c-Jun NH2-terminal kinase 1 plays a critical role in intestinal homeostasis and tumor suppression

Chang Tong, Zhinan Yin, Zibo Song, Ashley Dockendorff, Chuanshu Huang, John Mariadason, Richard A. Flavell, Roger J. Davis, Leonard H. Augenlicht, Wancai Yang

Research output: Contribution to journalArticle

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Abstract

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 p21 WAF1/cip1, a cyclln-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, butyrateinduced 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.

Original languageEnglish (US)
Pages (from-to)297-303
Number of pages7
JournalAmerican Journal of Pathology
Volume171
Issue number1
DOIs
StatePublished - Jul 2007

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JNK Mitogen-Activated Protein Kinases
Carcinogenesis
Homeostasis
Colonic Neoplasms
Cell Line
Neoplasms
Butyrates
Intestinal Mucosa
Knockout Mice
Small Interfering RNA
Intestines
Cell Differentiation
Signal Transduction
Mucous Membrane
Phosphotransferases
Up-Regulation
Down-Regulation
Epithelial Cells
Phosphorylation
Cell Proliferation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Tong, C., Yin, Z., Song, Z., Dockendorff, A., Huang, C., Mariadason, J., ... Yang, W. (2007). c-Jun NH2-terminal kinase 1 plays a critical role in intestinal homeostasis and tumor suppression. American Journal of Pathology, 171(1), 297-303. https://doi.org/10.2353/ajpath.2007.061036

c-Jun NH2-terminal kinase 1 plays a critical role in intestinal homeostasis and tumor suppression. / Tong, Chang; Yin, Zhinan; Song, Zibo; Dockendorff, Ashley; Huang, Chuanshu; Mariadason, John; Flavell, Richard A.; Davis, Roger J.; Augenlicht, Leonard H.; Yang, Wancai.

In: American Journal of Pathology, Vol. 171, No. 1, 07.2007, p. 297-303.

Research output: Contribution to journalArticle

Tong, C, Yin, Z, Song, Z, Dockendorff, A, Huang, C, Mariadason, J, Flavell, RA, Davis, RJ, Augenlicht, LH & Yang, W 2007, 'c-Jun NH2-terminal kinase 1 plays a critical role in intestinal homeostasis and tumor suppression', American Journal of Pathology, vol. 171, no. 1, pp. 297-303. https://doi.org/10.2353/ajpath.2007.061036
Tong, Chang ; Yin, Zhinan ; Song, Zibo ; Dockendorff, Ashley ; Huang, Chuanshu ; Mariadason, John ; Flavell, Richard A. ; Davis, Roger J. ; Augenlicht, Leonard H. ; Yang, Wancai. / c-Jun NH2-terminal kinase 1 plays a critical role in intestinal homeostasis and tumor suppression. In: American Journal of Pathology. 2007 ; Vol. 171, No. 1. pp. 297-303.
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