Expression regulation and genomic organization of human polynucleotide phosphorylase, hPNPase(old-35), a Type I interferon inducible early response gene.
An overlapping pathway screening (OPS) approach designed to identify and clone genes displaying parallel expression profiles as a function of induction of terminal differentiation and cellular senescence in human cells identified a novel gene old-35. Sequence and functional analysis indicates that old-35 encodes human polynucleotide phosphorylase, hPNPase(old-35). Polynucleotide phosphorylases comprise a family of phosphate dependent 3'-5' RNA exonucleases implicated in RNA regulation. Treatment of HO-1 human melanoma and additional diverse normal and tumor-derived human cell types with Type I interferon (IFN), IFN-beta or IFN-alpha, induces hPNPase(old-35) expression. To provide insights into the regulation of hPNPase(old-35), we cloned and analyzed the promoter region of this gene. These studies demonstrate that IFN-beta controls hPNPase(old-35) expression by transcriptional modulation rather than by altering mRNA stability. Transcriptional activation of hPNPase(old-35) by IFN-beta is primarily mediated by the interferon stimulatory response element (ISRE) present in its promoter. Analysis of hPNPase(old-35) expression in cell lines defective in various IFN signaling molecules confirms that hPNPase(old-35) expression is dependent upon the Janus activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Furthermore, gel shift analyses document that hPNPase(old-35) is a direct target of the interferon stimulated gene factor 3 (ISGF3) complex. The hPNPase(old-35) gene spans approximately 54 kb of genomic DNA and is distributed on 28 exons and 27 introns. hPNPase(old-35) maps to 2p15-2p16.1, a region implicated in hereditary nonpolyposis colorectal cancer, Carney complex, Doyne's honeycomb retinal dystrophy and several other diseases. To provide insights into PNPase function in vivo, we have also cloned the mouse PNPase(old-35) cDNA, mPNPase(old-35). Induction of hPNPase(old-35) by IFN treatment as well as during differentiation and senescence suggest that this gene may play a significant role in regulating cellular growth and that overlapping gene expression changes, also induced by IFN, may contribute to these important physiological processes.
Leszczyniecka
Magdalena
M
Department of Pathology, College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Su
Zao-zhong
ZZ
Kang
Dong-chul
DC
Sarkar
Devanand
D
Fisher
Paul B
PB
D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005091:Exons; D005095:Exoribonucleases / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005796:Genes / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016899:Interferon-beta / Q000494:pharmacology; D007438:Introns; D053613:Janus Kinase 1; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009841:Oligonucleotides / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011544:Pseudogenes / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D050794:STAT1 Transcription Factor; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D024363:Transcription Initiation Site; D024101:Mitochondrial Proteins
D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; D005095:Exoribonucleases; D007370:Interferon Type I; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016899:Interferon-beta; D053613:Janus Kinase 1; D009841:Oligonucleotides; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; C494227:IRF9 protein, human; C494228:Isgf3g protein, mouse; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; C476417:PNPT1 protein, human; D024101:Mitochondrial Proteins