Activation of double-stranded RNA-dependent protein kinase, a new pathway by which human polynucleotide phosphorylase (hPNPaseold-35) induces apoptosis

Devanand Sarkar, Sook Park Eun, Glen N Barber, Paul B. Fisher

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Human polynucleotide phosphorylase (hPNPaseold-35) is a type I IFN-inducible 3′,5′ exoribonuclease that mediates mRNA degradation. In melanoma cells, slow and sustained overexpression of hPNPaseold-35 induces G1 cell cycle arrest ultimately culminating in apoptosis, whereas rapid overexpression of hPNPaseold-35 directly promotes apoptosis without cell cycle changes. These observations imply that inhibition of cell cycle progression and induction of apoptosis by hPNPaseold-35 involve multiple intracellular targets and signaling pathways. We now provide evidence that the apoptosis-inducing activity of hPNPaseold-35 is mediated by activation of double-stranded RNA-dependent protein kinase (PKR). Activation of PKR by hPNPaseold-35 precedes phosphorylation of eukaryotic initiation factor-2α and induction of growth arrest and DNA damage-inducible gene 153 (GADD153) that culminates in the shutdown of protein synthesis and apoptosis. Activation of PKR by hPNPaseold-35 also instigates down-regulation of the antiapoptotic protein Bcl-xL. A dominant-negative inhibitor of PKR, as well as GADD153 antisense or bcl-x L overexpression, effectively inhibits apoptosis induction by hPNPaseold-35. These studies elucidate a novel pathway by which an evolutionary conserved RNA-metabolizing enzyme, hPNPaseold-35 , regulates cell growth and viability.

Original languageEnglish
Pages (from-to)7948-7953
Number of pages6
JournalCancer Research
Volume67
Issue number17
DOIs
StatePublished - Sep 1 2007

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Polyribonucleotide Nucleotidyltransferase
eIF-2 Kinase
Double-Stranded RNA
Apoptosis
DNA Damage
Cell Cycle
Growth
Eukaryotic Initiation Factor-2
G1 Phase Cell Cycle Checkpoints
RNA Stability
Genes
Melanoma
Cell Survival
Proteins
Down-Regulation
Phosphorylation
RNA
Enzymes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Activation of double-stranded RNA-dependent protein kinase, a new pathway by which human polynucleotide phosphorylase (hPNPaseold-35) induces apoptosis. / Sarkar, Devanand; Eun, Sook Park; Barber, Glen N; Fisher, Paul B.

In: Cancer Research, Vol. 67, No. 17, 01.09.2007, p. 7948-7953.

Research output: Contribution to journalArticle

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