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, 0021-9525/2000/4/17/ $5.00
The Journal of Cell Biology, Volume 149, Number 1, April 3, 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

Correspondence to: Robert G. Oshima, Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037. Tel:(858) 646-3147 Fax:(858) 713-6268 E-mail: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 escape embryoniclethality, develop inflammatory colorectal hyperplasia, mildliver abnormalities, and tolerate hepatectomy poorly. We showthat normal and malignant epithelial cells deficient in K8 andK18 are ~100 times more sensitive to TNF-induced death. K8 andK18 both bind the cytoplasmic domain of TNFR2 and moderate TNF-induced,Jun NH₂-terminal kinase (JNK) intracellular signaling and NF ${kappa}$ Bactivation. Furthermore, K8^- and K18^- mice are much more sensitiveto TNF dependent, apoptotic liver damage induced by the injectionof concanavalin A. This moderation of the effects of TNF maybe the fundamental function of K8 and K18 common to liver regeneration,inflammatory bowel disease, hepatotoxin sensitivity, and thediagnostic, persistent expression of these keratins in manycarcinomas.

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

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