title: Neuron-restrictive silencer factor (NRSF) represses cocaine- and amphetamine-regulated transcript (CART) transcription and antagonizes cAMP-response element-binding protein signaling through a dual NRSE mechanism.
abstract: Cocaine- and amphetamine-regulated transcript (CART) peptide plays a pivotal role in neuroprotection against stroke-related brain injury. However, the regulatory mechanism on CART transcription, especially the repression mechanism, is not fully understood. Here, we show that the transcriptional repressor neuron-restrictive silencer elements (NRSF, also known as REST) represses CART expression through direct binding to two NRSF-binding elements (NRSEs) in the CART promoter and intron 1 (named pNRSE and iNRSE, respectively). EMSA show that NRSF binds to pNRSE and iNRSE directly in vitro. ChIP assays show that NRSF recruits differential co-repressor complexes including CoREST and HDAC1 to these NRSEs. The presence of both NRSEs is required for efficient repression of CART transcription as indicated by reporter gene assays. NRSF overexpression antagonizes forskolin-mediated up-regulation of CART mRNA and protein. Ischemia insult triggered by oxygen-glucose deprivation (OGD) enhances NRSF mRNA levels and then NRSF antagonizes the CREB signaling on CART activation, leading to augmented cell death. Depletion of NRSF in combination with forskolin treatment increases neuronal survival after ischemic insult. These findings reveal a novel dual NRSE mechanism by which NRSF represses CART expression and suggest that NRSF may serve as a therapeutic target for stroke treatment.
authors.affiliation: Stem Cell and Regenerative Medicine Laboratory, Beijing Institute of Transfusion Medicine, Beijing 100850, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Sihan
authors.initials: S
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.forename: Yinxiang
authors.initials: Y
authors.lastname: Yang
authors.forename: Bowen
authors.initials: B
authors.lastname: Zhang
authors.forename: Qingbin
authors.initials: Q
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Wen
authors.initials: W
authors.lastname: Yue
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Li
authors.forename: Xuetao
authors.initials: X
authors.lastname: Pei
mesh_terms: D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D056970:Co-Repressor Proteins / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007438:Introns / Q000235:genetics; D007511:Ischemia / Q000235:genetics / Q000473:pathology; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D000099229:RE1-Silencing Transcription Factor
chemical_list: D056970:Co-Repressor Proteins; D005576:Colforsin; D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D000099229:RE1-Silencing Transcription Factor; C115163:CREB1 protein, human