Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 33, Pages 23788-23797Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.452029
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Funding
- National Institutes of Health [AI074957]
- Grants-in-Aid for Scientific Research [23590071] Funding Source: KAKEN
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The epithelium of mucosal and skin surfaces serves as a permeability barrier and affords mechanisms for local immune defense. Crucial to the development and maintenance of a properly functioning epithelium is the balance of cell proliferation, differentiation, and death. Here we show that this balance depends on cross-regulatory interactions among multiple protein kinase-mediated signals and their coordinated transmission. From an investigation of conditional gene knock-out mice, we find that epithelial-specific loss of the protein kinase p38 alpha leads to aberrant activation of TAK1, JNK, EGF receptor, and ERK in distinct microanatomical areas of the intestines and skin. Consequently, the epithelial tissues display excessive proliferation, inadequate differentiation, and sensitivity to apoptosis. These anomalies leave the tissue prone to damage and collapse at the trigger of an environmental insult. The vulnerability of p38 alpha-deficient epithelium predicts adverse effects of long term pharmacological p38 alpha inhibition; yet such limitations could be overcome by concomitant blockade of one or more of the dysregulated protein kinase signaling pathways.
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