Lung-targeted expression of the c-Raf-1 kinase in transgenic mice exposes a novel oncogenic character of the wild-type protein.
The c-Raf-1 kinase is a downstream effector of Ras signaling. Both proteins are highly oncogenic when they are mutationally activated, but only the Ras GTPase is frequently mutated in naturally occurring tumors. Although the c-Raf-1 protein was found to be amplified in different lung cancer cell lines, overexpression of the wild-type c-Raf-1 protein was shown to be insufficient to transform cultured cells. Here we have addressed the question of whether overexpression of the wild-type c-Raf-1 kinase can induce lung cancer in mice. We show that lung-targeted expression of oncogenically activated or wild-type c-Raf-1 proteins induces morphologically indistinguishable lung adenomas in transgenic mice. Compared with mice transgenic for the activated c-Raf-1-BxB, tumor development is delayed and occurs at a lower incidence in wild-type c-Raf-1 transgenic mice. Our studies show that the c-Raf-1 expression level is a critical parameter in tumor development and should be analyzed in more detail to evaluate its potential in the induction of cancer.
Kerkhoff
E
E
Institut für medizinische Strahlenkunde und Zellforschung, Universität Würzburg, Germany.
Fedorov
L M
LM
Siefken
R
R
Walter
A O
AO
Papadopoulos
T
T
Rapp
U R
UR
D000236:Adenoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000818:Animals; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011510:Proteolipids / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000032:analysis / Q000235:genetics*; D011663:Pulmonary Surfactants / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics
D011510:Proteolipids; D011663:Pulmonary Surfactants; D011993:Recombinant Fusion Proteins; D019908:Proto-Oncogene Proteins c-raf