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: Jing Zhang, Sihan Wang, Lin Yuan, Yinxiang Yang, Bowen Zhang, Qingbin Liu, Lin Chen, Wen Yue, Yanhua Li, Xuetao Pei
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 51 Pg. 42574-87 (Dec 14 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 23086924 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CREB1 protein, human
• Co-Repressor Proteins
• Cyclic AMP Response Element-Binding Protein
• Nerve Tissue Proteins
• RE1-silencing transcription factor
• Repressor Proteins
• cocaine- and amphetamine-regulated transcript protein
• Colforsin
• Cyclic AMP-Dependent Protein Kinases
• Glucose

Topics

• Base Sequence
• Cell Death (drug effects)
• Cell Hypoxia (drug effects, genetics)
• Cell Survival (drug effects, genetics)
• Co-Repressor Proteins (metabolism)
• Colforsin (pharmacology)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Glucose (deficiency, metabolism)
• HeLa Cells
• Humans
• Introns (genetics)
• Ischemia (genetics, pathology)
• Molecular Sequence Data
• Nerve Tissue Proteins (genetics)
• Neurons (drug effects, metabolism, pathology)
• Promoter Regions, Genetic (genetics)
• Repressor Proteins (metabolism)
• Signal Transduction (drug effects, genetics)
• Transcription, Genetic (drug effects)
• Up-Regulation (drug effects, genetics)