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Carcinogenesis Advance Access originally published online on June 10, 2008
Carcinogenesis 2008 29(8):1632-1638; 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

* To whom correspondence should be addressed. Tel: +86 21 54920916; Fax: +86 21 54920291; Email: ychen3{at}sibs.ac.cn

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.

Abbreviations: BrdU, bromodeoxyuridine; DMBA, 7, 12-dimethylbenz(a)anthracene; ERK, extracellular signal-regulated kinase; HPF, high-power microscope field; IHC, immunohistochemistry; MEK, mitogen-activated and extracellular signal-regulated kinase kinase; MTT, 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan; RKTG, Raf kinase trapping to Golgi; TPA, 12-O-tetradecanoylphorbol-13-acetate; TUNEL, TdT-mediated dUTP-biotin nick end labeling

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


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