Mechanism of a arsenic-mediated cancer development

点击翻译按钮获取中文摘要

More than ten million people in the world suffered drinking water with high concentration of arsenic (>5 mg/1). It is reported that a risk of cancer development in skin, lung, liver or bladder increases in human in epidemiological research. These reports suggest that arsenic is a carcinogen in the human. To prevent against an explosive increase of cancer in the people who drink arsenic-polluted water, we need to clarify the mechanism of arsenic-induced cancer for establishing effective therapies.The c-RET proto-oncogene encodes a receptor type tyrosine. Ligand of c-RET is glial cell line-derived neurotrophic factor (GDNF), and its signaling is essential for renal organogenesis and enteric neurogenesis. The Ret kinase is activated by point mutations or gene rearrangement. Germ line mutations of the c-RET proto-oncogene are associated with the development of multiple endocrine neoplasia type 2A (MEN2A). Enhancement of oncogenic RET activity through autophosphorylation of tyrosine 905 and tyrosine 1062 are crucially important for transformation.In this study, we clarified mechanism of arsenic-mediated cancer development through analysis of RET tyrosine kinase activation.1) Arsenic-mediated superactivation of RET-MEN2A tyrosine kinase.Arsenic promotes c-RET proto-oncogene product activity (c-RET protein tyrosine kinase). Arsenic superactivates kinase activity of RET oncogene product (RET-MEN2A: c-RET with cysteine 634 replaced arginine), in which kinase activity was 3-10 fold augmented by genetic mutation.2) Arsenic promoted autophosphorylation of key tyrosines for activation in c-RET.Autophosphorylation of tyrosines 905 and 1062 were reported to be crucially important for c-RET kinase activation. Arsenic promoted autophosphorylation of 905 and 1062 tyrosines in c-RET.3) Effect of SOD1 (superoxide dismutase 1) on arsenic-mediated RET kinase activation.We showed that SOD1 inhibited UV-mediated but not arsenic-mediated RET tyrosine kinase activity.