Intronic miR-211 Assumes the Tumor Suppressive Function of Its Host Gene in Melanoma

Levy, Carmit; Khaled, Mehdi; Iliopoulos, Dimitrios; Janas, Maja M.; Schubert, Steffen; Pinner, Sophie; Chen, Po-Hao; Li, Shuqiang; Fletcher, Anne; Yokoyama, Satoru; Scott, Kenneth L.; Garraway, Levi A.; Song, Jun S.; Granter, Scott R.; Turley, Shannon J.; Fisher, David E.; Novina, Carl D.

doi:10.1016/j.molcel.2010.11.020

Cited by 244 publications

(324 citation statements)

References 29 publications

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“…However, many reports have indicated that NFAT5 protein level is tightly regulated, particularly during differentiation and in response to hyper-osmotic stresses (Woo et al, 2000;Ferraris et al, 2002). It has been shown that NFAT5 protein level is regulated by several mechanisms involving protein stability and miRNA-mediated mRNA silencing (Dahl et al, 2001;Irarrazabal et al, 2010;Levy et al, 2010). We now report that NFAT5 protein level can also be regulated by the coupling of splicing to the NMD pathway (Figures 4, 5 and 6).…”

Section: Discussionmentioning

confidence: 51%

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

et al. 2012

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Ddx5 and ddx17 are two highly related RNA helicases involved in both transcription and splicing. These proteins coactivate transcription factors involved in cancer such as the estrogen receptor alpha, p53 and beta-catenin. Ddx5 and ddx17 are part of the splicing machinery and can modulate alternative splicing, the main mechanism increasing the proteome diversity. Alternative splicing also has a role in gene expression level regulation when it is coupled to the nonsensemediated mRNA decay (NMD) pathway. In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. Second, at the splicing level, ddx5 and ddx17 increase the inclusion of NFAT5 exon 5. As exon 5 contains a pre-mature translation termination codon, its inclusion leads to the regulation of NFAT5 mRNAs by the NMD pathway and to a decrease in NFAT5 protein level. Therefore, we demonstrated for the first time that a transcriptional coregulator can simultaneously regulate the transcriptional activity and alternative splicing of a transcription factor. This dual regulation, where ddx5 and ddx17 enhance the transcriptional activity of NFAT5 although reducing its protein expression level, suggests a critical role for ddx5 and ddx17 in tumor cell migration through the fine regulation of NFAT5 pathway.

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Section: Discussionmentioning

confidence: 51%

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

et al. 2012

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“…Intronic miRNAs have roles that may complement (18,19) or sometimes actually antagonize those of their host genes (20). We now show that expression of the FGF13 locus, including miR-504, is negatively regulated by p53.…”

mentioning

confidence: 66%

Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival

Bublik

Bursać

Sheffer

et al. 2016

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

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The microRNA miR-504 targets TP53 mRNA encoding the p53 tumor suppressor. miR-504 resides within the fibroblast growth factor 13 (FGF13) gene, which is overexpressed in various cancers. We report that the FGF13 locus, comprising FGF13 and miR-504, is transcriptionally repressed by p53, defining an additional negative feedback loop in the p53 network. Furthermore, we show that FGF13 1A is a nucleolar protein that represses ribosomal RNA transcription and attenuates protein synthesis. Importantly, in cancer cells expressing high levels of FGF13, the depletion of FGF13 elicits increased proteostasis stress, associated with the accumulation of reactive oxygen species and apoptosis. Notably, stepwise neoplastic transformation is accompanied by a gradual increase in FGF13 expression and increased dependence on FGF13 for survival ("nononcogene addiction"). Moreover, FGF13 overexpression enables cells to cope more effectively with the stress elicited by oncogenic Ras protein. We propose that, in cells in which activated oncogenes drive excessive protein synthesis, FGF13 may favor survival by maintaining translation rates at a level compatible with the protein qualitycontrol capacity of the cell. Thus, FGF13 may serve as an enabler, allowing cancer cells to evade proteostasis stress triggered by oncogene activation.proteostasis | p53 | miR-504 | FGF13 | ribosomal biogenesis

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“…MML-1 cells were seeded in six-well dishes and transfected with the modified PLKO.1 vectors using Lipofectamine 2000 (Invitrogen). PLKO-mcherry-luc-puroshSCR and PLKO-mcherry-luc-puro-miR-211-5p (Addgene plasmids 29780 and 29784, respectively) were a kind gift from Carl Novina, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston (33). Two days posttransfection, the cells were grown with 1 μg/mL of puromycin (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

BRAF ^V600 inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

Lunavat

Cheng

Einarsdottir

et al. 2017

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

106

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The BRAF inhibitors vemurafenib and dabrafenib can be used to treat patients with metastatic melanomas harboring BRAF V600 mutations. Initial antitumoral responses are often seen, but drug-resistant clones with reactivation of the MEK-ERK pathway soon appear. Recently, the secretome of tumor-derived extracellular vesicles (EVs) has been ascribed important functions in cancers. To elucidate the possible functions of EVs in BRAF-mutant melanoma, we determined the RNA content of the EVs, including apoptotic bodies, microvesicles, and exosomes, released from such cancer cells after vemurafenib treatment. We found that vemurafenib significantly increased the total RNA and protein content of the released EVs and caused significant changes in the RNA profiles. RNA sequencing and quantitative PCR show that cells and EVs from vemurafenib-treated cell cultures and tumor tissues harvested from cell-derived and patient-derived xenografts harbor unique miRNAs, especially increased expression of miR-211-5p. Mechanistically, the expression of miR-211-5p as a result of BRAF inhibition was induced by increased expression of MITF that regulates the TRPM1 gene resulting in activation of the survival pathway. In addition, transfection of miR-211 in melanoma cells reduced the sensitivity to vemurafenib treatment, whereas miR-211-5p inhibition in a vemurafenib resistant cell line affected the proliferation negatively. Taken together, our results show that vemurafenib treatment induces miR-211-5p upregulation in melanoma cells both in vitro and in vivo, as well as in subsets of EVs, suggesting that EVs may provide a tool to understand malignant melanoma progression.small RNAs | extracellular vesicles | cancer | noncoding RNAs

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Intronic miR-211 Assumes the Tumor Suppressive Function of Its Host Gene in Melanoma

Cited by 244 publications

References 29 publications

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival

BRAF ^V600 inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

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Intronic miR-211 Assumes the Tumor Suppressive Function of Its Host Gene in Melanoma

Cited by 244 publications

References 29 publications

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival

BRAF V600 inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

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BRAF ^V600 inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells