The role of the transcription factor AP-1 in colitis-associated and beta-catenin-dependent intestinal tumorigenesis in mice.
Chronic inflammation is an important cancer risk factor but the molecular pathways linking inflammation and cancer are incompletely understood. The transcription factor c-Jun/AP-1 (activator protein 1) is involved in inflammatory responses and tumorigenesis and has been proposed as an essential mediator of oncogenic beta-catenin signaling in the intestine. Here, we examined the functions of c-Jun in two distinct mouse models of conditional and intestine-specific activation of beta-catenin. c-Jun is strongly expressed in the small intestine of mutant mice. However, beta-catenin-dependent cell proliferation is surprisingly not affected in mice lacking c-jun in intestinal epithelium, suggesting that c-Jun is not an essential immediate target of beta-catenin signaling in the small intestine. To examine the functions of Jun and Fos proteins during inflammation and cancer in the colon, colitis-associated tumors were induced chemically in the respective knockout mice. Tumors were characterized by activated beta-catenin and strongly expressed c-Jun and JunB. However, tumorigenesis was not affected by inactivation of c-Jun in either intestinal epithelium or myeloid cells. Moreover, tumorigenesis was not altered in mice lacking junB, junD, c-fos, fra-1 or fra-2, suggesting that inhibition of c-Jun or other single AP-1 proteins is not a determining factor in colitis-associated cancer in mice.
Hasselblatt
P
P
Research Institute of Molecular Pathology, Dr Bohr Gasse 7, Vienna, Austria.
Gresh
L
L
Kudo
H
H
Guinea-Viniegra
J
J
Wagner
E F
EF
D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D003092:Colitis / Q000150:complications*; D003110:Colonic Neoplasms / Q000209:etiology*; D017491:Genes, APC; D007413:Intestinal Mucosa / Q000737:chemistry; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D051176:beta Catenin; C528955:junD protein, mouse; D001397:Azoxymethane