Differential oncogenic potential of activated RAS isoforms in melanocytes
Differential oncogenic potential of activated RAS isoforms in melanocytes
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DOI：
10.1038/sj.onc.1210239
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发表时间：
2007-07-01
期刊：
影响因子：
8
通讯作者：
Holmen, S. L.
中科院分区：
文献类型：
--
作者：
Whitwam, T.;VanBrocklin, M. W.;Holmen, S. L.
RAS基因在大约30%的人类癌症中发生突变。有趣的是，在不同细胞来源的肿瘤中存在强烈的偏好，仅有利于三个主要RAS基因之一的突变。NRAS突变发生在大约20%的人类黑色素瘤中，而HRAS和KRAS突变在这种疾病中很少见。敬德。在黑素细胞中这种偏好的机制中，我们比较了突变型NRAS和KRAS在永生的、非转化的Ink 4a/Arf缺陷黑素细胞中的转化效率。NRAS突变导致细胞增殖增加，并具有潜在的致瘤性。相比之下，KRAS突变不增强黑素细胞增殖，并且自身仅具有弱致瘤性。虽然NRAS和KRAS都能激活丝裂原活化蛋白激酶信号，但只有NRAS能增强这些细胞中的MYC活性。我们的数据表明，特定的RAS亚型的活性是上下文依赖性的，并提供了一个可能的解释NRAS突变的黑色素瘤的患病率。此外，了解这种机制将对靶向RAS通路的癌症治疗具有重要意义。
RAS genes are mutated in approximately 30% of all human cancers. Interestingly, there exists a strong bias in favor of mutation of only one of the three major RAS genes in tumors of different cellular origins. NRAS mutations occur in approximately 20% of human melanomas, whereas HRAS and KRAS mutations are rare in this disease. To de. ne the mechanism(s) responsible for this preference in melanocytes, we compared the transformation efficiencies of mutant NRAS and KRAS in immortal, non-transformed Ink4a/Arf-deficient melanocytes. NRAS mutation leads to increased cellular proliferation and is potently tumorigenic. In contrast, KRAS mutation does not enhance melanocyte proliferation and is only weakly tumorigenic on its own. Although both NRAS and KRAS activate mitogen-activated protein kinase signaling, only NRAS enhances MYC activity in these cells. Our data suggest that the activity of specific RAS isoforms is context-dependent and provide a possible explanation for the prevalence of NRAS mutations in melanoma. In addition, understanding this mechanism will have important implications for cancer therapies targeting RAS pathways.