Magnesium-sensitive upstream ORF controls PRL phosphatase expression to mediate energy metabolism

Hardy, Serge; Kostantin, Elie; Wang, Shan Jin; Hristova, Tzvetena; Galicia-Vázquez, Gabriela; Baranov, Pavel V.; Tremblay, Michel L.

doi:10.1073/pnas.1815361116

Cited by 48 publications

(70 citation statements)

References 61 publications

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“…For example, decreased intracellular Mg 2+ levels suppress cell cycle progression and are consequently associated with cell growth impairment [2]. Recent studies therefore have focused on intracellular Mg 2+ concentration as a central mechanism for cellular metabolism and proliferation [3].…”

Section: Introductionmentioning

confidence: 99%

“…Intracellular Mg 2+ and ATP levels are closely associated, as ATP must be bound to this cation to be biologically active[1]. Indeed, previous studies have shown that PRL-2 knockdown and decreased intracellular Mg 2+ levels, reduce intracellular ATP levels and regulate cellular metabolism[3][57].Given that ARL15 overexpression reduced CNNM-mediated Mg 2+ uptake, the expression of ARL15 may indirectly regulate cellular metabolism. Indeed, ARL15 has been associated with a wide range of metabolic parameters and diseases in GWAS, including adiponectin, HDL, diabetes mellitus and body shape[58][59][60][61][62][63].As these studies did not analyze Mg 2+ status as a modifying factor, it cannot be excluded that ARL15 has additional functions that explain these associations.…”

mentioning

confidence: 99%

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ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

Zolotarov

González‐Recio

Hardy

et al. 2020

Preprint

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Cyclin M (CNNM1-4) proteins maintain cellular and body magnesium (Mg2+) homeostasis. Using various biochemical approaches, we have identified members of the CNNM family as direct interacting partners of ADP-ribosylation factor-like protein 15 (ARL15), a small GTP-binding protein. ARL15 interacts with CNNMs at their carboxyl-terminal conserved cystathionine-β-synthase (CBS) domains. In silico modeling of the interaction using the reported structures of both CNNM2 and ARL15 supports that the small GTPase specifically binds the CBS1 domain. Immunocytochemical experiments demonstrate that CNNM2 and ARL15 co-localize in the kidney, with both proteins showing subcellular localization in the Golgi-apparatus. Most importantly, we found that ARL15 is required for forming complex N-glycosylation of CNNMs. Overexpression of ARL15 promotes complex N-glycosylation of CNNM3. Mg2+ uptake experiments with a stable isotope demonstrate that there is a significant increase of 25Mg2+ uptake upon knockdown of ARL15 in multiple kidney cancer cell lines. Altogether, our results establish ARL15 as a novel negative regulator of Mg2+ transport by promoting the complex N-glycosylation of CNNMs.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

Zolotarov

González‐Recio

Hardy

et al. 2020

Preprint

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“…26,27 A recent study reported the dysregulation of uORF in tumors and its important regulatory role in tumorigenesis. 28 In this study, TFAP4-66aa-uORF was downregulated in glioma tissues and in glioma cells. Overexpression of TFAP4-66aa-uORF inhibited the malignant biological behavior of glioma cells.…”

Section: Discussionmentioning

confidence: 53%

“…Its primary function is to regulate the translation of the mRNA CDS region . A recent study reported the dysregulation of uORF in tumors and its important regulatory role in tumorigenesis . In this study, TFAP4‐66aa‐uORF was downregulated in glioma tissues and in glioma cells.…”

Section: Discussionmentioning

confidence: 56%

Transcription factor AP‐4 (TFAP4)‐upstream ORF coding 66 aa inhibits the malignant behaviors of glioma cells by suppressing the TFAP4/long noncoding RNA 00520/microRNA‐520f‐3p feedback loop

et al. 2020

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Upstream ORF (uORF) is a translational initiation element located in the 5′UTR of eukaryotic mRNAs. Studies have found that uORFs play an important regulatory role in many diseases. Based on The Cancer Genome Atlas database, the results of our experiments and previous research evidence, we investigated transcription factor AP‐4 (TFAP4) and its uORF, LIM and SH3 protein 1 (LASP1), long noncoding RNA 00520 (LINC00520), and microRNA (miR)‐520f‐3p as candidates involved in glioma malignancy, which is a poorly understood process. Both TFAP4‐66aa‐uORF and miR‐520f‐3p were downregulated, and TFAP4, LASP1, and LINC00520 were highly expressed in glioma tissues and cells. TFAP4‐66aa‐uORF or miR‐520f‐3p overexpression or TFAP4, LASP1, or LINC00520 knockdown inhibited glioma cell proliferation, migration, and invasion, but promoted apoptosis. TFAP4‐66aa‐uORF inhibited the translation of TFAP4 by binding to the TFAP4 mRNA. MicroRNA‐520f‐3p inhibited TFAP4 expression by binding to its 3′UTR. However, LINC00520 could promote the expression of TFAP4 by competitively binding to miR‐520f‐3p. In addition, TFAP4 transcriptionally activated LASP1 and LINC00520 expression by binding to their promoter regions, forming a positive feedback loop of TFAP4/LINC00520/miR‐520f‐3p. Our findings together indicated that TFAP4‐66aa‐uORF inhibited the TFAP4/LINC00520/miR‐520f‐3p feedback loop by directly inhibiting TFAP4 expression, subsequently leading to inhibition of glioma malignancy. This provides a basis for developing new therapeutic approaches for glioma treatment.

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“…CPuORF 38 , as a positive control. Besides the PTP4A1 CPuORF, we selected CPuORFs with well-conserved C-terminal regions.…”

Section: Sequence-dependent Effects Of Cpuorfs On Morf Translationmentioning

confidence: 99%

Exhaustive identification of conserved upstream open reading frames with potential translational regulatory functions from animal genomes

Takahashi

Miyaki

Onouchi

et al. 2019

Preprint

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28Background: Upstream open reading frames (uORFs) are located in the 5′-untranslated regions of many 29 eukaryotic mRNAs, and some peptides encoded in these regions play important regulatory roles in controlling 30 main ORF (mORF) translation. To comprehensively identify uORFs encoding functional peptides, genome-wide 31 searches for uORFs with conserved peptide sequences (CPuORFs) have been conducted in various organisms 32 using comparative genomic approaches. However, in animals, CPuORFs have been identified only by comparing 33 uORF sequences between a limited number of closely related species, and it is unclear how many previously 34identified CPuORFs encode regulatory peptides. 35Results: Here, we conducted exhaustive genome-wide searches for animal CPuORFs conserved in various 36 taxonomic ranges, using the ESUCA pipeline, which we recently developed for efficient comprehensive 37 identification of CPuORFs. ESUCA can efficiently compare uORF sequences between an unlimited number of 38 species using BLAST and automatically determine the taxonomic ranges of sequence conservation for each 39CPuORF. By applying ESUCA to human, chicken, zebrafish, and fruit fly genomes, 1,430 (1,339 novel and 91 40 known) CPuORFs were identified. We examined the effects of 14 human CPuORFs on mORF translation using 41 a transient expression assay. Through this analysis, we identified six novel regulatory CPuORFs that repressed 42 mORF translation in a sequence-dependent manner, all of which were conserved beyond Amniota. 43 Conclusions:We discovered a much higher number of animal CPuORFs than previously identified. 44Furthermore, our results suggest that human CPuORFs conserved beyond Amniota are more likely to encode 45 regulatory peptides than those conserved in narrower taxonomic ranges. 46 47 -3 -Determination of the taxonomic range of uORF sequence conservation for animal CPuORFs 104

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Magnesium-sensitive upstream ORF controls PRL phosphatase expression to mediate energy metabolism

Cited by 48 publications

References 61 publications

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

Transcription factor AP‐4 (TFAP4)‐upstream ORF coding 66 aa inhibits the malignant behaviors of glioma cells by suppressing the TFAP4/long noncoding RNA 00520/microRNA‐520f‐3p feedback loop

Exhaustive identification of conserved upstream open reading frames with potential translational regulatory functions from animal genomes

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