Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA

Human cancer is caused by the interplay of mutations in oncogenes and tumor suppressor genes and inherited variations in cancer susceptibility genes. While many of the tumor initiating mutations are well characterized, the effect of genetic background variation on disease onset and progression is less understood. We have used C. elegans genetics to identify genetic modifiers of the oncogenic RAS/MAPK signaling pathway. Quantitative trait locus analysis of two highly diverged C. elegans isolates combined with allele swapping experiments identified the polymorphic monoamine oxidase A (MAOA) gene amx-2 as a negative regulator of RAS/MAPK signaling. We further show that the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), which is a product of MAOA catalysis, systemically inhibits RAS/MAPK signaling in different organs of C. elegans. Thus, MAOA activity sets a global threshold for MAPK activation by controlling 5-HIAA levels. To our knowledge, 5-HIAA is the first endogenous small molecule that acts as a systemic inhibitor of RAS/MAPK signaling.

人类癌症的发生，是致癌基因、抑癌基因的突变与癌症易感基因遗传性变异共同作用的结果。尽管目前已对众多肿瘤起始突变进行了充分表征，但遗传背景变异对疾病发生与进展的影响仍未得到充分阐明。我们利用秀丽隐杆线虫（C. elegans）遗传学模型，筛选得到致癌RAS/MAPK信号通路的遗传调控因子。对两株高度分化的秀丽隐杆线虫分离株开展数量性状位点分析，并结合等位基因替换实验，最终将多态性单胺氧化酶A（monoamine oxidase A, MAOA）基因amx-2鉴定为RAS/MAPK信号通路的负调控因子。我们进一步证实，作为单胺氧化酶A催化产物的血清素代谢物5-羟吲哚乙酸（5-HIAA），可在秀丽隐杆线虫的不同器官中系统性抑制RAS/MAPK信号通路。因此，单胺氧化酶A通过调控5-HIAA的水平，为MAPK激活设定了全局阈值。据我们所知，5-HIAA是首个可作为RAS/MAPK信号通路系统性抑制剂的内源性小分子。