Protein kinase Ciota is required for Ras transformation and colon carcinogenesis in vivo.
Protein kinase C iota (PKCiota) has been implicated in Ras signaling, however, a role for PKCiota in oncogenic Ras-mediated transformation has not been established. Here, we show that PKCiota is a critical downstream effector of oncogenic Ras in the colonic epithelium. Transgenic mice expressing constitutively active PKCiota in the colon are highly susceptible to carcinogen-induced colon carcinogenesis, whereas mice expressing kinase-deficient PKCiota (kdPKCiota) are resistant to both carcinogen- and oncogenic Ras-mediated carcinogenesis. Expression of kdPKCiota 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 kdPKCiota. Our data demonstrate that PKCiota is required for oncogenic Ras- and carcinogen-mediated colon carcinogenesis in vivo and define a procarcinogenic signaling axis consisting of Ras, PKCiota, and Rac1.
Murray
Nicole R
NR
Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Building, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.
Jamieson
Lee
L
Yu
Wangsheng
W
Zhang
Jie
J
Gökmen-Polar
Yesim
Y
Sier
Deborah
D
Anastasiadis
Panos
P
Gatalica
Zoran
Z
Thompson
E Aubrey
EA
Fields
Alan P
AP
D000818:Animals; D001397:Azoxymethane / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000099293:Protein Kinase C-lambda
D001397:Azoxymethane; D002273:Carcinogens; D007527:Isoenzymes; D011493:Protein Kinase C; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins; D000099293:Protein Kinase C-lambda