Defining the mechanism by which IFN-beta dowregulates c-myc expression in human melanoma cells: pivotal role for human polynucleotide phosphorylase (hPNPaseold-35).
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.
Sarkar
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D
Department of Pathology, Herbert Irving Comprehensive Caner Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA.
Park
E S
ES
Fisher
P B
PB
D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D005095:Exoribonucleases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology / Q000502:physiology*; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000096:biosynthesis; D024101:Mitochondrial Proteins
D005095:Exoribonucleases; D016899:Interferon-beta; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C476417:PNPT1 protein, human; D024101:Mitochondrial Proteins