Phosphatase activity of small C-terminal domain phosphatase 1 (SCP1) controls the stability of the key neuronal regulator RE1-silencing transcription factor (REST)

Burkholder, Nathaniel T.; Mayfield, Joshua E.; Irani, Seema; Arce, Daniel K.; Jiang, Faqin; Matthews, Wendy L.; Xue, Yuanchao; Zhang, Yan Jessie

doi:10.1074/jbc.ra118.004722

Cited by 19 publications

(33 citation statements)

References 45 publications

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“…Among these studies, Burkholder et al showed that miR‐124a suppressed the expression of small C‐terminal domain phosphatase 1 ( SCP1 ) by targeting its 3′‐UTR region. Interestingly, SCP1 , on the other hand, dephosphorylates RE1‐silencing transcription factor ( REST ) and protects it from degradation . REST , in turn, is a neuronal repressor that negatively regulates miR‐124a expression.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-124a inhibits endoderm lineage commitment by targeting Sox17 and Gata6 in mouse embryonic stem cells

et al. 2019

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The role of microRNAs (miRNAs) during mouse early development, especially in endoderm germ layer formation, is largely unknown. Here, via miRNA profiling during endoderm differentiation, we discovered that miR‐124a negatively regulates endoderm lineage commitment in mouse embryonic stem cells (mESCs). To further investigate the functional role of miR‐124a in early stages of differentiation, transfection of embryoid bodies with miR‐124a mimic was performed. We showed that overexpression of miR‐124a inhibits endoderm differentiation in vitro through targeting the 3′‐untranslated region (UTR) of Sox17 and Gata6, revealing the existence of interplay between miR‐124a and the Sox17/Gata6 transcription factors in hepato‐specific gene regulation. In addition, we presented a feasible in vivo system that utilizes teratoma and gene expression profiling from microarray to quantitatively evaluate the functional role of miRNA in lineage specification. We demonstrated that ectopic expression of miR‐124a in teratomas by intratumor delivery of miR‐124a mimic and Atelocollagen, significantly suppressed endoderm and mesoderm lineage differentiation while augmenting the differentiation into ectoderm lineage. Collectively, our findings suggest that miR‐124a plays a significant role in mESCs lineage commitment.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-124a inhibits endoderm lineage commitment by targeting Sox17 and Gata6 in mouse embryonic stem cells

et al. 2019

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“…Another cooperative factor, active during neuronal differentiation, is the C-terminal domain phosphatase 1 (SCP1), an enzyme that regulates the phosphorylation of REST. SCP1 protects REST from degradation, making possible the typical changes of its level at specific sites of differentiation (4). Plant Homeo Domain Finger protein 8 (PHF8), a chromatin regulator in many cell types, operates as a transcriptional activator.…”

Section: Cooperative Interactionsmentioning

confidence: 99%

“…High REST is present also in neurons and neural cells, limited, however, to their stem and early progenitor states, where regulation is peculiar [3][4][5]. For these reasons, the early cells share properties with non-neural cells.…”

Section: Introductionmentioning

confidence: 99%

“…However, high levels of REST are transient in neurons as much as, during more advanced development, the level of the factor becomes much lower, mostly due to its increased turnover. Upon such reduction, neuron-specific genes undergo extensive transcription, governing the ensuing increase of specific proteins and RNAs [1,3,4], especially microRNAs (miRNAs) [5].…”

Section: Introductionmentioning

confidence: 99%

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News about the Role of the Transcription Factor REST in Neurons: From Physiology to Pathology

García-Manteiga

D’Alessandro

Meldolesi

2019

IJMS

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RE-1 silencing transcription factor (REST) (known also as NRSF) is a well-known transcription repressor whose strong decrease induces the distinction of neurons with respect to the other cells. Such distinction depends on the marked increased/decreased expression of specific genes, accompanied by parallel changes of the corresponding proteins. Many properties of REST had been identified in the past. Here we report those identified during the last 5 years. Among physiological discoveries are hundreds of genes governed directly/indirectly by REST, the mechanisms of its neuron/fibroblast conversions, and the cooperations with numerous distinct factors induced at the epigenetic level and essential for REST specific functions. New effects induced in neurons during brain diseases depend on the localization of REST, in the nucleus, where functions and toxicity occur, and in the cytoplasm. The effects of REST, including cell aggression or protection, are variable in neurodegenerative diseases in view of the distinct mechanisms of their pathology. Moreover, cooperations are among the mechanisms that govern the severity of brain cancers, glioblastomas, and medulloblastomas. Interestingly, the role in cancers is relevant also for therapeutic perspectives affecting the REST cooperations. In conclusion, part of the new REST knowledge in physiology and pathology appears promising for future developments in research and brain diseases.

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“…An alternative strategy may therefore be to modulate REST activity indirectly by targeting CTDSP1, the phosphatase that protects it from degradation. While CTDSP1 knockdown has been shown to promote neurotrophic factors expression in HEK-293 cells [19], it is not known whether it effectively promotes neurotrophic factor expression in neurons or in support cells. Here, we investigate whether the REST pathway is active in MPCs.…”

Section: Introductionmentioning

confidence: 99%

C-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration

Gervasi¹,

Dimitchev²,

Clark³

et al. 2020

Preprint

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Background: Peripheral Nerve Injury (PNI) represents a major clinical and economic burden. Despite the ability of peripheral neurons to regenerate their axons after an injury, patients are often left with motor and/or sensory disability and may develop chronic pain. Successful regeneration and target organ reinnervation require comprehensive transcriptional changes in both injured neurons and support cells located at the site of injury. The expression of most of the genes required for axon growth and guidance and for synapsis formation is repressed by a single master transcriptional regulator, the Repressor Element 1 Silencing Transcription factor (REST). Sustained increase of REST levels after injury inhibits axon regeneration and leads to chronic pain. REST is stabilized by the Carboxy-terminal domain small phosphatase 1 (CTDSP1), which prevents REST targeting to the proteasome. Here, we explore whether knockdown of CTDSP1 promotes neurotrophic factor expression in mesenchymal progenitor cells (MPCs), a type of support cells that can be harvested from the site of injury during surgical debridement, and in dorsal root ganglion (DRG) neurons. In addition, we explore whether CTDSP1 knockdown supports DRG neurite regeneration. Methods: Cultured human MPCs or rat DRG neurons were transfected with REST or CTDSP1 specific siRNA. Neurotrophic factor expression was analyzed by RT-qPCR and Western Blot. Brain-derived Neurotrophic Factor (BDNF) in cell culture medium was quantified by ELISA. Axon regeneration was quantified measuring the length of the longest neurite of a neuron. Results: Knockdown of REST or CTDSP1 in MPCs results in increased expression of BDNF and nerve growth factor (NGF). In addition, knockdown of CTDSP1 leads to increased release of BDNF in cell culture medium from MPCs and to reduced levels of REST protein. Finally, knockdown of CTDSP1 in DRG neurons results in increased levels of BDNF and increased DRG neurite growth rate.Conclusions: CTDSP1 knockdown promotes neurotrophic factor expression in both DRG neurons and the support cells MPCs. In addition, it promotes DRG neuron regeneration. Therapeutics targeting CTDSP1 activity may represent a novel epigenetic strategy to promote peripheral nerve regeneration after PNI by promoting the regenerative program repressed by injury-induced increased levels of REST in both neurons and support cells.

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Phosphatase activity of small C-terminal domain phosphatase 1 (SCP1) controls the stability of the key neuronal regulator RE1-silencing transcription factor (REST)

Cited by 19 publications

References 45 publications

MicroRNA-124a inhibits endoderm lineage commitment by targeting Sox17 and Gata6 in mouse embryonic stem cells

MicroRNA-124a inhibits endoderm lineage commitment by targeting Sox17 and Gata6 in mouse embryonic stem cells

News about the Role of the Transcription Factor REST in Neurons: From Physiology to Pathology

C-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration

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