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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]