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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 Caulina, Carl F. Wareb, Thomas M. Maginc, and Robert G. Oshimaa

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 macrophages and T lymphocytes that acts through two distinct receptors, TNFR1 (60 kD, CD120a) and TNFR2 (80 kD, CD120b), to affect cellular proliferation, differentiation, survival, and cell death. In addition to its proinflammatory actions in mucosal tissue, TNF is important for liver regeneration. Keratin 8 (K8) and keratin 18 (K18) form intermediate filaments characteristic of liver and other single cell layered, internal epithelia and their derivative cancers. K8-deficient (K8–) mice, which escape embryonic lethality, develop inflammatory colorectal hyperplasia, mild liver abnormalities, and tolerate hepatectomy poorly. We show that normal and malignant epithelial cells deficient in K8 and K18 are ~100 times more sensitive to TNF-induced death. K8 and K18 both bind the cytoplasmic domain of TNFR2 and moderate TNF-induced, Jun NH2-terminal kinase (JNK) intracellular signaling and NF{kappa}B activation. Furthermore, K8– and K18– mice are much more sensitive to TNF dependent, apoptotic liver damage induced by the injection of concanavalin A. This moderation of the effects of TNF may be the fundamental function of K8 and K18 common to liver regeneration, inflammatory bowel disease, hepatotoxin sensitivity, and the diagnostic, persistent expression of these keratins in many carcinomas.

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

© 2000 The Rockefeller University Press

Abbreviations used in this paper: CHX, cycloheximide; ConA, concanavalin A; GST, glutathione S-transferase; JNK, Jun NH2-terminal kinase; K8, keratin 8; K18, keratin 18; K8–, homozygous null Krt2-8 targeted mutation; K18–, homozygous null Krt1-18 targeted mutation; TNF, tumor necrosis factor; TNFR1, tumor necrosis factor receptor 1; TNFR2, tumor necrosis factor receptor 2; TRAF, TNF receptor associated factors.


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J. Cell Biol. 2000 149: 1-2. [Full Text] [PDF]



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