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Published 15 March 2004. doi:10.1083/jcb.200311011
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 6, 797-802
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 Protein kinase C{iota} is required for Ras transformation and colon carcinogenesis in vivo

Nicole R. Murray1, Lee Jamieson1, Wangsheng Yu2, Jie Zhang1, Yesim Gökmen-Polar3, Deborah Sier1, Panos Anastasiadis1, Zoran Gatalica4, E. Aubrey Thompson1, and Alan P. Fields1

1 Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL 32224
2 Lexicon Genetics Inc., The Woodlands, TX 77381
3 Indiana University School of Medicine, Indianapolis, IN 46202
4 Department of Pathology, Creighton University, Omaha, NE 68131

Address correspondence to Alan P. Fields, Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Building, 4500 San Pablo Rd., Jacksonville, FL 32224. Tel.: (904) 953-6109. Fax: (904) 953-0277. email: fields.alan{at}mayo.edu

Protein kinase C {iota} (PKC{iota}) has been implicated in Ras signaling, however, a role for PKC{iota} in oncogenic Ras-mediated transformation has not been established. Here, we show that PKC{iota} is a critical downstream effector of oncogenic Ras in the colonic epithelium. Transgenic mice expressing constitutively active PKC{iota} in the colon are highly susceptible to carcinogen-induced colon carcinogenesis, whereas mice expressing kinase-deficient PKC{iota} (kdPKC{iota}) are resistant to both carcinogen- and oncogenic Ras-mediated carcinogenesis. Expression of kdPKC{iota} in Ras-transformed rat intestinal epithelial cells blocks oncogenic Ras-mediated activation of Rac1, cellular invasion, and anchorage-independent growth. Constitutively active Rac1 (RacV12) restores invasiveness and anchorage-independent growth in Ras-transformed rat intestinal epithelial cells expressing kdPKC{iota}. Our data demonstrate that PKC{iota} is required for oncogenic Ras- and carcinogen-mediated colon carcinogenesis in vivo and define a procarcinogenic signaling axis consisting of Ras, PKC{iota}, and Rac1.

Key Words: Rac1; transgenic mice; rat intestinal epithelial cells; cell invasion; soft agar growth

N.R. Murray and L. Jamieson contributed equally to this work.

Abbreviations used in this paper: ACF, aberrant crypt foci; AOM, azoxymethane; caPKC{iota}, constitutively active PKC{iota}; kdPKC{iota}, kinase-deficient PKC{iota}; RacN17, dominant negative Rac1; RacV12, constitutively active Rac1; RIE, rat intestinal epithelial; RIE/Ras, Ras-transformed RIE.


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