Suppressive function of RKTG on chemical carcinogen-induced skin carcinogenesis in mouse.
Raf kinase trapping to Golgi (RKTG) 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(a)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 extracellular signal-regulated kinase 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.
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Xiaoduo
X
Xie
Yixuan
Y
Zhang
Yuhui
Y
Jiang
Weizhong
W
Liu
Hong
H
Ma
Zhenzhen
Z
Wang
Yan
Y
Chen
D000818:Animals; D016588:Anticarcinogenic Agents; D001973:Bromodeoxyuridine; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002455:Cell Division; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics*; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D025521:Tumor Suppressor Proteins / Q000502:physiology
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C523677:RKTG protein, mouse; D025521:Tumor Suppressor Proteins; D001973:Bromodeoxyuridine