TGF-beta Family Signaling in Embryonic Stem Cells

Park, Kyung-Soon

doi:10.15283/ijsc.2011.4.1.18

Cited by 33 publications

(26 citation statements)

References 41 publications

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“…Confirming that, up-regulation of the TGF␤ pathway was observed in REST-deficient NT embryos, revealing TGF␤ pathway is suppressed by REST in NT embryos. TGF␤ pathway has been implicated in the development and maintenance of various organs (19,20), and is necessary for the maintenance of self-renewal and pluripotency of both human and mouse ESCs (21). During embryonic development, the pathway is believed to play critical roles in the specification of cell identities in embryonic and extra embryonic lineages of the post-implantation embryo (19,(22)(23)(24).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Lefty is a member of the transforming growth factor-β (TGF-β) superfamily with two variants that are respectively designated as human Lefty1 (Lefty B in mouse) and human Lefty2 (Lefty A in mouse). 2 Lefty is a secretory protein, and the relative molecular weight of preproprotein is 42 kDa. After cleavage with proteolytic enzymes at two sites (Arg77 and Arg135), two mature peptides, 34 and 28 kDa, are respectively formed.…”

Section: Introductionmentioning

confidence: 99%

Lefty inhibits in vitro decidualization by regulating P57 and cyclin D1 expressions

Bai

et al. 2014

Cell Biochemistry & Function

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Endometrial decidualization is highly important for successful construction and maintenance of embryo implantation and pregnancy. Lefty gene at different menstrual cycle phases has different expressions, indicating its regulatory significance. To study the mechanism of Lefty in decidualization, human endometrial stromal cells (hESCs) were cultured and induced with medroxyprogesterone acetate (MPA) and 8-bromoadenosine-cAMP (8-Br-cAMP) in vitro as a research model. Our results showed that Lefty1 overexpression inhibited MPA- and 8-Br-cAMP-induced hESC decidualization and significantly reduced the secretion of prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP-1). With the inhibition of Lefty1 expression, hESC decidualization induced by MPA and 8-Br-cAMP became more remarkable, and the secretions of PRL and IGFBP-1 were higher too. Further tests indicated that during the process of decidualization, P57 expression increased, whereas cyclin D1 expression decreased. Although Lefty1 overexpression did not significantly change the expressions of P57 and cyclin D1, inhibition of Lefty1 expression resulted in more evident changes in P57 and cyclin D1 expressions. Meanwhile, cell cycle examination showed that Lefty1 overexpression reduced the cell cycle arrest at G1/S phase in the in vitro hESC decidualization model. Therefore, Lefty1 could regulate the cell cycle via modulating the expressions of P57 and cyclin D1 and then inhibit the decidualization in vitro.

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“…Apparently, this function duality is attributed to the fact that Smads activate different sets of target genes in pluripotent and differentiating cells, depending on its level of activation and the availability of co-factors [83]. Indeed, TGF-ß superfamily ligands, including TGF-ß isoforms, Activin, Nodal, growth and differentiation factors (GDFs), anti-Müllerian hormone (AMH), and BMPs, bind to and activate type I (1-7) and II (1-5) receptor serine/threonine kinases, which in turn, together with activin-receptor like kinases (Alk) (1-7), phosphorylate the regulatory Smad proteins (R-Smad 1, 2, 3, 5, 8) [195].…”

Section: Specific Protein Kinases and Associated Signaling Pathwaymentioning

confidence: 99%

“…The recent comparative receptor tyrosine kinase expression and phosphorylation profiling for hESCs and hiESCs performed by Son et al [80] revealed up-regulation of EPHA1, ERBB-2/EGFR-2, FGFR-4 and VEGFR-2 and down-regulation of AXL, EPHA4, PDGFRß and TYRO3 as related to the maintenance of hESCs. As of yet, the basic PKs signaling framework described in PSCs is defined by Insulin/IGF/FGF/LIF signaling through PI3K [81, 82], TGF-ß/Activin A/Nodal signaling through Smad [83, 84], FGF signaling through the Ras/MAPK/Raf/Mek/Erk pathway [82, 85], and the canonical Wnt/Gsk3 signaling pathway [86, 87]. The JAK/STAT [88] and Src pathways [89] have also a significant impact on this process.…”

Section: General Introduction To Protein Kinases and Pluripotencymentioning

confidence: 99%

Protein Kinases and Associated Pathways in Pluripotent State and Lineage Differentiation

Shoni

Lui

Vavvas

et al. 2014

CSCR

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Protein kinases (PKs) mediate the reversible conversion of substrate proteins to phosphorylated forms, a key process in controlling intracellular signaling transduction cascades. Pluripotency is, among others, characterized by specifically expressed PKs forming a highly interconnected regulatory network that culminates in a finely-balanced molecular switch. Current high-throughput phosphoproteomic approaches have shed light on the specific regulatory PKs and their function in controlling pluripotent states. Pluripotent cell-derived endothelial and hematopoietic developments represent an example of the importance of pluripotency in cancer therapeutics and organ regeneration. This review attempts to provide the hitherto known kinome profile and the individual characterization of PK-related pathways that regulate pluripotency. Elucidating the underlying intrinsic and extrinsic signals may improve our understanding of the different pluripotent states, the maintenance or induction of pluripotency, and the ability to tailor lineage differentiation, with a particular focus on endothelial cell differentiation for anti-cancer treatment, cell-based tissue engineering, and regenerative medicine strategies.

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TGF-beta Family Signaling in Embryonic Stem Cells

Cited by 33 publications

References 41 publications

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

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

Lefty inhibits in vitro decidualization by regulating P57 and cyclin D1 expressions

Protein Kinases and Associated Pathways in Pluripotent State and Lineage Differentiation

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