Maertens Ophélia, Cichowski Karen
Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA.
Adv Biol Regul. 2014 May;55:1-14. doi: 10.1016/j.jbior.2014.04.002. Epub 2014 Apr 30.
The RAS pathway is one of the most commonly deregulated pathways in human cancer. Mutations in RAS genes occur in nearly 30% of all human tumors. However in some tumor types RAS mutations are conspicuously absent or rare, despite the fact that RAS and downstream effector pathways are hyperactivated. Recently, RAS GTPase Activating Proteins (RAS GAPs) have emerged as an expanding class of tumor suppressors that, when inactivated, provide an alternative mechanism of activating RAS. RAS GAPs normally turn off RAS by catalyzing the hydrolysis of RAS-GTP. As such, the loss of a RAS GAP would be expected to promote excessive RAS activation. Indeed, this is the case for the NF1 gene, which plays an established role in a familial tumor predisposition syndrome and a variety of sporadic cancers. However, there are 13 additional RAS GAP family members in the human genome. We are only now beginning to understand why there are so many RAS GAPs, how they differentially function, and what their potential role(s) in human cancer are. This review will focus on our current understanding of RAS GAPs in human disease and will highlight important outstanding questions.
RAS 信号通路是人类癌症中最常发生失调的信号通路之一。RAS 基因的突变在所有人类肿瘤中发生率近 30%。然而，在某些肿瘤类型中，尽管 RAS 及其下游效应器信号通路过度激活，但 RAS 突变却明显缺失或罕见。最近，RAS 鸟苷三磷酸酶激活蛋白（RAS GAPs）已成为一类不断扩大的肿瘤抑制因子，当其失活时，可提供激活 RAS 的另一种机制。RAS GAPs 通常通过催化 RAS-GTP 的水解来关闭 RAS。因此，RAS GAP 的缺失预计会促进 RAS 的过度激活。事实上，NF1 基因就是如此，它在家族性肿瘤易感综合征和多种散发性癌症中发挥着既定作用。然而，人类基因组中还有另外 13 个 RAS GAP 家族成员。我们直到现在才开始理解为什么会有这么多 RAS GAPs，它们如何发挥不同的功能，以及它们在人类癌症中的潜在作用是什么。本综述将聚焦于我们目前对人类疾病中 RAS GAPs 的理解，并突出重要的悬而未决的问题。
