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Human Polynucleotide Phosphorylase (hPNPase^old-35)

A Potential Link between Aging and Inflammation

Departments of ¹ Pathology, ² Neurosurgery, and ³ Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York; and ⁴ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Chronic inflammation is a characteristic feature of aging, and the relationship between cellular senescence and inflammation, although extensively studied, is not well understood. An overlapping pathway screen identified human polynucleotide phosphorylase (hPNPase^old-35), an evolutionary conserved 3',5'-exoribonuclease, as a gene up-regulated during both terminal differentiation and cellular senescence. Enhanced expression of hPNPase^old-35 via a replication-incompetent adenovirus (Ad.hPNPase^old-35) in human melanoma cells and normal human melanocytes results in a characteristic senescence-like phenotype. Reactive oxygen species (ROS) play a key role in the induction of both in vitro and in vivo senescence. We now document that overexpression of hPNPase^old-35 results in increased production of ROS, leading to activation of the nuclear factor (NF)-B pathway. Ad.hPNPase^old-35 infection promotes degradation of IB and nuclear translocation of NF-B and markedly increases binding of the transcriptional activator p50/p65. The generation of ROS and activation of NF-B by hPNPase^old-35 are prevented by treatment with a cell-permeable antioxidant, N-acetyl-L-cysteine. Infection with Ad.hPNPase^old-35 enhances the production of interleukin (IL)-6 and IL-8, two classical NF-B-responsive cytokines, and this induction is inhibited by N-acetyl-L-cysteine. A cytokine array reveals that Ad.hPNPase^old-35 infection specifically induces the expression of proinflammatory cytokines, such as IL-6, IL-8, RANTES, and matrix metalloproteinase (MMP)-3. We hypothesize that hPNPase^old-35 might play a significant role in producing pathological changes associated with aging by generating proinflammatory cytokines via ROS and NF-B. Understanding the relationship between hPNPase^old-35 and inflammation and aging provides a unique opportunity to mechanistically comprehend and potentially intervene in these physiologically important processes.

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