Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.8 (polynucleotide phosphorylase)
 723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To fully comprehend cellular senescence, identification of relevant genes involved in this process is mandatory. Human polynucleotide phosphorylase (hPNPase(OLD-35)), an evolutionarily conserved 3', 5' exoribonuclease mediating mRNA degradation, was first identified as a predominantly mitochondrial protein overexpressed during terminal differentiation and senescence. Overexpression of hPNPase(OLD-35) in human melanoma cells and melanocytes induces distinctive changes associated with senescence, potentially mediated by direct degradation of c-myc mRNA by this enzyme. hPNPase(OLD-35) contains two RNase PH (RPH) domains, one PNPase domain, and two RNA binding domains. Using deletion mutation analysis in combination with biochemical and molecular analyses we now demonstrate that the presence of either one of the two RPH domains conferred similar functional activity as the full-length protein, whereas a deletion mutant containing only the RNA binding domains was devoid of activity. Moreover, either one of the two RPH domains induced the morphological, biochemical, and gene expression changes associated with senescence, including degradation of c-myc mRNA. Subcellular distribution confirmed hPNPase(OLD-35) to be localized both in mitochondria and the cytoplasm. The present study elucidates how a predominantly mitochondrial protein, via its localization in both mitochondria and cytoplasm, is able to target a specific cytoplasmic mRNA, c-myc, for degradation and through this process induce cellular senescence.
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PMID:Defining the domains of human polynucleotide phosphorylase (hPNPaseOLD-35) mediating cellular senescence. 1605 41

Type I interferons (IFN-alpha/-beta) are capable of suppressing c-myc mRNA expression by modulating post-transcriptional processing. However, the molecular mechanism of this phenomenon is poorly understood. We previously established that human polynucleotide phosphorylase (hPNPase(old-35)), a type I IFN-inducible 3',5' exoribonuclease involved in mRNA degradation, induces G1 cell cycle arrest and eventually apoptosis by specifically degrading c-myc mRNA. We now demonstrate a close association between IFN-beta-induced hPNPase(old-35) upregulation and c-myc downregulation in human melanoma cells. Employing stable melanoma cell clones expressing hPNPase(old-35) small inhibitory RNA, we demonstrate that hPNPase(old-35) is a key molecule coupled with IFN-beta-mediated downregulation of c-myc mRNA. Inhibition of hPNPase(old-35) or overexpression of c-myc protects melanoma cells from IFN-beta-mediated growth inhibition, emphasizing the importance of hPNPase(old-35) upregulation and consequent c-myc downregulation in IFN-beta-induced growth inhibition and apoptosis induction. In these contexts, targeted overexpression of hPNPase(old-35) might be a novel therapeutic strategy for c-myc-overexpressing and IFN-resistant tumors, such as melanomas.
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PMID:Defining the mechanism by which IFN-beta dowregulates c-myc expression in human melanoma cells: pivotal role for human polynucleotide phosphorylase (hPNPaseold-35). 1641 Aug 5