Keratin-Dependent, Epithelial Resistance to Tumor Necrosis Factor-Induced Apoptosis

doi:10.1083/jcb.149.1.17

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© The Rockefeller University Press, 0021-9525/2000//17 $5.00
The Journal of Cell Biology, Volume 149, Number 1, , 2000 17-22

Brief Report

Keratin-Dependent, Epithelial Resistance to Tumor Necrosis Factor-Induced Apoptosis

Carlos Caulin^a, Carl F. Ware^b, Thomas M. Magin^c, and Robert G. Oshima^a

^a Cancer Research Center, The Burnham Institute, La Jolla, California 92037
^b La Jolla Institute for Allergy and Immunology, San Diego, California 92121
^c Institut fuer Genetik, Abteilung Molekulargenetik, Universitaet Bonn, Bonn, Germany
Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037.(858) 713-6268(858) 646-3147

rgoshima{at}burnham-inst.org

Tumor necrosis factor (TNF) is a cytokine produced by macrophagesand T lymphocytes that acts through two distinct receptors,TNFR1 (60 kD, CD120a) and TNFR2 (80 kD, CD120b), to affect cellularproliferation, differentiation, survival, and cell death. Inaddition to its proinflammatory actions in mucosal tissue, TNFis important for liver regeneration. Keratin 8 (K8) and keratin18 (K18) form intermediate filaments characteristic of liverand other single cell layered, internal epithelia and theirderivative cancers. K8-deficient (K8^–) mice, which escapeembryonic lethality, develop inflammatory colorectal hyperplasia,mild liver abnormalities, and tolerate hepatectomy poorly. Weshow that normal and malignant epithelial cells deficient inK8 and K18 are $~$ 100 times more sensitive to TNF-induced death.K8 and K18 both bind the cytoplasmic domain of TNFR2 and moderateTNF-induced, Jun NH₂-terminal kinase (JNK) intracellular signalingand NF ${kappa}$ B activation. Furthermore, K8^– and K18^– miceare much more sensitive to TNF dependent, apoptotic liver damageinduced by the injection of concanavalin A. This moderationof the effects of TNF may be the fundamental function of K8and K18 common to liver regeneration, inflammatory bowel disease,hepatotoxin sensitivity, and the diagnostic, persistent expressionof these keratins in many carcinomas.

Key Words: cytoskeleton • intermediate filament • inflammatory bowel disease • tumor necrosis factor • receptor 2

Abbreviations used in this paper: CHX, cycloheximide; ConA,concanavalin A; GST, glutathione S-transferase; JNK, Jun NH₂-terminalkinase; K8, keratin 8; K18, keratin 18; K8^–, homozygousnull Krt2-8 targeted mutation; K18^–, homozygous null Krt1-18targeted mutation; TNF, tumor necrosis factor; TNFR1, tumornecrosis factor receptor 1; TNFR2, tumor necrosis factor receptor2; TRAF, TNF receptor associated factors.

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