Forkhead Transcription Factor 3a (FOXO3a) Modulates Hypoxia Signaling via Up-regulation of the von Hippel-Lindau Gene (VHL)

Liu, Xing; Cai, Xiaolian; Hu, Bo; Mei, Zhichao; Zhang, Dawei; Ouyang, Gang; Wang, Jing; Zhang, Wei; Xiao, Wuhan

doi:10.1074/jbc.m116.745471

Cited by 31 publications

(28 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S3B). Moreover, several reports have suggested that the function of FOXO3 is relevant to a hypoxic condition (13)(14)(15). Based on these findings, we postulated that hypoxia has a positive effect on construction of the dormant state in oocytes.…”

Section: Induction Of the Dormant State By Forced Expression Of Constmentioning

confidence: 56%

Hypoxia induces the dormant state in oocytes through expression of Foxo3

Shimamoto

Nishimura

Nagamatsu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

In mammals, most immature oocytes remain dormant in the primordial follicles to ensure the longevity of female reproductive life. A precise understanding of mechanisms underlying the dormancy is important for reproductive biology and medicine. In this study, by comparing mouse oogenesis in vivo and in vitro, the latter of which bypasses the primordial follicle stage, we defined the gene-expression profile representing the dormant state of oocytes. Overexpression of constitutively active FOXO3 partially reproduced the dormant state in vitro. Based on further geneexpression analysis, we found that a hypoxic condition efficiently induced the dormant state in vitro. The effect of hypoxia was severely diminished by disruption of the Foxo3 gene and inhibition of hypoxia-inducible factors. Our findings provide insights into the importance of environmental conditions and their effectors for establishing the dormant state. oocytes | hypoxia | Foxo3

show abstract

Section: Induction Of the Dormant State By Forced Expression Of Constmentioning

confidence: 56%

Hypoxia induces the dormant state in oocytes through expression of Foxo3

Shimamoto

Nishimura

Nagamatsu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…hypoxia tolerance) remain largely unknown. Recent work in our laboratory has shown that hypoxia tolerance involves the hypoxiainducible factor (HIF) 2 signaling pathway, but the molecular mechanisms involved require further exploration (10,11).…”

mentioning

confidence: 99%

Deletion of the fih gene encoding an inhibitor of hypoxia-inducible factors increases hypoxia tolerance in zebrafish

Cai

Zhang

Wang

et al. 2018

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Many aerobic organisms have developed molecular mechanism to tolerate hypoxia, but the specifics of these mechanisms remain poorly understood. It is important to develop genetic methods that confer increased hypoxia tolerance to intensively farmed aquatic species, as these are maintained in environments with limited available oxygen. As an asparaginyl hydroxylase of hypoxia-inducible factors (HIFs), factor inhibiting HIF (FIH) inhibits transcriptional activation of hypoxia-inducible genes by blocking the association of HIFs with the transcriptional coactivators CREB-binding protein (CBP) and p300. Therefore, here we sought to test whether is involved in regulating hypoxia tolerance in the commonly used zebrafish model. Overexpressing the zebrafish gene in epithelioma papulosum cyprini (EPC) cells and embryos, we found that inhibits the transcriptional activation of zebrafish HIF-α proteins. Using CRISPR/Cas9 to obtain-null zebrafish mutants, we noted that the deletion makes zebrafish more tolerant of hypoxic conditions than their WT siblings, but does not result in oxygen consumption rates that significantly differ from those of WT fish. Of note, we identified fewer apoptotic cells in adult-null zebrafish brains and in -null embryos, possibly explaining why the-null mutant had greater hypoxia tolerance than the WT. Moreover, the deletion up-regulated several hypoxia-inducible genes in-null zebrafish exposed to hypoxia. The findings of our study suggest that plays a role in hypoxia tolerance by affecting the rate of cellular apoptosis in zebrafish.

show abstract

“…S5C). To test if Foxo3b upregulation contributes to EJC mutant phenotypes, we obtained a previously described foxo3b null allele, foxo3b ihb404 (47, 48), generated magoh; foxo3b and rbm8a; foxo3b doubly heterozygous adults, and examined muscle and motor neuron development in single, double, and compound mutant embryos. As expected, motor axon outgrowth in foxo3b mutant embryos is indistinguishable from wild-type siblings (data not shown); in contrast, as noted above, motor axons barely extend beyond the horizontal myoseptum in EJC mutant embryos (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This gene encodes a forkhead box transcription factor that acts as a hub for integration of several stress stimuli, and functions in processes such as cell cycle, apoptosis, and autophagy (61, 62). In zebrafish, Foxo3b contributes to survival under hypoxic stress (48), and negatively regulates antiviral responses (47) as well as the canonical wnt signaling pathway (63). FOXO3, the mammalian ortholog of Foxo3b, physically interacts with p53, and both act synergistically to induce apoptosis in response to stress (64).…”

Section: Discussionmentioning

confidence: 99%

Stop codon-proximal 3′UTR introns in vertebrates can elicit EJC-dependent Nonsense-Mediated mRNA Decay

Gangras

Patton

et al. 2019

Preprint

View full text Add to dashboard Cite

17The Exon Junction Complex (EJC) regulates many steps in post-transcriptional gene 18 expression and is essential for cellular function and organismal development; however, 19 EJC-regulated genes and genetic pathways during development remain largely 20 unknown. To study EJC function during zebrafish development, we first established that 21 zebrafish EJCs mainly bind ~24 nucleotides upstream of exon-exon junctions, and are 22 also detected at more distant non-canonical positions. We then generated mutations in 23 two zebrafish EJC core genes, rbm8a and magoh, and observed that homozygous 24 mutant embryos show paralysis, muscle disorganization, neural cell death, and motor 25 neuron outgrowth defects. Coinciding with developmental defects, mRNAs subjected to 26 Nonsense-Mediated mRNA Decay (NMD) due to translation termination ≥ 50 nts 27 upstream of the last exon-exon junction are upregulated in EJC mutant embryos.28 Surprisingly, several transcripts containing 3′UTR introns (3′UI) < 50 nts downstream of 29 a stop codon are also upregulated in EJC mutant embryos. These proximal containing transcripts are also upregulated in NMD-compromised zebrafish embryos, 31 cultured human cells, and mouse embryonic stem cells. Loss of function of foxo3b, one 32 of the upregulated proximal 3′UI-containing genes, partially rescues EJC mutant motor 33 neuron outgrowth. In addition to foxo3b, 166 other genes contain a proximal 3′UI in 34 zebrafish, mouse and humans, and these genes are enriched in nervous system 35 development and RNA binding functions. A proximal 3′UI-containing 3′UTR from one of 36 these genes, HNRNPD, is sufficient to reduce steady state transcript levels when fused 37 to a β-globin reporter in HeLa cells. Overall, our work shows that genes with stop 38 codon-proximal 3′UIs encode a new class of EJC-regulated NMD targets with critical 39 roles during vertebrate development.40 84 suggesting that 3′UIs may play an important role in regulating tissue-specific 85 developmental programs via EJC-dependent NMD. However, specific mRNAs, genetic 86 5 pathways, and developmental events that are regulated by 3′UI-dependent NMD 87 remain largely unknown. 88In this work, we establish zebrafish as a model to study EJC developmental 89 functions. As expected from work in human cells, we show that in zebrafish embryos 90 the EJC mainly binds ~24 nts upstream of exon-exon junctions and is also detected on 91 more distant exonic positions. Zebrafish Rbm8a and Magoh are crucial for early 92 zebrafish embryonic development, with muscle and neural lineages being particularly 93 sensitive to the loss of EJC. We find that EJC-dependent NMD is disrupted in rbm8a 94 and magoh mutant embryos. Strikingly, we uncover a class of genes that contain a stop 95 codon-proximal 3′UI (intron within 50 nts of the stop codon) and are upregulated in 96 zebrafish EJC mutant embryos and upf1 morphants. We show that loss of foxo3b, a 97 proximal 3′UI-containing gene whose transcript and protein levels are elevated in EJC 98 mutants, partially...

show abstract

Forkhead Transcription Factor 3a (FOXO3a) Modulates Hypoxia Signaling via Up-regulation of the von Hippel-Lindau Gene (VHL)

Cited by 31 publications

References 62 publications

Hypoxia induces the dormant state in oocytes through expression of Foxo3

Hypoxia induces the dormant state in oocytes through expression of Foxo3

Deletion of the fih gene encoding an inhibitor of hypoxia-inducible factors increases hypoxia tolerance in zebrafish

Stop codon-proximal 3′UTR introns in vertebrates can elicit EJC-dependent Nonsense-Mediated mRNA Decay

Contact Info

Product

Resources

About