Retinoic acid activation of the ERK pathway is required for embryonic stem cell commitment into the adipocyte lineage

Bost, Fréd́eric; Caron, Leslie; Marchetti, Irène; Dani, Christian; Marchand-Brustel, Y. Le; Binétruy, Bernard

doi:10.1042/0264-6021:3610621

Cited by 109 publications

(60 citation statements)

References 46 publications

(13 reference statements)

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“…Under these conditions large clusters of mature adipocytes are present in 70 to 80% of the embryoid bodies. Our laboratory has investigated the role of the ERK pathway during ES cell commitment into the adipocyte lineage [17]. We showed that retinoic acid activates the ERK pathway, and not the other MAPK pathways, in embryoid bodies during early events of adipocyte differentiation.…”

Section: The Erk Pathway In Adipogenesis: the Model Of Embryonic Stemmentioning

confidence: 99%

The role of MAPKs in adipocyte differentiation and obesity

et al. 2005

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that is activated and on the cellular model analysed. In addition, the duration of the stimulus can also affect the cellular response. A wide panel of different stimuli are capable to activate the MAPK pathways, but a good correlation has been found between the types of stimulus and the function assigned to the pathway. Schematically, ERK is preferentially activated by mitogens such as the serum or growth factors and, accordingly, this pathway is an important regulator of cell cycle and cell proliferation. p38 and JNK are more responsive to various stress stimuli from UV to cytokines and they have been involved in apoptosis and/or in the response to cellular stresses. Because they have been extensively studied (see for reviews [2] [3]), these general aspects will not be detailed in this review, except for their specific relevance towards adipogenesis.Regarding the process of differentiation, the role of MAPKs is extremely complex and depends on multiple parameters. The complexity is due, firstly, to the biological process itself, which, most of the time, involves different successive steps. Furthermore, each of these steps can be modulated by MAPKs leading, sometimes, to opposite effects. Probably because this complexity renders experimental models extremely sensitive, most of the tools used for Because of its essential role in cell proliferation and the fact that adipogenic stimuli, such as insulin, activate the ERK pathway, the role of this pathway in normal and pathological adipogenesis has been intensively investigated the last decade. Indeed, obesity is due to the hypertrophy of adipocytes and to the recruitment of new adipocytes from precursor cells, two processes largely dependent on regulation of adipocyte differentiation. In addition, obesity is associated with insulin resistance both in experimental models and in humans, and the role of adipose tissue and, consequently, of adipocyte differentiation is important in this pathology. Although the implication of MAPKs in insulin resistance is largely documented, our review does not discuss this aspect in details because Gual et al. review it in this series.Although much of the knowledge originates from analysis of preadipocyte cell lines, such as 3T3-L1 or 3T3-F442A, various cellular models are now available; they are summarized in figure 2.

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Section: The Erk Pathway In Adipogenesis: the Model Of Embryonic Stemmentioning

confidence: 99%

The role of MAPKs in adipocyte differentiation and obesity

et al. 2005

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“…Furthermore, major cell signaling pathways have been shown to mediate some of the effects of RA in ES and human cancer cells (Frédéric et al, 2002; Pettersson et al, 2004; Kogai et al, 2008; reviewed by Niles, 2004). Our antibody microarray analyses indicated that cells treated with a combination of RA plus AC expressed members of the p38/MAPK and PI3K/AKT pathways in a differential manner as compared to cells treated with RA only, which suggests their involvement on the induction of ES to endodermal differentiation by RARβ2.…”

Section: Discussionmentioning

confidence: 99%

RARβ2-dependent signaling represses neuronal differentiation in mouse ES cells

Kona

Shrestha

et al. 2017

Differentiation

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Embryonic Stem (ES) cells are pluripotent cells that can be induced to differentiate into cells of all three lineages: mesoderm, endoderm, and ectoderm. In culture, ES cells can be differentiated into mature neurons by treatment with Retinoic Acid (RA) and this effect is mediated mainly through the activation of the RA nuclear receptors (RAR α, β, and γ), and their isoforms. However, little is known about the role played by specific RAR types on ES cell differentiation. Here, we found that treatment of ES cells with AC55649, an RARβ2 agonist, increased endodermal marker gene expression. On the other hand, we found that the inhibition of RARβ with 5 μM LE135, together with RA treatment, increased the efficiency of mouse ES cell differentiation into neurons by more than 4-fold as compared to cells treated with RA only. Finally, we performed proteomic analyses on ES cells treated with RA vs RA plus AC55649 in order to identify the signaling pathways activated by the RARβ agonist. Our proteomic analyses using antibody microarrays indicated that proteins such as p38 and AKT were upregulated in cells treated with RA plus the agonist, as compared to cells treated with RA alone. Our results indicate that RARβ may function as a repressor of neuronal differentiation through the activation of major cell signaling pathways, and that the pharmacological inhibition of this nuclear receptor may constitute a novel method to increase the efficiency of ES to neuronal differentiation in culture.

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“…PD98059, a selective inhibitor of the mitogen-activated protein kinase kinase (MAPKK/MEK) in the MAPK pathway 55 , inhibits at RA-induced MAPK activation 56 and cell differentiation 57 . In addition, MAPK activation increases the expression of the Raldh2 58 gene that encodes the enzyme responsible for the conversion of RAL to at RA and therefore, PD98059 can inhibit MAPK-induced at RA biosynthesis 59 .…”

Section: Discussionmentioning

confidence: 99%

Identification of compounds that modulate retinol signaling using a cell-based qHTS assay

Chen

Sakamuru

Huang

et al. 2016

Toxicology in Vitro

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In vertebrates, the retinol (vitamin A) signaling pathway (RSP) controls the biosynthesis and catabolism of all-trans retinoic acid (atRA), which regulates transcription of genes essential for embryonic development. Chemicals that interfere with the RSP to cause abnormal intracellular levels of atRA are potential developmental toxicants. To assess chemicals for the ability to interfere with retinol signaling, we have developed a cell-based RARE (Retinoic Acid Response Element) reporter gene assay to identify RSP disruptors. To validate this assay in a quantitative high-throughput screening (qHTS) platform, we screened the Library of Pharmacologically Active Compounds (LOPAC) in both agonist and antagonist modes. The screens detected known RSP agonists, demonstrating assay reliability, and also identified novel RSP agonists including kenpaullone, niclosamide, PD98059 and SU4312, and RSP antagonists including Bay 11-7085, LY294002, 3,4-Methylenedioxy-β-nitrostyrene, and topoisomerase inhibitors (camptothecin, topotecan, amsacrine hydrochloride, and idarubicin). When evaluated in the P19 pluripotent cell, these compounds were found to affect the expression of the Hoxa1 gene that is essential for embryo body patterning. These results show that the RARE assay is an effective qHTS approach for screening large compound libraries to identify chemicals that have the potential to adversely affect embryonic development through interference with retinol signaling.

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Retinoic acid activation of the ERK pathway is required for embryonic stem cell commitment into the adipocyte lineage

Cited by 109 publications

References 46 publications

The role of MAPKs in adipocyte differentiation and obesity

The role of MAPKs in adipocyte differentiation and obesity

RARβ2-dependent signaling represses neuronal differentiation in mouse ES cells

Identification of compounds that modulate retinol signaling using a cell-based qHTS assay

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