miR‐483‐3p controls proliferation in wounded epithelial cells

Bertero, Thomas; Gastaldi, Cécile; Bourget, Isabelle; Imbert, Véronique; Loubat, Agnès; Selva, Éric; Buscà, Roser; Mari, Bernard; Hofman, Paul; Barbry, Pascal; Meneguzzi, Guerríno; Ponzio, Gilles; Rezzonico, Roger

doi:10.1096/fj.10-168401

Cited by 79 publications

(74 citation statements)

References 52 publications

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“…miRNAs have been identified to be critical in wound healing (24,(36)(37)(38). Our results demonstrate an inhibited miRNA signature in the wounds of diabetic rats accompanied by decreased Dicer levels.…”

Section: Discussionmentioning

confidence: 57%

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Bhattacharya

Aggarwal

Singh

et al. 2015

Mol Med

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Delayed wound healing is a major complication associated with diabetes and is a result of a complex interplay among diverse deregulated cellular parameters. Although several genes and pathways have been identified to be mediating impaired wound closure, the role of microRNAs (miRNAs) in these events is not very well understood. Here, we identify an altered miRNA signature in the prolonged inflammatory phase in a wound during diabetes, with increased infiltration of inflammatory cells in the basal layer of the epidermis. Nineteen miRNAs were downregulated in diabetic rat wounds (as compared with normal rat wound, d 7 postwounding) together with inhibited levels of the central miRNA biosynthesis enzyme, Dicer, suggesting that in wounds of diabetic rats, the decreased levels of Dicer are presumably responsible for miRNA downregulation. Compared with unwounded skin, Dicer levels were significantly upregulated 12 d postwounding in normal rats, and this result was notably absent in diabetic rats that showed impaired wound closure. In a wound-healing specific quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) array, 10 genes were significantly altered in the diabetic rat wound and included growth factors and collagens. Network analyses demonstrated significant interactions and correlations between the miRNA predicted targets (regulators) and the 10 wound-healing specific genes, suggesting altered miRNAs might fine-tune the levels of these genes that determine wound closure. Dicer inhibition prevented HaCaT cell migration and affected wound closure. Altered levels of Dicer and miRNAs are critical during delayed wound closure and offer promising targets to address the issue of impaired wound healing.

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Section: Discussionmentioning

confidence: 57%

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Bhattacharya

Aggarwal

Singh

et al. 2015

Mol Med

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“…Many of the bovine miRNAs differentially expressed in large atretic follicles are reportedly involved in regulating the proliferation and survival of different cell types (miR-483, miR-150, miR-21, miR-409a, miR-31, miR-34b, miR-33a; Yamakuchi et al 2008, Bertero et al 2011, Liu et al 2011, Brabletz 2012, Cirera-Salinas et al 2012, Weng et al 2012 as well as immune cell activation (miR-150, miR-21, miR-31; Xiao et al 2007, Xue et al 2013, Das et al 2014, which is consistent with an active role of these miRNAs in follicular fate decisions. The involvement of miR-21 in the promotion of cell survival is well established, including in mouse granulosa cells during ovulation (Carletti et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Characterization of microRNAs differentially expressed during bovine follicle development

Sontakke¹,

Mohammed²,

McNeilly³

et al. 2014

Reproduction

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Several different miRNAs have been proposed to regulate ovarian follicle function; however, very limited information exists on the spatiotemporal patterns of miRNA expression during follicle development. The objective of this study was to identify, using microarray, miRNA profiles associated with growth and regression of dominant-size follicles in the bovine monovular ovary and to characterize their spatiotemporal distribution during development. The follicles were collected from abattoir ovaries and classified as small (4-8 mm) or large (12-17 mm); the latter were further classified as healthy or atretic based on estradiol and CYP19A1 levels. Six pools of small follicles and individual large healthy (nZ6) and large atretic (nZ5) follicles were analyzed using Exiqon's miRCURY LNA microRNA Array 6th gen, followed by qPCR validation. A total of 17 and 57 sequences were differentially expressed (greater than or equal to twofold; P!0.05) between large healthy and each of small and large atretic follicles respectively. Bovine miRNAs confirmed to be upregulated in large healthy follicles relative to small follicles (bta-miR-144, bta-miR-202, bta-miR-451, bta-miR-652, and bta-miR-873) were further characterized. Three of these miRNAs (bta-miR-144, bta-miR-202, and bta-miR-873) were also downregulated in large atretic follicles relative to large healthy follicles. Within the follicle, these miRNAs were predominantly expressed in mural granulosa cells. Further, body-wide screening revealed that bta-miR-202, but not other miRNAs, was expressed exclusively in the gonads. Finally, a total of 1359 predicted targets of the five miRNAs enriched in large healthy follicles were identified, which mapped to signaling pathways involved in follicular cell proliferation, steroidogenesis, prevention of premature luteinization, and oocyte maturation.

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“…13 Additional miR-483-3p target genes including BBC3/ PUMA, SMAD4, CTNNB1 and GDF3 have been identified in other tissues (Wilm's tumors, adrenocortical carcinomas, HCT116 colon and HepG2 hepatocellular carcinoma cell lines, and adipose tissue). [14][15][16][17][18] We demonstrate now that CDC25A has a key role in the mediation of the anti-proliferative effects of miR-483-3p in keratinocytes by controlling the binding between CDK6/4 and CCNDs.…”

mentioning

confidence: 99%

CDC25A targeting by miR-483-3p decreases CCND–CDK4/6 assembly and contributes to cell cycle arrest

et al. 2013

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Disruption of contact inhibition and serum afflux that occur after a tissue injury activate cell cycle, which then stops when confluence is reached again. Although the events involved in cell cycle entry have been widely documented, those managing cell cycle exit have remained so far ill defined. We have identified that the final stage of wound closure is preceded in keratinocytes by a strong accumulation of miR-483-3p, which acts as a mandatory signal triggering cell cycle arrest when confluence is reached. Blocking miR-483-3p accumulation strongly delays cell cycle exit, maintains cells into a proliferative state and retards their differentiation program. Using two models of cell cycle synchronization (i.e. mechanical injury and serum addition), we show that an ectopic upregulation of miR-483-3p blocks cell cycle progression in early G1 phase. This arrest results from a direct targeting of the CDC25A phosphatase by miR-483-3p, which can be impeded using an anti-miRNA against miR-483-3p or a protector that blocks the complex formation between miR-483-3p and the 3 0 -untranslated region (UTR) of CDC25A transcript. We show that the miRNA-induced silencing of CDC25A increases the tyrosine phosphorylation status of CDK4/6 cyclin-dependent kinases which, in turn, abolishes CDK4/6 capacity to associate with D-type cyclins. This prevents CDK4/6 kinases' activation, impairs downstream events such as cyclin E stimulation and sequesters cells in early G1. We propose this new regulatory process of cyclin-CDK association as a general mechanism coupling miRNA-mediated CDC25A invalidation to CDK posttranscriptional modifications and cell cycle control.

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miR‐483‐3p controls proliferation in wounded epithelial cells

Cited by 79 publications

References 52 publications

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Characterization of microRNAs differentially expressed during bovine follicle development

CDC25A targeting by miR-483-3p decreases CCND–CDK4/6 assembly and contributes to cell cycle arrest

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