title: Retinoblastoma (Rb) protein upregulates expression of the Ifi202 gene encoding an interferon-inducible negative regulator of cell growth.
abstract: Studies have indicated that ectopic expression of p202, an interferon (IFN)-inducible retinoblastoma (Rb)-binding protein, in cultured cells retards cell proliferation and modulates cell survival. Consistent with a role of p202 in cell cycle regulation, levels of p202 increase in cells arrested in the G0/G1 phase of cell cycle after withdrawal of serum growth factors. However, a role for p202 in cell growth arrest remains to be defined. Moreover, it remains unclear how levels of p202 are upregulated during the cell growth arrest. Here, we report that Rb upregulates expression of Ifi202 gene. We found that basal as well as IFN-induced levels of p202 were significantly higher in wild-type (Rb(+/+)) mouse embryonic fibroblasts (MEFs) than isogenic Rb(-/-) MEFs. Consistent with the regulation of Ifi202 gene by Rb, expression of functional Rb, but not a pocket mutant of it, stimulated the activity of a reporter whose expression was driven by the 5'-regulatory region of Ifi202 gene. Importantly, the stimulation by Rb was dependent, in part, on a JunD/AP-1 DNA-binding site present in the 5'-regulatory region of the Ifi202 gene. Moreover, basal levels of p202 were significantly higher in wild-type (JunD(+/+)) than isogenic JunD(-/-) MEFs. Additionally, we found that increased expression of p202 potentiated the Rb-mediated inhibition of cell growth and mutations in the Rb-binding motif (LxCxE) of p202 significantly reduced cell survival. Together, our observations support the idea that the transcriptional activation of Ifi202 gene by Rb/JunD may be important for the regulation of cell growth and survival.
authors.affiliation: Department of Radiation Oncology, Stritch School of Medicine, Loyola University Medical Center, 2160 South First Avenue, Building No. 1, Mail code: 114B, Maywood, IL 60153, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Rocky
authors.initials: R
authors.lastname: Pramanik
authors.forename: Divaker
authors.initials: D
authors.lastname: Choubey
mesh_terms: D016475:3T3 Cells / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D001859:Bone Neoplasms / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002455:Cell Division; D002460:Cell Line / Q000166:cytology / Q000378:metabolism; D002461:Cell Line, Transformed / Q000378:metabolism; D002470:Cell Survival; D002472:Cell Transformation, Viral; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D016161:Genes, Retinoblastoma; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009857:Oncogenes; D012516:Osteosarcoma / Q000473:pathology; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D025941:Protein Interaction Mapping; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection; D014410:Tumor Stem Cell Assay; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D002352:Carrier Proteins; D016895:Culture Media, Serum-Free; C092537:Ifi202b protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; C498301:TP53BP1 protein, human; D018808:Transcription Factor AP-1; D000071857:Tumor Suppressor p53-Binding Protein 1; D007372:Interferons