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dc.contributor.authorXie, Ronglin
dc.contributor.authorGupta, Sunita
dc.contributor.authorMiele, Angela
dc.contributor.authorShiffman, Dov
dc.contributor.authorStein, Janet L.
dc.contributor.authorStein, Gary S.
dc.contributor.authorVan Wijnen, Andre J.
dc.date2022-08-11T08:09:02.000
dc.date.accessioned2022-08-23T16:16:19Z
dc.date.available2022-08-23T16:16:19Z
dc.date.issued2003-05-07
dc.date.submitted2008-11-25
dc.identifier.citationJ Biol Chem. 2003 Jul 18;278(29):26589-96. Epub 2003 May 5. <a href="http://dx.doi.org/10.1074/jbc.M301491200">Link to article on publisher's site</a>
dc.identifier.issn0021-9258 (Print)
dc.identifier.doi10.1074/jbc.M301491200
dc.identifier.pmid12732645
dc.identifier.urihttp://hdl.handle.net/20.500.14038/34303
dc.description.abstractCell growth control by interferons (IFNs) involves up-regulation of the tumor suppressor interferon regulatory factor 1 (IRF1). To exert its anti-proliferative effects, this factor must ultimately control transcription of several key genes that regulate cell cycle progression. Here we show that the G1/S phase-related cyclin-dependent kinase 2 (CDK2) gene is a novel proliferation-related downstream target of IRF1. We find that IRF1, but not IRF2, IRF3, or IRF7, selectively represses CDK2 gene transcription in a dose- and time-dependent manner. We delineate the IRF1-responsive repressor element between nt -68 to -31 of the CDK2 promoter. For comparison, the tumor suppressor p53 represses CDK2 promoter activity independently of IRF1 through sequences upstream of nt -68, and the CDP/cut/Cux1 homeodomain protein represses transcription down-stream of -31. Thus, IRF1 repression represents one of three distinct mechanisms to attenuate CDK2 levels. The -68/-31 segment lacks a canonical IRF responsive element but contains a single SP1 binding site. Mutation of this element abrogates SP1-dependent enhancement of CDK2 promoter activity as expected but also abolishes IRF1-mediated repression. Forced elevation of SP1 levels increases endogenous CDK2 levels, whereas IRF1 reduces both endogenous SP1 and CDK2 protein levels. Hence, IRF1 represses CDK2 gene expression by interfering with SP1-dependent transcriptional activation. Our findings establish a causal series of events that functionally connect the anti-proliferative effects of interferons with the IRF1-dependent suppression of the CDK2 gene, which encodes a key regulator of the G1/S phase transition.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=12732645&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1074/jbc.M301491200
dc.subject3T3 Cells; Animals; Base Sequence; *CDC2-CDC28 Kinases; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; DNA; DNA-Binding Proteins; Genes, Reporter; Humans; Interferon Regulatory Factor-1; Mice; Phosphoproteins; Podophyllin; Podophyllotoxin; *Promoter Regions (Genetics); Protein-Serine-Threonine Kinases; Recombinant Fusion Proteins; Sequence Deletion; Suppression, Genetic; Trans-Activation (Genetics); Transfection; Tumor Suppressor Protein p53
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleThe tumor suppressor interferon regulatory factor 1 interferes with SP1 activation to repress the human CDK2 promoter
dc.typeJournal Article
dc.source.journaltitleThe Journal of biological chemistry
dc.source.volume278
dc.source.issue29
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_sp/954
dc.identifier.contextkey672227
html.description.abstract<p>Cell growth control by interferons (IFNs) involves up-regulation of the tumor suppressor interferon regulatory factor 1 (IRF1). To exert its anti-proliferative effects, this factor must ultimately control transcription of several key genes that regulate cell cycle progression. Here we show that the G1/S phase-related cyclin-dependent kinase 2 (CDK2) gene is a novel proliferation-related downstream target of IRF1. We find that IRF1, but not IRF2, IRF3, or IRF7, selectively represses CDK2 gene transcription in a dose- and time-dependent manner. We delineate the IRF1-responsive repressor element between nt -68 to -31 of the CDK2 promoter. For comparison, the tumor suppressor p53 represses CDK2 promoter activity independently of IRF1 through sequences upstream of nt -68, and the CDP/cut/Cux1 homeodomain protein represses transcription down-stream of -31. Thus, IRF1 repression represents one of three distinct mechanisms to attenuate CDK2 levels. The -68/-31 segment lacks a canonical IRF responsive element but contains a single SP1 binding site. Mutation of this element abrogates SP1-dependent enhancement of CDK2 promoter activity as expected but also abolishes IRF1-mediated repression. Forced elevation of SP1 levels increases endogenous CDK2 levels, whereas IRF1 reduces both endogenous SP1 and CDK2 protein levels. Hence, IRF1 represses CDK2 gene expression by interfering with SP1-dependent transcriptional activation. Our findings establish a causal series of events that functionally connect the anti-proliferative effects of interferons with the IRF1-dependent suppression of the CDK2 gene, which encodes a key regulator of the G1/S phase transition.</p>
dc.identifier.submissionpathgsbs_sp/954
dc.contributor.departmentDepartment of Cell Biology
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.source.pages26589-96


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