MicroRNA-21 is an important downstream component of BMP signalling in epidermal keratinocytes

Ahmed, Mohammed I.; Mardaryev, Andrei N.; Lewis, Christopher J.; Sharov, Andrey A.; Botchkareva, Natalia V.

doi:10.1242/jcs.086710

Cited by 95 publications

(83 citation statements)

References 42 publications

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“…Our results suggest that one mechanism underlying these effects of miR-21 on skin tumorigenesis is down-regulation of tumor suppressors and DNA repair genes such as MSH2. In addition to MSH2, our gene list of likely miR-21 targets identified several other genes that could contribute to tumorigenesis through cell cycle regulation and DNA repair (Figure 4a; Supplementary Table S2) (17, 46), the predominant processes affected by miR-21 perturbation in keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

“…In fact studies have also identified other factors including AP1 that can also drive up miR-21 in tumors (47), and BMP4 as an inhibitor of miR-21 expression in keratinocytes (17). Furthermore, miR-21 itself was recently shown to target Grhl3 (44), suggesting the possibility of a feed-forward autoregulatory loop between Grhl3 and miR-21.…”

Section: Discussionmentioning

confidence: 99%

“…miR-21 is abundantly expressed in skin (2, 14-17), and is upregulated in pathological conditions such as psoriasis, atopic dermatitis (18-20), and squamous cell carcinoma (SCC) (21), indicative of its potential importance in skin homeostasis. Therefore, it is intriguing that miR-21 is up regulated in Grhl3 deficient skin, which exhibits impaired differentiation and hyperplasia.…”

Section: Introductionmentioning

confidence: 99%

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The Grainyhead transcription factor Grhl3/Get1 suppresses miR-21 expression and tumorigenesis in skin: modulation of the miR-21 target MSH2 by RNA-binding protein DND1

et al. 2012

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Epidermal differentiation and stratification, crucial for barrier formation, are regulated by a complex interplay of transcription factors, including the evolutionarily conserved Grainyhead-like 3 (Grhl3/Get1); Grhl3-deleted mice exhibit impaired epidermal differentiation and decreased expression of multiple differentiation genes. To test whether Grhl3 regulates epidermal genes indirectly by controlling the expression of specific microRNAs (miRs), we performed miR profiling and identified 11 miRs that are differentially regulated in Grhl3-/- skin, one of which is miR-21, previously shown to be upregulated in diseased skin, including in psoriasis and squamous cell skin cancer. We found that miR-21 is normally expressed in the post-mitotic suprabasal layers of the epidermis, overlapping with Grhl3. The miR-21 promoter is bound and repressed by Grhl3 indicating that these two factors are involved in a regulatory loop maintaining homeostasis in the epidermis. While miR-21 overexpression in normal keratinocytes had mild effects on the expression of several known miR-21 targets, an enhanced downregulation of the miR-21 tumor-related targets, including MSH2, was observed in Ras-transformed keratinocytes. The increased sensitivity of transformed keratinocytes to miR-21′s effects occurs in part through downregulation of the RNA-binding protein DND1 during the transformation process. Additionally, we observed increased tumorigenesis in mice subcutaneously injected with transformed keratinocytes lacking Grhl3. These findings indicate that decreased Grhl3 expression contributes to tumor progression and upregulation of the oncomir miR-21 in squamous cell carcinoma of the skin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Grainyhead transcription factor Grhl3/Get1 suppresses miR-21 expression and tumorigenesis in skin: modulation of the miR-21 target MSH2 by RNA-binding protein DND1

et al. 2012

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“…Often a miRNA has hundreds of different target genes, regulating biological functions through the modulation of their expression (9,10). Several miRNAs have been identified to have important and specific functions in the skin, both in keratinocytes (11)(12)(13)(14)(15)(16) and in other cell types (17,18), showing the relevance of this class of molecules in skin biology.…”

Section: Introductionmentioning

confidence: 99%

Activation of Toll‐like receptors alters the microRNA expression profile of keratinocytes

Meisgen

Landén

Bouez

et al. 2014

Experimental Dermatology

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Additional Supporting Information may be found in the online version of this article:Data S1. Method. Figure S1. Expression of AhR and ARNT in the lesional skin of AD and psoriasis patients and in the healthy skin of the control group. Figure S2. Expression of AhR and ARNT in the lesional skin of AD and psoriasis patients and in the healthy skin of the control group. Figure S3. Effect of TCDD and PCB on normal human epidermal keratinocytes. Figure S4. Abstract: Keratinocytes recognize invading pathogens by various receptors, among them Toll-like receptors (TLRs), and provide the first line of defense in skin immunity. The role of microRNAs in this important defense mechanism has not been explored yet. Our aim was to identify microRNAs involved in the innate immune response of keratinocytes. MicroRNA expression profiling revealed that the TLR2 ligand zymosan, the TLR3 ligand poly(I:C) or the TLR5 ligand flagellin significantly altered the microRNA expression in keratinocytes. The regulation of microRNAs was concentration-dependent and it could be neutralized by siRNAs specific for TLR2, TLR3 and TLR5, respectively, confirming the specificity of the TLR response. Interestingly, one microRNA, miR-146a, was strongly induced by all studied TLR ligands, while other microRNAs were regulated in a TLR-or time point-specific manner. These findings suggest an important role for microRNAs in the innate immune response of keratinocytes and provide a basis for further investigations.

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“…The physiological mechanism of hair growth is extremely complex requiring the coordinated regulation of many growth factors. MicroRNAs regulate animal hair growth by targeting growth factor genes (Ahmed et al, 2011;Yuan et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Alpaca fiber growth is mediated by microRNA let-7b via down-regulation of target gene FGF5

et al. 2015

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ABSTRACT. MicroRNAs are very small endogenous RNA molecules that play a crucial role in an array of biological processes, including regulation of skin morphogenesis. The microRNA let-7b is thought to modulate animal hair growth, by binding target genes that encode growth factors. Fibroblast growth factor 5 (FGF5) has been previously reported to be involved in the initiation of the catagen phase of hair growth. In this study, we combined previous reports with bioinformatic analysis techniques to identify and validate FGF5 and, using lucerifase assay, confirmed targeted binding of let-7b to FGF5. To investigate the interaction between let-7b and FGF5, alpaca skin fibroblasts were transfected with let-7b over-expression vectors, and then mRNA and protein expression levels of FGF5 and the gene encoding its receptor, FGFR1, were evaluated. Levels of FGF5 mRNA and protein were remarkably lower in transfected groups, as compared to controls. In summary, this study confirmed that let-7b acts as a regulator of skin morphogenesis, by directly targeting FGF5 and down-regulating its 13754-13763 (2015) expression. It provides the evidence of hair growth regulated by miRNAs in animals and may have important applications in wool production.

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MicroRNA-21 is an important downstream component of BMP signalling in epidermal keratinocytes

Cited by 95 publications

References 42 publications

The Grainyhead transcription factor Grhl3/Get1 suppresses miR-21 expression and tumorigenesis in skin: modulation of the miR-21 target MSH2 by RNA-binding protein DND1

The Grainyhead transcription factor Grhl3/Get1 suppresses miR-21 expression and tumorigenesis in skin: modulation of the miR-21 target MSH2 by RNA-binding protein DND1

Activation of Toll‐like receptors alters the microRNA expression profile of keratinocytes

Alpaca fiber growth is mediated by microRNA let-7b via down-regulation of target gene FGF5

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