Chinese Academy of Sciences

D ow nloaded from RKTG (Raf Kinase Trapping to Golgi) is a newly characterized negative regulator of the Ras-Raf-MEK-ERK signaling pathway via sequestrating Raf-1 to the Golgi apparatus. However, little is known about the physiological functions of RKTG in mitogenic pathway and carcinogenesis. Here we describe a suppressive role of RKTG in skin carcinogenesis by analyzing chemical carcinogen-induced tumorigenesis. Epidermis hyperplasia and proliferation are increased in RKTG deficient mice (RKTG-/-) after acute treatment with 7, 12-dimethylbenz anthracene (DMBA) and 12-O-tetradecanoylphorbol 13-acetate (TPA). Using a two-stage DMBA/TPA carcinogenesis protocol on mouse skin, the number and size of papillomas are increased in RKTG-/- mice, accompanied by shortened tumor latency and enhanced keratinocyte proliferation. The regression of the carcinogen-induced tumors is also prolonged in RKTG-/- mice. Consistently, the levels of Raf-1 and ERK phosphorylation in primary keratinocytes as well as skin tumors are elevated when RKTG is disrupted. Collectively, our results indicate that RKTG has a suppressive activity in chemical carcinogen-induced mitogenesis and tumor formation in mouse skin.