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Carcinogenesis Advance Access published online on June 10, 2008
Carcinogenesis, doi:10.1093/carcin/bgn139
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Suppressive function of RKTG on chemical carcinogen-induced skin carcinogenesis in mouse

Xiaoduo Xie, Yixuan Zhang, Yuhui Jiang, Weizhong Liu, Hong Ma, Zhenzhen Wang and Yan Chen*

Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China

* Corresponding Author: Yan Chen, M.D., Ph.D., Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Rd., Shanghai 200031, China Email: ychen3{at}sibs.ac.cn Tel: 86-21-54920916, Fax: 86-21-54920291

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.

Key Words: RKTG • skin carcinogenesis • Raf • Ras • mouse models

Received January 17, 2008; revised April 25, 2008; accepted June 3, 2008.


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