Max F Perutz Laboratories, Center for Molecular Biology, University of Vienna, Vienna, Austria.
Oncogene. 2011 Aug 11;30(32):3477-88. doi: 10.1038/onc.2011.160. Epub 2011 May 16.
Raf are conserved, ubiquitous serine/protein kinases discovered as the cellular elements hijacked by transforming retroviruses. The three mammalian RAF proteins (A, B and CRAF) can be activated by the human oncogene RAS, downstream from which they exert both kinase-dependent and kinase-independent, tumor-promoting functions. The kinase-dependent functions are mediated chiefly by the MEK/ERK pathway, whose activation is associated with proliferation in a broad range of human tumors. Almost 10 years ago, activating BRAF mutations were discovered in a subset of human tumors, and in the past year treatment with small-molecule RAF inhibitors has yielded unprecedented response rates in melanoma patients. Thus, Raf qualifies as an excellent molecular target for anticancer therapy. This review focuses on the role of BRAF and CRAF in different aspects of carcinogenesis, on the success of molecular therapies targeting Raf and the challenges they present.
Raf 是一种保守的、普遍存在的丝氨酸/蛋白激酶，最初被发现是被转化逆转录病毒劫持的细胞元件。三种哺乳动物 RAF 蛋白（A、B 和 CRAF）可被人类致癌基因 RAS 激活，它们在 RAS 下游发挥激酶依赖和激酶非依赖的促肿瘤作用。激酶依赖的功能主要通过 MEK/ERK 通路介导，其激活与广泛的人类肿瘤中的增殖有关。大约 10 年前，在人类肿瘤的一部分中发现了激活的 BRAF 突变，在过去的一年中，小分子 RAF 抑制剂的治疗在黑色素瘤患者中产生了前所未有的反应率。因此，Raf 是一种优秀的抗癌治疗的分子靶标。这篇综述重点介绍了 BRAF 和 CRAF 在致癌作用的不同方面的作用，以及针对 Raf 的分子治疗的成功和它们所带来的挑战。
