Activating SRC mutation in a subset of advanced human colon cancers
Activating SRC mutation in a subset of advanced human colon cancers
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DOI：
10.1038/5971
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发表时间：
1999-02-01
期刊：
影响因子：
30.8
通讯作者：
Yeatman, TJ
中科院分区：
文献类型：
--
作者：
Irby, RB;Mao, WG;Yeatman, TJ
劳斯肉瘤病毒（RSV）的发现导致了细胞Src （c-Src）的鉴定，这是一种非受体酪氨酸激酶，此后被认为与许多人类癌症的发展有关（1-4）。已经发现c-Src在结肠癌中高度活化，特别是在那些转移到肝脏的癌症中（5-11）。对c-Src调控机制的研究表明，c-Src激酶活性通过一个关键羧基末端酪氨酸的磷酸化而下调（人c-Src中的Tyr 530，相当于鸡Src中的Tyr 527），并暗示在这个c-末端调控区域存在激活突变（12-18）。我们在此报告了在12%的晚期人类结肠癌病例中发现了SRC密码子531处的截断突变，并证明该突变具有激活、转化、致瘤性和促进转移的作用。这些结果首次提供了基因证据，证明激活SRC突变可能在人类结肠癌的恶性进展中起作用。
The discovery of Rous sarcoma virus (RSV) led to the identification of cellular Src (c-Src), a non-receptor tyrosine kinase, which has since been implicated in the development of numerous human cancers(1-4). c-Src has been found to be highly activated in colon cancers, particularly in those metastatic to the liver(5-11) Studies of the mechanism of c-Src regulation have suggested that c-Src kinase activity is downregulated by phosphorylation of a critical carboxy-terminal tyrosine (Tyr 530 in human c-Src, equivalent to Tyr 527 in chicken Src) and have implied the existence of activating mutations in this C-terminal regulatory region(12-18). We report here the identification of a truncating mutation in SRC at codon 531 in 12% of cases of advanced human colon cancer tested and demonstrate that the mutation is activating, transforming, tumorigenic and promotes metastasis. These results provide, for the first time, genetic evidence that activating SRC mutations may have a role in the malignant progression of human colon cancer.