Open AccessTumor suppressor function of the interferon-induced double-stranded RNA-activated protein kinase.
Author(s) -
Éliane Meurs,
Julien Galabru,
Glen N. Barber,
Michael G. Katze,
Ara G. Hovanessian
Publication year - 1993
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.90.1.232
Subject(s) - protein kinase r , cyclin dependent kinase 2 , map2k7 , mitogen activated protein kinase kinase , cyclin dependent kinase 9 , protein kinase a , c raf , microbiology and biotechnology , biology , cyclin dependent kinase 4 , map kinase kinase kinase , kinase , eif 2 kinase , ask1 , protein kinase domain , interferon , map3k7 , chemistry , biochemistry , mutant , virology , gene
RNA-dependent protein kinase is a M(r) 68,000 protein in human cells (p68 kinase) or a M(r) 65,000 protein in murine cells (p65 kinase). p65/p68 is a serine/threonine kinase induced by interferon treatment and generally activated by double-stranded RNAs. Once activated, the known function of this kinase is inhibition of protein synthesis through phosphorylation of the eukaryotic initiation factor 2. Here we have investigated the potential for tumorigenicity in mice of murine NIH 3T3 clones expressing human p68 kinase, either the wild-type or a mutant inactive kinase with a single amino acid substitution in the invariant lysine-296 in the catalytic domain II. Expression of the mutant p68 kinase was correlated with a malignant transformation phenotype, giving rise to the production of large tumors of at least 1 cm in diameter within 7-12 days in all inoculated mice. In contrast, no tumor growth was observed for several weeks in mice inoculated with NIH 3T3 cell clones expressing either the wild-type recombinant p68 kinase or only the endogenous p65 kinase, the murine analogue of the p68 kinase. These results suggest that functional p65/p68 kinase (recently called PKR), by a still undefined mechanism, may also act as a tumor suppressor. Consequently, one of the pathways by which interferon inhibits tumor growth might be through its capacity to induce the enhanced expression of this kinase.