Retinoic acid inhibits leukemia inhibitory factor signaling pathways in mouse embryonic stem cells

Tighe, Ann P.; Gudas, Lorraine J.

doi:10.1002/jcp.10424

Cited by 48 publications

(31 citation statements)

References 35 publications

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“…This result clearly suggests that hypoxia down-regulates the expression of LIFR, an upstream signaling receptor involved in STAT3 activation. In accordance with the previous report (17), retinoic acid, a well known differentiation factor, also inhibited LIFR expression in our culture conditions (Fig. 2D), further supporting that hypoxia induces mESC differentiation through down-regulation of LIFR.…”

Section: Resultssupporting

confidence: 93%

Hypoxia-inducible Factor-1α Inhibits Self-renewal of Mouse Embryonic Stem Cells in Vitro via Negative Regulation of the Leukemia Inhibitory Factor-STAT3 Pathway

Jeong

Cha

et al. 2007

Journal of Biological Chemistry

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During mammalian embryogenesis, the early embryo grows in a relatively hypoxic environment due to a restricted supply of oxygen. The molecular mechanisms underlying modulation of self-renewal and differentiation of mouse embryonic stem cells (mESCs) under such hypoxic conditions remain to be established. Here, we show that hypoxia inhibits mESC self-renewal and induces early differentiation in vitro, even in the presence of leukemia inhibitory factor (LIF). These effects are mediated by down-regulation of the LIF-STAT3 signaling pathway. Under conditions of hypoxia, hypoxia-inducible factor-1␣ (HIF-1␣) suppresses transcription of LIF-specific receptor (LIFR) by directly binding to the reverse hypoxia-responsive element located in the LIFR promoter. Ectopic expression and small interference RNA knockdown of HIF-1␣ verified the inhibitory effect on LIFR transcription. Our findings collectively suggest that hypoxia-induced in vitro differentiation of mESCs is triggered, at least in part, by the HIF-1␣-mediated suppression of LIF-STAT3 signaling. Analysis of mESCs2 isolated from the inner cell mass of preimplantation embryos has aided in elucidating the early molecular events and mechanisms responsible for maintenance of ESC pluripotency (1). In contrast to human ESCs (hESCs), selfrenewal of mESCs can be sustained indefinitely in feeder-free conditions if supplemented with LIF (2). mESC lines can be derived directly from embryos in the presence of LIF, indicating that this factor is specifically required for the maintenance of pluripotency. Intracellular signaling cascades initiated by LIF are mediated through the heterodimerization of LIFR and glycoprotein 130 (gp130). This complex activates Janus-associated tyrosine kinase and the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Activation of STAT3 by LIF is crucial in mediating self-renewal signals in mESCs (3, 4).During mammalian development, oxygen needed for cellular metabolism in the early embryo is supplied by simple diffusion from fluids within the oviduct and uterus. Thus, the early embryo develops in a relatively hypoxic environment until the onset of vascularization after implantation (5). Actually, oxygen tension in the mammalian reproductive tract is reported to be less than half the atmospheric oxygen tension (6). Low oxygen tension triggers a wide range of cellular events centered on the regulation of hypoxia-inducible factor-1 (HIF-1) (7), which consists of a common ␤ subunit (HIF-1␤) and an oxygen-sensitive ␣ subunit (HIF-1␣). Under normoxia, HIF-1␣ is rapidly degraded via the von Hippel-Lindau protein-mediated ubiquitin-proteasome pathway (8). Although the role and biological relevance of HIF-1 during murine embryonic development have been established (9 -11), our understanding of how HIF-1 affects the early differentiation of mESCs at the molecular level is beginning to emerge.Our previous study demonstrated the presence of hypoxic regions during normal mouse development (12), which prompted us to study the role of hy...

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Section: Resultssupporting

confidence: 93%

Hypoxia-inducible Factor-1α Inhibits Self-renewal of Mouse Embryonic Stem Cells in Vitro via Negative Regulation of the Leukemia Inhibitory Factor-STAT3 Pathway

Jeong

Cha

et al. 2007

Journal of Biological Chemistry

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“…In addition, our laboratory has demonstrated that RA can override the self-renewing effects of LIF on ES cells, partially by down-regulating the expression of the LIF receptor (LIFR) (34,96). Because higher levels of Oct3/4 mRNA expression after RA treatment were observed in Hoxa1 Ϫ/Ϫ ES cells than in the other ES cell lines, we hypothesized that Hoxa1 may be involved in the RA-induced differentiation of ES cells grown in monolayer.…”

Section: Expression Of the Es Stem Cell Markers Fgf4 Oct3/4 And Rexmentioning

confidence: 99%

Differences in Gene Expression between Wild Type and Hoxa1 Knockout Embryonic Stem Cells after Retinoic Acid Treatment or Leukemia Inhibitory Factor (LIF) Removal

Martinez‐Ceballos

Chambon

Gudas

2005

Journal of Biological Chemistry

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Homeobox (Hox) genes encode a family of transcription factors that regulate embryonic patterning and organogenesis. In embryos, alterations of the normal pattern of Hox gene expression result in homeotic transformations and malformations. Disruption of the Hoxa1 gene, the most 3 member of the Hoxa cluster and a retinoic acid (RA) direct target gene, results in abnormal ossification of the skull, hindbrain, and inner ear deficiencies, and neonatal death. We have generated Hoxa1 genes positioned at the 3Ј-end are expressed earlier and more anterior, whereas 5Ј-end genes are expressed at later times and more posterior (reviewed in Refs. 1 and 5). Colinear gene expression from these Hox gene clusters may involve an initial change in chromatin structure (histone modification and chromatin decondensation) of the entire loci, which would then facilitate the programmed expression of genes along the clusters by a progressive 3Ј to 5Ј change in higher order chromatin structure (6). Treatment of teratocarcinoma cells or embryonic stem cells with retinoic acid (RA), which acts via the retinoic acid receptors (RAR␣, -␤, and -␥ and their isoforms (reviewed in Refs. 7 and 8), results in the sequential activation of several Hox genes in a manner that resembles their positions in the clusters, e.g. 3Ј genes are activated before 5Ј genes (7-9). Moreover, our laboratory discovered the presence of a retinoic acid response element (RARE) in the 3Ј enhancer of the Hoxa1 gene (10 -13). This RARE is also functional in transgenic mice (14 -16). We also demonstrated that unlike F9 Wt cells, F9 RAR␥ Ϫ/Ϫ cells fail to express the Hoxa1 gene in response to RA (17). Alterations in the normal pattern of Hox gene expression in embryos result in homeotic transformations and malformations, and frequently, in perinatal lethality (3,18). For instance, the targeted inactivation in mice of both alleles of the most 3Ј member of the Hoxa cluster, the Hoxa1 gene, leads to numerous developmental defects, including hindbrain deficiencies and abnormal skull ossification, and ultimately, to neonatal death (19 -22). Numerous studies have demonstrated that the hindbrain defects in Hoxa1 Ϫ/Ϫ mice result in part from the failure of Hoxb1 to reach its anterior limit of expression at the presumptive rhombomere 3/rhombomere 4 (r3/4) boundary, which initiates a cascade of gene misexpression that results in the misspecification of the hindbrain compartments from r2 to r5 (23-26). Furthermore, the ectopic expression of Hoxa1 in transgenic mice leads to the ectopic activation of Hoxb1 in r2, produces anterior abnormalities, including the reorganization of the developing hindbrain, and ultimately results in embryonic death (27). These observations highlight the importance of the Hoxa1 gene and suggest that the regulatory effects of retinoids on cell growth and on embryonic patterning may be * This work was supported by National Institutes of Health Grants R01CA43796 (to L. J. G.) and UR 2U19HDO35466. The costs of publication of this article were defrayed in part by th...

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“…Currently, the effector molecules and cascade signaling of the early retinoid signaling in the vertebrate embryo are barely known. Mechanistic studies showed that RA is not just initiating the differentiation, but also actively decrease the pluripotency via binding to RARE in Oct3/4 promoter (Pikarsky, Sharir et al 1994) and regulation of LIF-signaling (Tighe and Gudas 2004). Indeed, Oct3/4 is not changing significantly between day 0 and day 4 in our data, but it is actively down-regulated following RA-treatment.…”

Section: Retinoic Acid Induced Downregulation Of Stem Cell Pluripotenmentioning

confidence: 48%

Retinoid Signaling is a Context-Dependent Regulator of Embryonic Stem Cells

Simándi¹,

Nagy²

2011

Embryonic Stem Cells - Differentiation and Pluripotent Alternatives

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Retinoic acid inhibits leukemia inhibitory factor signaling pathways in mouse embryonic stem cells

Cited by 48 publications

References 35 publications

Hypoxia-inducible Factor-1α Inhibits Self-renewal of Mouse Embryonic Stem Cells in Vitro via Negative Regulation of the Leukemia Inhibitory Factor-STAT3 Pathway

Hypoxia-inducible Factor-1α Inhibits Self-renewal of Mouse Embryonic Stem Cells in Vitro via Negative Regulation of the Leukemia Inhibitory Factor-STAT3 Pathway

Differences in Gene Expression between Wild Type and Hoxa1 Knockout Embryonic Stem Cells after Retinoic Acid Treatment or Leukemia Inhibitory Factor (LIF) Removal

Retinoid Signaling is a Context-Dependent Regulator of Embryonic Stem Cells

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