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Published online before print May 10, 2007
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From the Department of Pathology,* University of Illinois at Chicago, Chicago, Illinois; the Department of Medicine, Section of Rheumatology, and the Howard Hughes Medical Institute and Section of Immunobiology,¶ Yale University School of Medicine, New Haven, Connecticut; the Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine and Cancer Center, Bronx, New York; the Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York; and the Howard Hughes Medical Institute and Program in Molecular Medicine,|| University of Massachusetts Medical School, Worcester, Massachusetts
@ To whom correspondence should be addressed. E-mail: wyang06{at}uic.edu.
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Abstract |
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The c-Jun NH2-terminal kinase (JNK) signal transduction pathway plays important roles in cellular processes and stress. However, the role of JNK1 in intestinal homeostasis and tumorigenesis is unknown. Therefore, we used a JNK1 knockout mouse model to characterize intestinal cell maturation and tumorigenesis. In addition, colon cancer cell lines were used to validate the role of JNK1 and to elucidate the underlying molecular mechanisms in vitro. To our surprise, we found that mice with targeted inactivation of JNK1 spontaneously developed intestinal tumors. The normal mucosa in JNK1-deficient mice showed decreased cell differentiation and increased cell proliferation. This tumorigenesis was closely linked to the down-regulation of p21WAF1/cip1, a cyclin-dependent kinase inhibitor, in intestinal epithelial cells. Immunohistochemical staining showed that JNK1 was highly expressed in the differentiation compartment of the intestinal mucosa and that the expression of JNK1 was significantly decreased in both human colonic and mouse intestinal tumors. In the colon cancer cell lines, JNK1 expression was up-regulated during spontaneous differentiation, corresponding to the up-regulation of p21WAF1/cip1. Moreover, butyrate-induced p21 expression was linked to phosphorylation of JNK1. Reduced JNK1 expression by small interfering RNA suppressed butyrate-induced apoptosis. We concluded that JNK1 plays a critical role in the regulation of homeostasis and in the suppression of tumor formation in the intestine, which was linked to the altered expression of p21WAF1/cip1.
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