Regulation and role of REST and REST4 variants in modulation of gene expression in in vivo and in vitro in epilepsy models

Spencer, Eleanor Mary; Chandler, Kate; Haddley, K.; Howard, Mark; Hughes, David J.; Belyaev, Nikolai D.; Coulson, Judy M.; Stewart, James P.; Buckley, Noel J.; Kipar, Anja; Walker, Matthew C.; Quinn, John P.

doi:10.1016/j.nbd.2006.04.020

Cited by 76 publications

(76 citation statements)

References 49 publications

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“…Recently, however, REST was shown to be important also in mature nerve cells. Heterogeneous expression of their proteins was noticed among neurons (Sun et al, 2005), whereas changes induced by pathological events were shown to contribute to cytotoxicity (Calderone et al, 2003;Spencer et al, 2006;Formisano et al, 2007). REST appears therefore to participate in the control of gene expression throughout the whole life of nerve cells.…”

Section: Introductionmentioning

confidence: 99%

The Rest Repression of the Neurosecretory Phenotype Is Negatively Modulated by BHC80, a Protein of the BRAF/HDAC Complex

Klajn¹,

Ferrai²,

Stucchi³

et al. 2009

J. Neurosci.

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Expression of neurosecretion by nerve cells requires the levels of the transcription repressor element-1 silencing transcription factor (REST) to be very low. However, when high-REST clones of PC12 cells, defective of neurosecretion, were fused to other high-REST, non-neurosecretory cells, some neurosecretion was recovered. To clarify the mechanism of this recovery, we fused defective PC12 cells with human lymphocytes. A cytogenetic analysis revealed all hybrid clones that recovered neurosecretion to contain a fragment of chromosome 11 including the gene encoding BHC80, a protein of one of the complexes that mediate REST repression. In these clones, REST levels were as high as in defective PC12, whereas BHC80, localized in the nucleus, was 4-to 5-fold higher. Transient transfection of defective PC12 with various amounts of BHC80 cDNA induced (1) in defective PC12, the reexpression of only neurosecretion mRNAs; (2) in defective PC12 cotransfected with the REST negative construct DNA-binding domain (to attenuate gene repression), the recovery of a weak, but complete neurosecretory phenotype, including dense-core granules and their regulated exocytosis. Chromatin immunoprecipitation and immunodepletion analyses revealed the extensive BHC80 association with REST at the genes of two neurosecretion proteins, chromograninB and SNAP25, however only in the low-REST PC12, whereas in high-REST defective PC12 no association was appreciable. In defective PC12 transfected with BHC80 some association was reestablished. Therefore, the recovery of neurosecretion observed after fusion/transfection of defective PC12 depends on the reciprocal level of BHC80 and REST, with BHC80 working as a negative modulator of REST repression. This role appears of possible cell physiological and pathological importance.

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Section: Introductionmentioning

confidence: 99%

The Rest Repression of the Neurosecretory Phenotype Is Negatively Modulated by BHC80, a Protein of the BRAF/HDAC Complex

Klajn¹,

Ferrai²,

Stucchi³

et al. 2009

J. Neurosci.

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“…RE-1 silencer of transcription (REST) represses TAC1 expression in mesenchymal stem cells (15). The link between REST and TAC1 could be relevant to disorders such as tumorigenesis and hippocampal seizure (16).…”

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confidence: 99%

RE-1–silencing transcription factor shows tumor-suppressor functions and negatively regulates the oncogenic TAC1 in breast cancer cells

Reddy¹,

Greco²,

Patel

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Breast cancer remains the most prevalent cancer among women in the United States. Substance P, a peptide derived from the TAC1 gene, mediates oncogenic properties in breast and other cancers. TAC1 expression facilitates the entry of breast cancer cells into bone marrow. The transcriptional repressor element 1-silencing transcription factor (REST) has been implicated in both oncogenic and tumor-suppressor functions. REST binds to the 5 untranslated region of the TAC1 promoter and suppresses its expression. This study investigated a role for REST in TAC1 induction in breast cancer. Western blots and real-time PCR indicated that REST expression in breast cancer cells was inversely proportional to the cells' aggressiveness, for both cell lines and primary breast cancer cells. REST knockdown in low-metastatic T47D cells and nontumorigenic MCF12A cells resulted in increases in TAC1 induction, proliferation, and migration. These parameters were negatively affected by ectopic expression of REST in highly aggressive MDA-MB-231 cells. Together, these findings show a central role for REST in the oncogenic function of TAC1 and suggest a tumor-suppressor role for REST in breast cancer.REST ͉ substance P ͉ tachykinin D espite advances in diagnostic technologies and treatments, breast cancer (BC) continues to be among the leading causes of cancer-related deaths among women (1). The TAC1 gene has been implicated in the development of breast and other cancers (2-4). TAC1 (preprotachykinin-A) is a single-copy gene with 7 exons (5). Through alternative splicing and posttranslational modification, TAC1 produces peptides belonging to the tachykinin family (5-7). Substance P (SP) is the predominant peptide produced from TAC1 (8, 9).BC cells (BCCs) produce high levels of SP (6). SP binds with varying affinities to 3 G protein-coupled, 7-transmembrane receptors: neurokinin (NK)1, NK2, and NK3 (6, 10). NK1 and NK2 have been reported on BCCs. SP mediates BCC proliferation, imparts radiation resistance, protects from apoptosis, induces growth-and angiogenic-promoting factors, and facilitates BC metastasis to bone marrow (2,4,11,12). The truncated NK1 has also been linked to oncogenesis, partly through the induction of TAC1 (2).Stromal-derived factor-1␣, which is implicated in BC biology, regulates TAC1 expression (4, 13). Other cytokines also induce TAC1 expression in BCCs via autocrine stimulation (2, 14). RE-1 silencer of transcription (REST) represses TAC1 expression in mesenchymal stem cells (15). The link between REST and TAC1 could be relevant to disorders such as tumorigenesis and hippocampal seizure (16).REST, also known as neural restrictive silencing factor, is a zinc finger transcriptional repressor of neuronal genes in nonneuronal and immature neuronal cells (17). REST facilitates chromatin remodeling and inhibits gene expression by assembling a repressor complex (18), Sin3A/histone deacetylase, and co-REST at the N and C termini, respectively (18). REST has been implicated in both oncogenic and tumor-suppressor roles (19,20)....

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“…Repressor element 1 silencing transcription factor continues to be expressed in many post-mitotic neurons, notably in the adult hippocampus, where both REST and its target genes are modulated in response to ischemic (Calderone et al 2003) or epileptic insults (Spencer et al 2006). REST also contributes to the down-regulation of MOPr expression in hippocampal neurons of rats subjected to transient global ischemia (Formisano et al 2007).…”

Section: Discussionmentioning

confidence: 99%

“…REST expression decreases during neurogenesis, but has been detected in the adult rat brain (Palm et al 1998) and is up-regulated in response to global ischemia (Calderone et al 2003) and induction of epilepsy (Spencer et al 2006). Thus, the REST concentration seems to influence its function and the expression of neuronal genes, and may have different effects in embryonic and differentiated neurons (Su et al 2004;Sun et al 2005).…”

mentioning

confidence: 99%

Transcriptional activation of human mu‐opioid receptor gene by insulin‐like growth factor‐I in neuronal cells is modulated by the transcription factor REST

Bedini

Baiula

Spampinato

2008

Journal of Neurochemistry

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The human mu‐opioid receptor gene (OPRM1) promoter contains a DNA sequence binding the repressor element 1 silencing transcription factor (REST) that is implicated in transcriptional repression. We investigated whether insulin‐like growth factor I (IGF‐I), which affects various aspects of neuronal induction and maturation, regulates OPRM1 transcription in neuronal cells in the context of the potential influence of REST. A series of OPRM1‐luciferase promoter/reporter constructs were transfected into two neuronal cell models, neuroblastoma‐derived SH‐SY5Y cells and PC12 cells. In the former, endogenous levels of human mu‐opioid receptor (hMOPr) mRNA were evaluated by real‐time PCR. IGF‐I up‐regulated OPRM1 transcription in: PC12 cells lacking REST, in SH‐SY5Y cells transfected with constructs deficient in the REST DNA binding element, or when REST was down‐regulated in retinoic acid‐differentiated cells. IGF‐I activates the signal transducer and activator of transcription‐3 signaling pathway and this transcription factor, binding to the signal transducer and activator of transcription‐1/3 DNA element located in the promoter, increases OPRM1 transcription. We propose that a reduction in REST is a critical switch enabling IGF‐I to up‐regulate hMOPr. These findings help clarify how hMOPr expression is regulated in neuronal cells.

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Regulation and role of REST and REST4 variants in modulation of gene expression in in vivo and in vitro in epilepsy models

Cited by 76 publications

References 49 publications

The Rest Repression of the Neurosecretory Phenotype Is Negatively Modulated by BHC80, a Protein of the BRAF/HDAC Complex

The Rest Repression of the Neurosecretory Phenotype Is Negatively Modulated by BHC80, a Protein of the BRAF/HDAC Complex

RE-1–silencing transcription factor shows tumor-suppressor functions and negatively regulates the oncogenic TAC1 in breast cancer cells

Transcriptional activation of human mu‐opioid receptor gene by insulin‐like growth factor‐I in neuronal cells is modulated by the transcription factor REST

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