This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sarkar, D. Articles by Fisher, P. B. Search for Related Content PubMed PubMed Citation Articles by Sarkar, D. Articles by Fisher, P. B.

Activation of Double-Stranded RNA–Dependent Protein Kinase, A New Pathway by Which Human Polynucleotide Phosphorylase (hPNPase^old-35) Induces Apoptosis

Departments of ¹ Urology, ² Pathology, and ³ Neurosurgery, Herbert Irving Comprehensive Caner Center, Columbia University, College of Physicians and Surgeons, New York, New York and ⁴ Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida

Requests for reprints: Devanand Sarkar or Paul B. Fisher, Departments of Urology and Pathology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. Phone: 212-305-3642; Fax: 212-305-8177; E-mail: ds2039{at}columbia.edu or pbf1{at}columbia.edu.

Human polynucleotide phosphorylase (hPNPase^old-35) is a type I IFN-inducible 3',5' exoribonuclease that mediates mRNA degradation. In melanoma cells, slow and sustained overexpression of hPNPase^old-35 induces G₁ cell cycle arrest ultimately culminating in apoptosis, whereas rapid overexpression of hPNPase^old-35 directly promotes apoptosis without cell cycle changes. These observations imply that inhibition of cell cycle progression and induction of apoptosis by hPNPase^old-35 involve multiple intracellular targets and signaling pathways. We now provide evidence that the apoptosis-inducing activity of hPNPase^old-35 is mediated by activation of double-stranded RNA–dependent protein kinase (PKR). Activation of PKR by hPNPase^old-35 precedes phosphorylation of eukaryotic initiation factor-2 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 hPNPase^old-35 also instigates down-regulation of the antiapoptotic protein Bcl-x_L. A dominant-negative inhibitor of PKR, as well as GADD153 antisense or bcl-x_L overexpression, effectively inhibits apoptosis induction by hPNPase^old-35. These studies elucidate a novel pathway by which an evolutionary conserved RNA-metabolizing enzyme, hPNPase^old-35, regulates cell growth and viability. [Cancer Res 2007;67(17):7948–53]