The role of wild type RAS isoforms in cancer.
The role of wild type RAS isoforms in cancer.
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DOI：
10.1016/j.semcdb.2016.07.012
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发表时间：
2016-10
影响因子：
7.3
通讯作者：
Cox, Adrienne D.
中科院分区：
文献类型：
--
作者：
Zhou, Bingying;Der, Channing J.;Cox, Adrienne D.
突变激活的RAS蛋白是近30%人类癌症的关键致癌驱动因素。与突变型RAS一样，野生型RAS蛋白在肿瘤发生、肿瘤维持和转移中的作用是上下文相关的。由于多种RAS基因(HRAS、KRAS、NRAS)和蛋白质“异构体”(KRAS4A、KRAS4B)的存在，由于RAS信号网络的日益复杂，以及对存在和不存在突变RAS的癌症中大量遗传异常的日益识别，引入了复杂性。大量的小鼠模型致癌研究和对患者肿瘤的检查表明，在RAS突变的癌症中，野生型RAS蛋白很可能作为肿瘤抑制因子，而突变的RAS具有相同的异构体。这一证据在KRAS突变癌症中尤其明显，这种癌症经常表现出野生型KRAS的抑制或丢失，但对NRAS则不那么强烈。相反，尽管尚未完全阐明，但大多数证据表明，当突变的RAS具有不同的异构体时，野生型RAS蛋白起到促进肿瘤的作用。在非RAS突变的癌症中，野生型RAS被认为是致癌信号的中介，这是因为通过RAS供养的上游受体酪氨酸激酶的慢性激活。此外，在缺乏突变型RAS的情况下，野生型RAS的激活可能会导致负RAS调控因子如NF1 GAP或SPRY蛋白的丢失而导致癌症发生。在这里，我们探索关于野生型RAS蛋白在人类癌症中的作用的知识现状。
Mutationally activated RAS proteins are critical oncogenic drivers in nearly 30% of all human cancers. As with mutant RAS, the role of wild type RAS proteins in oncogenesis, tumour maintenance and metastasis is context-dependent. Complexity is introduced by the existence of multiple RAS genes (HRAS, KRAS, NRAS) and protein "isoforms" (KRAS4A, KRAS4B), by the ever more complicated network of RAS signaling, and by the increasing identification of numerous genetic aberrations in cancers that do and do not harbour mutant RAS. Numerous mouse model carcinogenesis studies and examination of patient tumours reveal that, in RAS-mutant cancers, wild type RAS proteins are likely to serve as tumour suppressors when the mutant RAS is of the same isoform. This evidence is particularly robust in KRAS mutant cancers, which often display suppression or loss of wild type KRAS, but is not as strong for NRAS. In contrast, although not yet fully elucidated, the preponderance of evidence indicates that wild type RAS proteins play a tumour promoting role when the mutant RAS is of a different isoform. In non-RAS mutant cancers, wild type RAS is recognized as a mediator of oncogenic signaling due to chronic activation of upstream receptor tyrosine kinases that feed through RAS. Additionally, in the absence of mutant RAS, activation of wild type RAS may drive cancer upon the loss of negative RAS regulators such as NF1 GAP or SPRY proteins. Here we explore the current state of knowledge with respect to the roles of wild type RAS proteins in human cancers.
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DOI：
10.1073/pnas.82.23.7810
发表时间：
1985-01-01
影响因子：
11.1
作者：
GUERRERO, I;VILLASANTE, A;PELLICER, A
通讯作者：
PELLICER, A
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
3
作者：
Dimauro T;David G
通讯作者：
David G
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
64.5
作者：
BREMNER, R;BALMAIN, A
通讯作者：
BALMAIN, A