Competition between RNA-binding proteins CELF1 and HuR modulates MYC translation and intestinal epithelium renewal

Liu, Lan; Ouyang, Ming; Rao, Jaladanki N.; Zou, Tongtong; Xiao, Lan; Chung, Hee Kyoung; Wu, Jing; Donahue, James M.; Gorospe, Myriam; Wang, Jianying

doi:10.1091/mbc.e14-11-1500

Cited by 80 publications

(102 citation statements)

References 63 publications

(112 reference statements)

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“…Interestingly, the Cyp19a1 3= UTR represses the expression of the reporter gene at the protein level in a CELF1-dependent manner, but not at the mRNA level. This suggests that CELF1 represses the translation of Cyp19a1, in accordance with known properties of CELF1 (10,(16)(17)(18)(19). These results in HeLa cells seem to contradict the in vivo results, as we detected high levels of Cyp19a1 mRNA in Celf1 Ϫ/Ϫ testes (Fig.…”

Section: Discussionsupporting

confidence: 55%

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Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice

Boulanger

Cibois

Viet

et al. 2015

Molecular and Cellular Biology

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CELF1 is a multifunctional RNA-binding protein that controls several aspects of RNA fate. The targeted disruption of the Celf1 gene in mice causes male infertility due to impaired spermiogenesis, the postmeiotic differentiation of male gametes. Here, we investigated the molecular reasons that underlie this testicular phenotype. By measuring sex hormone levels, we detected low concentrations of testosterone in Celf1-null mice. We investigated the effect of Celf1 disruption on the expression levels of steroidogenic enzyme genes, and we observed that Cyp19a1 was upregulated. Cyp19a1 encodes aromatase, which transforms testosterone into estradiol. Administration of testosterone or the aromatase inhibitor letrozole partly rescued the spermiogenesis defects, indicating that a lack of testosterone associated with excessive aromatase contributes to the testicular phenotype. In vivo and in vitro interaction assays demonstrated that CELF1 binds to Cyp19a1 mRNA, and reporter assays supported the conclusion that CELF1 directly represses Cyp19a1 translation. We conclude that CELF1 downregulates Cyp19a1 (Aromatase) posttranscriptionally to achieve high concentrations of testosterone compatible with spermiogenesis completion. We discuss the implications of these findings with respect to reproductive defects in men, including patients suffering from isolated hypogonadotropic hypogonadism and myotonic dystrophy type I.

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Section: Discussionsupporting

confidence: 55%

“…In the nucleus, it controls pre-mRNA alternative splicing (11,12). In the cytoplasm, it targets bound mRNAs for rapid decay (13,14) and/or modulates their translation (15)(16)(17)(18)(19). The cytoplasmic functions are probably mediated by interactions with molecular partners, like the poly(A) nuclease PARN (20) or the translation initiation complex eIF2 (21).…”

mentioning

confidence: 99%

Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice

Boulanger

Cibois

Viet

et al. 2015

Molecular and Cellular Biology

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“…However, when single IGF2BP3 binding sites were deleted in the MYC and CDK6 3′UTR, the majority of these deletions failed to reverse the phenotype in the reporter assay. The complexity of 3′UTR targeting is illustrated by the variety of RBPs and noncoding RNAs that have been reported to bind to the MYC and CDK6 3′UTRs (46)(47)(48)(49). Hence, RBP action on its cognate targets is likely dose dependent and cooperative; multiple RBPs have to bind to the same 3′UTR at different locations to exert an effect.…”

Section: Cdk6 and Myc Mrnas Are Targets Of Igf2bp3 In Vitro And In Vivomentioning

confidence: 99%

RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation

Palanichamy¹,

Tran²,

Howard³

et al. 2016

Journal of Clinical Investigation

131

180

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Posttranscriptional control of gene expression is important for defining both normal and pathological cellular phenotypes. In vitro, RNA-binding proteins (RBPs) have recently been shown to play important roles in posttranscriptional regulation; however, the contribution of RBPs to cell specification is not well understood. Here, we determined that the RBP insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is specifically overexpressed in mixed lineage leukemia-rearranged (MLLrearranged) B-acute lymphoblastic leukemia (B-ALL), which constitutes a subtype of this malignancy associated with poor prognosis and high risk of relapse. IGF2BP3 was required for the survival of B-ALL cell lines, as knockdown led to decreased proliferation and increased apoptosis. Enforced expression of IGF2BP3 provided murine BM cells with a strong survival advantage, led to proliferation of hematopoietic stem and progenitor cells, and skewed hematopoietic development to the B cell/myeloid lineage. Cross-link immunoprecipitation and high throughput sequencing uncovered the IGF2BP3-regulated transcriptome, which includes oncogenes MYC and CDK6 as direct targets. IGF2BP3 regulated transcripts via targeting elements within 3' untranslated regions (3'UTR), and enforced IGF2BP3 expression in mice resulted in enhanced expression of Myc and Cdk6 in BM. Together, our data suggest that IGF2BP3-mediated targeting of oncogenic transcripts may represent a critical pathogenetic mechanism in MLL-rearranged B-ALL and support IGF2BP3 and its cognate RNA-binding partners as potential therapeutic targets in this diseas

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“…Not only do CELF proteins bind to introns in pre-mRNAs to mediate alternative splicing in the nucleus, they are also powerful modulators of mRNA decay, as they compete with other RNA-binding proteins for the binding to GU-rich elements (Liu et al, 2015;Vlasova-St Louis et al, 2013). In the cytoplasm, CELFs bind to 5′ and 3′UTRs in mature mRNAs to regulate deadenylation, mRNA stability and translation (Dasgupta and Ladd, 2012).…”

Section: Mirnas Target Alternative Splicing Factorsmentioning

confidence: 99%

miRNA targeting and alternative splicing in the stress response – events hosted by membrane-less compartments

Kucherenko

Shcherbata

2018

Journal of Cell Science

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Stress can be temporary or chronic, and mild or acute. Depending on its extent and severity, cells either alter their metabolism, and adopt a new state, or die. Fluctuations in environmental conditions occur frequently, and such stress disturbs cellular homeostasis, but in general, stresses are reversible and last only a short time. There is increasing evidence that regulation of gene expression in response to temporal stress happens post-transcriptionally in specialized subcellular membrane-less compartments called ribonucleoprotein (RNP) granules. RNP granules assemble through a concentrationdependent liquid-liquid phase separation of RNA-binding proteins that contain low-complexity sequence domains (LCDs). Interestingly, many factors that regulate microRNA (miRNA) biogenesis and alternative splicing are RNA-binding proteins that contain LCDs and localize to stress-induced liquid-like compartments. Consequently, gene silencing through miRNAs and alternative splicing of premRNAs are emerging as crucial post-transcriptional mechanisms that function on a genome-wide scale to regulate the cellular stress response. In this Review, we describe the interplay between these two post-transcriptional processes that occur in liquid-like compartments as an adaptive cellular response to stress.

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Competition between RNA-binding proteins CELF1 and HuR modulates MYC translation and intestinal epithelium renewal

Abstract: ELAV-like family member 1, or CELF1, competes with another RNA-binding protein, HuR, to modulate MYC translation and plays an important role in the regulation of intestinal epithelial renewal.

Cited by 80 publications

References 63 publications

Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice

Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice

RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation

miRNA targeting and alternative splicing in the stress response – events hosted by membrane-less compartments

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