The 58-kilodalton inhibitor of the interferon-induced double-stranded RNA-activated protein kinase is a tetratricopeptide repeat protein with oncogenic properties

Glen N Barber, Samantha Thompson, Tae Gyu Lee, Ted Strom, Rosemary Jagus, Andre Darveau, Michael G. Katze

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

The interferon-induced RNA-dependent protein kinase (PKR) is considered to play an important role in the cellular defense against viral infection and, in addition, has been suggested to be a tumor suppressor gene because of its growth-suppressive properties. Activation of PKR by double-stranded RNAs leads to the phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF-2α) and a resultant block to protein synthesis initiation. To avoid the consequences of kinase activation, many viruses have developed strategies to down-regulate PKR. Recently, we reported on the purification and characterization of a cellular inhibitor of PKR (referred to as p58), which is activated during influenza virus infection. Subsequent cloning and sequencing has revealed that p58 is a member of the tetratricopeptide repeat (TPR) family of proteins. To further examine the physiological role of this PKR inhibitor, we stably transfected NIH 3T3 cells with a eukaryotic expression plasmid containing p58 cDNA under control of the cytomegalovirus early promoter. By taking advantage of a recently characterized p58 species-specific monoclonal antibody, we isolated cell lines that overexpressed p58. These cells exhibited a transformed phenotype, growing at faster rates and higher saturation densities and exhibiting anchorage-independent growth. Most importantly, inoculation of nude mice with p58-overexpressing cells gave rise to the production of tumors. Finally, murine PKR activity and endogenous levels of eIF-2α phosphorylation were reduced in the p58-expressing cell lines compared with control cells. These data, taken together, suggest that p58 functions as an oncogene and that one mechanism by which the protein induces malignant transformation is through the down-regulation of PKR and subsequent deregulation of protein synthesis.

Original languageEnglish
Pages (from-to)4278-4282
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number10
StatePublished - May 10 1994
Externally publishedYes

Fingerprint

eIF-2 Kinase
Double-Stranded RNA
Interferons
Eukaryotic Initiation Factor-2
Virus Diseases
Proteins
Down-Regulation
Phosphorylation
Virus Activation
Cell Line
NIH 3T3 Cells
Growth
Orthomyxoviridae
Tumor Suppressor Genes
Cytomegalovirus
Oncogenes
Nude Mice
Organism Cloning
Plasmids
Phosphotransferases

Keywords

  • eIF-2
  • Oncogene
  • Translation

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

The 58-kilodalton inhibitor of the interferon-induced double-stranded RNA-activated protein kinase is a tetratricopeptide repeat protein with oncogenic properties. / Barber, Glen N; Thompson, Samantha; Lee, Tae Gyu; Strom, Ted; Jagus, Rosemary; Darveau, Andre; Katze, Michael G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 91, No. 10, 10.05.1994, p. 4278-4282.

Research output: Contribution to journalArticle

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