title: GREBP, a cGMP-response element-binding protein repressing the transcription of natriuretic peptide receptor 1 (NPR1/GCA).
abstract: NPR1/GCA (natriuretic peptide receptor 1/guanylyl cyclase A) expression is controlled by several agents, including ANP (atrial natriuretic peptide). After ANP stimulation, NPR1/GCA down-regulates the transcriptional activity of its gene via a cGMP-dependent mechanism. Because we previously identified a cis-acting element responsible for this cGMP sensitivity, we proceed here to explore novel putative protein binding to cGMP-response element (cGMP-RE). Using the yeast one-hybrid technique with a human kidney cDNA library, we identified a strong positive clone able to bind cGMP-RE. The clone was derived from 1083-bp-long cDNA of a gene of yet unknown function localized on human chromosome 1 (1p33.36). We named this new protein GREBP (for cGMP-response element-binding protein). DNA binding assays showed 18-fold higher cGMP-RE binding capacity than the controls, whereas an electromobility shift assay indicated a specific binding for the cGMP-RE, and chromatin immunoprecipitation confirmed the binding of GREBP to the element under physiological conditions. By acting on cGMP-RE, GREBP inhibited the expression of a luciferase-coupled NPR1 promoter construct. In H295R cells, ANP heightened GREBP expression by 60% after just 3 h of treatment while inhibiting NPR1/GCA expression by 30%. Silencing GREBP with specific small interfering RNA increased the activity of the luciferase-coupled NPR1 promoter and GCA/NPR1 mRNA levels. GREBP is a nuclear protein mainly expressed in the heart. We report here the existence of a human-specific gene that acts as a transcriptional repressor of the NPR1/GCA gene.
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec H1W 4A4, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Martel
authors.forename: Pavel
authors.initials: P
authors.lastname: Hamet
authors.forename: Johanne
authors.initials: J
authors.lastname: Tremblay
mesh_terms: D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D002878:Chromosomes, Human, Pair 1; D003001:Cloning, Molecular; D006152:Cyclic GMP / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry / Q000302:isolation & purification; D016373:DNA, Antisense / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007668:Kidney; D008969:Molecular Sequence Data; D010957:Plasmids; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D016373:DNA, Antisense; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C022994:cyclic GMP-binding protein; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP
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