构域的半胱氨酸是MUC1-C二聚化的必要条件和充分条件，以及ii)这些CQC基序的半胱氨酸是靶向MUC1-C功能的致命弱点。
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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影响因子：
11.2
作者：
Raina D;Ahmad R;Joshi MD;Yin L;Wu Z;Kawano T;Vasir B;Avigan D;Kharbanda S;Kufe D
通讯作者：
Kufe D
影响因子：
50.3
作者：
Ren, J;Agata, N;Kufe, D
通讯作者：
Kufe, D
DOI：
10.1073/pnas.0707723105
发表时间：
2008-06-17
影响因子：
11.1
作者：
Leichert, Lars I.;Gehrke, Florian;Jakob, Ursula
通讯作者：
Jakob, Ursula
影响因子：
20.3
作者：
Yin, Li;Wu, Zekui;Kufe, Donald
通讯作者：
Kufe, Donald
影响因子：
6.6
作者：
Brandes N;Schmitt S;Jakob U
通讯作者：
Jakob U