<scp>PI</scp>3K/Akt pathway regulates retinoic acid‐induced <i>Hox</i> gene expression in F9 cells

Lee, Youra; Lee, Ji-Yeon; Kim, Myoung Hee

doi:10.1111/dgd.12152

Cited by 21 publications

(17 citation statements)

References 45 publications

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“…In addition, this compound completely blocks RALDH2 enzyme expression in human basophils 67 . Furthermore, LY294002 delays at RA-induced expression of certain Hox cluster genes in mouse F9 embryonic carcinoma cells 66 , suggesting a PI3K/Akt-dependent regulation. These findings provide an explanation for the compound's inhibition on the Hoxa1 expression in P19 cells, in which the expression of both Raldh2 and Hoxa1 genes can be significantly induced by retinol 36 .…”

Section: Discussionmentioning

confidence: 94%

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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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Section: Discussionmentioning

confidence: 94%

“…LY294002 inhibits the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway that regulates many cellular processes including at RA-induced cell differentiation 65; 66 . In addition, this compound completely blocks RALDH2 enzyme expression in human basophils 67 .…”

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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“…Furthermore, RA is crucial for temporal control of embryonic development, because embryonic molecular clock genes, such as limb clock hairy2 , are regulated by RA . The PI3K/AKT pathway was also reported to play an essential role in the process of RA‐induced cell differentiation . The PI3K/AKT signalling pathway was shown to also be important for the temporal control of limb development .…”

Section: Discussionmentioning

confidence: 99%

LncRNA‐SULT1C2A regulates Foxo4 in congenital scoliosis by targeting rno‐miR‐466c‐5p through PI3K‐ATK signalling

Chen

Tan

et al. 2019

J Cellular Molecular Medi

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Congenital scoliosis (CS) is the result of anomalous vertebrae development, but the pathogenesis of CS remains unclear. Long non‐coding RNAs (lncRNAs) have been implicated in embryo development, but their role in CS remains unknown. In this study, we investigated the role and mechanisms of a specific lncRNA, SULT1C2A, in somitogenesis in a rat model of vitamin A deficiency (VAD)‐induced CS. Bioinformatics analysis and quantitative real‐time PCR (qRT‐PCR) indicated that SULT1C2A expression was down‐regulated in VAD group, accompanied by increased expression of rno‐miR‐466c‐5p but decreased expression of Foxo4 and somitogenesis‐related genes such as Pax1 , Nkx3‐2 and Sox9 on gestational day (GD) 9. Luciferase reporter and small interfering RNA (siRNA) assays showed that SULT1C2A functioned as a competing endogenous RNA to inhibit rno‐miR‐466c‐5p expression by direct binding, and rno‐miR‐466c‐5p inhibited Foxo4 expression by binding to its 3′ untranslated region (UTR). The spatiotemporal expression of SULT1C2A, rno‐miR‐466c‐5p and Foxo4 axis was dynamically altered on GDs 3, 8, 11, 15 and 21 as detected by qRT‐PCR and northern blot analyses, with parallel changes in Protein kinase B (AKT) phosphorylation and PI3K expression. Taken together, our findings indicate that SULT1C2A enhanced Foxo4 expression by negatively modulating rno‐miR‐466c‐5p expression via the PI3K‐ATK signalling pathway in the rat model of VAD‐CS. Thus, SULT1C2A may be a potential target for treating CS.

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“…이 중 RA는 비타민 A의 유도체로 배아와 중추 신경계의 발달에 관 여하며 상피 조직의 성장과 분화를 조절하는 중요한 형태형성 인자(morphogen)이다 [4,22]. 또한 배자의 발생 과정 중 세포 수명 등 다양한 생물학적 기능을 조절하는 중요한 역할을 한 다 [13] …”

Section: 서 론unclassified

Histone Methylation Regulates Retinoic Acid-induced <sub>Hoxc</sub> Gene Expression in F9 EC Cells

Min¹,

Kim²

2015

Journal of Life Science

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Hox genes encode a highly conserved family of homeodomain-containing transcription factors controlling vertebrate pattern formation along the anteroposterior body axis during embryogenesis. Retinoic acid (RA) is a key morphogen in embryogenesis and a critical regulator of both adult and embryonic cellular activity. Specifically, RA regulates Hox gene expression in mouse-or human-derived embryonic carcinoma (EC) cells. Histone modification has been reported to play a pivotal role in the process of RA-induced gene expression and cell differentiation. As histone modification is thought to play an essential role in RA-induced Hox gene expression, we examined RA-induced initiation of collinear expression of Hox genes and the corresponding histone modifications in F9 murine embryonic teratocarcinoma (EC) cells. Hox expression patterns and histone modifications were analyzed by semiquantitative RT-PCR, RNA-sequencing, and chromatin immuno-precipitation (ChIP)-PCR analyses. The Hoxc4 gene (D0) was initiated earlier than the Hoxc5 to -c10 genes (D3) upon RA treatment (day 0 [D0], day 1 [D1], and day 3 [D3]). The Hox nonexpressing D0 sample had a strong repressive marker, H3K27me3, than the D1 and D3 samples. In the D1 and D3 samples, reduced enrichment of the H3K27me3 marker was observed in the whole cluster. The active H3K4me3 marker was closely associated with the collinear expression of Hoxc genes. Thus, the Hoxc4 gene (D1) and all Hoxc genes (D3) expressed H3K4me3 upon transcription activation. In conclusion, these data indicated that removing H3K27me3 and acquiring H3K4me3 regulated RA-induced Hoxc gene collinearity in F9 cells.Key words : F9 EC cells, histone modification, Hoxc cluster, RA, retinoic acid *Corresponding author *Tel : +82-2-2228-1647, Fax : +82-2-365-0700 *E-mail : mhkim1@yuhs.ac This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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PI3K/Akt pathway regulates retinoic acid‐induced Hox gene expression in F9 cells

Cited by 21 publications

References 45 publications

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

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

LncRNA‐SULT1C2A regulates Foxo4 in congenital scoliosis by targeting rno‐miR‐466c‐5p through PI3K‐ATK signalling

Histone Methylation Regulates Retinoic Acid-induced <sub>Hoxc</sub> Gene Expression in F9 EC Cells

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