Stemness Is Only a State of the Cell

Kagalwala, Mohamedi N.; Singh, Sanjay K.; Majumder, Sadhan

doi:10.1101/sqb.2008.73.042

Cited by 24 publications

(25 citation statements)

References 82 publications

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“…These findings raised questions regarding the mechanism by which high REST promotes its tumorigenic effects. The mechanism proposed, maintenance of cell stemness (Su et al, 2006;Kagalwala et al, 2008), could be appropriate for rapidly growing tumors, but not for differentiated neural cells.…”

Section: Discussionmentioning

confidence: 99%

“…Whether REST also has a role in the proliferation of competent neural cells remains unclear. In a rapidly growing, undifferentiated neural cell tumor, the medulloblastoma, high levels of the repressor were reported to maintain the stemness of the cells (Su et al, 2006;Kagalwala et al, 2008). This mechanism, however, should not work in proliferating neural cells characterized by a more differentiated phenotype.…”

Section: Introductionmentioning

confidence: 99%

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A signaling loop of REST, TSC2 and β-catenin governs proliferation and function of PC12 neural cells

Tomasoni

Negrini

Fiordaliso

et al. 2011

Journal of Cell Science

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SummaryThe RE-1-specific silencing transcription factor (REST or NRSF) is a transcription repressor that orchestrates differentiation and also operates in differentiated neurons and neurosecretory cells (neural cells). Its role in proliferation has been investigated so far only in rapidly growing tumors, with conflicting results: suppression in non-neural tumors, stimulation in medulloblastomas. Working with two clones of chromaffin-neuronal PC12 cells, which express different levels of REST, and using genetic complementation and knockdown approaches, we show that REST also promotes proliferation in differentiated neural cells. Mechanistically, this occurs by a signaling pathway involving REST, the GTPase-activating protein tuberin (TSC2) and the transcription co-factor b-catenin. In PC12 cells, raised expression of REST correlates with reduced TSC2 levels, nuclear accumulation and co-transcriptional activation of b-catenin, and increased expression of its target oncogenes Myc and Ccnd1, which might account for the proliferation advantage and the distinct morphology. Rest transcription is also increased, unveiling the existence of a self-sustaining, feed-forward REST-TSC2-b-catenin signaling loop that is also operative in another neural cell model, NT2/D1 cells. Transfection of REST, knockdown of TSC2 or forced expression of active b-catenin recapitulated the biochemical, functional and morphological properties of the high-expressing REST clone in wild-type PC12 cells. Upregulation of REST promoted proliferation and phenotypic changes, thus hindering neurosecretion. The new REST-TSC2-b-catenin signaling paradigm might have an important role in various aspects of neural cell physiology and pathology, including the regulation of proliferation and neurosecretion.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A signaling loop of REST, TSC2 and β-catenin governs proliferation and function of PC12 neural cells

Tomasoni

Negrini

Fiordaliso

et al. 2011

Journal of Cell Science

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“…The transcriptional repressor RE1 silencing transcriptional factor (REST) is a repressor of neuronal differentiation genes and a suppressor of neurogenesis in nonneural cells. 17,18 REST has been found to suppress numerous genes and can potentially regulate many biological processes in a context-dependent manner. [17][18][19][20] REST was recently found to regulate the tumorigenic properties of a subclass of GBM-derived stem cells (GSCs) called high-REST GSCs (HR-GSCs) and to produce distinct brain tumors.…”

Section: Neurooncologymentioning

confidence: 99%

REST represses miR-124 and miR-203 to regulate distinct oncogenic properties of glioblastoma stem cells

Marisetty

Singh

Nguyen

et al. 2016

NEUONC

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“…Furthermore, REST has different roles in different cellular contexts, such as oncogenic and tumor-supressor functions and hematopoietic and cardiac differentiation (7,8). In 2008, REST was proved to maintain self-renewal and pluripotency of mouse ESCs through suppression of microRNAs and believed to be a major pluripotent factor (9,10). However, it has not been elaborated in nuclear reprogramming.…”

mentioning

confidence: 99%

RE1-silencing Transcription Factor (REST) Is Required for Nuclear Reprogramming by Inhibiting Transforming Growth Factor β Signaling Pathway

Kong

Xie

Zhang

et al. 2016

Journal of Biological Chemistry

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Edited by Eric R. FearonDifferentiated cells can be reprogrammed by transcription factors, and these factors that are responsible for successful reprogramming need to be further identified. Here, we show that the neuronal repressor RE1-silencing transcription factor (REST) is rich in porcine oocytes and requires for nuclear transfer (NT)-mediated reprogramming through inhibiting TGF␤ signaling pathway. REST was dramatically degraded after oocyte activation, but the residual REST was incorporated into the transferred donor nuclei during reprogramming in NT embryos. Inhibition of REST function in oocytes compromised the development of NT embryos but not that of IVF and PA embryos. Bioinformation analysis of putative targets of REST indicated that REST might function on reprogramming in NT embryos by inhibiting TGF␤ pathway. Further results showed that the developmental failure of REST-inhibited NT embryos could be rescued by treatment of SB431542, an inhibitor of TGF␤ pathway. Thus, REST is a newly discovered transcription factor that is required for NT-mediated nuclear reprogramming.Embryonic cells differentiate into all three germ layers of the body as development progresses. Once differentiated, the reversion of the differentiated state to pluripotency is strictly limited in normal development. However, experimentally the differentiated state can be returned to the pluripotent state by transcription factors (1, 2). Despite numerous attempts, the factors responsible for successful nuclear reprogramming still need to elucidate. Transcription factors maintaining the pluripotency of embryonic stem cells (ESCs) 3 are called pluripotent factors, and they have an important role in nuclear reprogramming, such as Oct4, Sox2, and Nanog (3, 4). Thus, we can identify and characterize reprogramming factors by screening the pluripotent factors. The repressor element 1 (RE1)-silencing transcription factor (REST), as a zinc finger protein, binds 21-bp RE1 sites and functions as a key negative regulator of neurogenesis, so it is also called neuron-restrictive silencer element (5). Recently, REST has been reported to induce gene expression by recruiting TET3 to the DNA for directed 5hmC generation and Nuclear SET domain-containing protein 3-mediated H3K36 trimethylation in neurons (6). Furthermore, REST has different roles in different cellular contexts, such as oncogenic and tumor-supressor functions and hematopoietic and cardiac differentiation (7,8). In 2008, REST was proved to maintain self-renewal and pluripotency of mouse ESCs through suppression of microRNAs and believed to be a major pluripotent factor (9, 10). However, it has not been elaborated in nuclear reprogramming. Here, we provide evidence that REST plays a unique role in NT-mediated reprogramming as a supressor of the TGF␤ signaling pathway in pig. ResultsExpression Pattern of REST-We first investigated the expression of REST in porcine oocytes, nuclear transfer (NT), and parthenogenetic activation (PA) embryos by real-time PCR and Western blotting analysis. P...

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Stemness Is Only a State of the Cell

Cited by 24 publications

References 82 publications

A signaling loop of REST, TSC2 and β-catenin governs proliferation and function of PC12 neural cells

A signaling loop of REST, TSC2 and β-catenin governs proliferation and function of PC12 neural cells

REST represses miR-124 and miR-203 to regulate distinct oncogenic properties of glioblastoma stem cells

RE1-silencing Transcription Factor (REST) Is Required for Nuclear Reprogramming by Inhibiting Transforming Growth Factor β Signaling Pathway

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