Highly concentrated trehalose induces prohealing senescence-like state in fibroblasts via CDKN1A/p21
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PROVIDER: PRJNA766853 | ENA |
REPOSITORIES: ENA
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Project description:Trehalose is the nonreducing disaccharide of glucose, evolutionarily conserved in invertebrates. The living skin equivalent (LSE) is an organotypic coculture containing keratinocytes cultivated on fibroblast-populated dermal substitutes. We demonstrated that human primary fibroblasts treated with highly concentrated trehalose promote significantly extensive spread of the epidermal layer of LSE without any deleterious effects. The RNA-seq analysis of trehalose-treated 2D and 3D fibroblasts at early time points revealed the involvement of the CDKN1A pathway, the knockdown of which significantly suppressed the upregulation of DPT, ANGPT2, VEGFA, EREG, and FGF2. The trehalose-treated fibroblasts were positive for senescence-associated β-galactosidase. Finally, transplantation of the dermal substitute with trehalose-treated fibroblasts accelerated wound closure and increased capillary formation significantly in the experimental mouse wounds in vivo, which was canceled by the CDKN1A knockdown. These data indicate that high-concentration trehalose can induce the senescence-like state in fibroblasts via CDKN1A/p21, which may be therapeutically useful for optimal wound repair.
2023-01-10 | GSE184892 | GEO
Project description:p53-mediated cell cycle arrest during DNA damage is dependent on the induction of p21 protein, encoded by the CDKN1A gene. p21 inhibits cyclin-dependent kinases required for cell cycle progression to guarantee accurate repair of DNA lesions. Hence, fine-tuning of p21 levels is crucial to preserve genomic stability. Currently, the multilayered regulation of p21 levels during DNA damage is not fully understood. Herein, we identified the human RNA binding motif protein 42 (RBM42) as a novel regulator of p21 levels during DNA damage. Genome-wide transcriptome and interactome analysis revealed that RBM42 alters the expression of p53-regulated genes during DNA damage. Specifically, we demonstrated that RBM42 facilitates CDKN1A splicing by counteracting the splicing inhibitory effect of RBM4 protein. Unexpectedly, we also show that RBM42, underpins translation of various splicing targets, including CDKN1A. Concordantly, transcriptome-wide mapping of RBM42-RNA interactions using eCLIP further substantiates the dual function of RBM42 in regulating splicing and translation of its target genes, including CDKN1A. Collectively, our data show that RBM42 couples splicing and translation machineries to fine-tune gene expression during DNA damage response.
2023-11-03 | GSE245744 | GEO
Project description:Post-transcriptional modifications of tumor suppressors, including microRNA-mediated downregulation, are important events in tumor progression. To identify microRNAs involved in oncogenic transformation, we examined global microRNA profiles of three ras transgenic zebrafish models. Four microRNAs are upregulated in all transgenic systems. Analysis of the predicted targets shows that three of them target Jmjd6, and overexpression of Jmjd6 in ras transformed melanocytes blocks proliferation and melanoma development. We found that Jmjd6 functions to regulate splicing of the tumor suppressor cdkn1a/p21. Truncated cdkn1a/p21 transcripts, lacking the PCNA binding domain, accumulate in ras-expressing melanocytes during melanoma development. These findings implicate Jmjd6 in a novel mechanism for inactivation of a major tumor suppressor pathway in melanoma.
2017-01-01 | GSE37015 | GEO
Project description:Gene expression profiles were obtained via Nanostring nCounter Expression Assay (PanCancer Progression Panel, Nanostring Technologies, Hamburg, Germany). We aimed to obtain a gene expression signature associated to the kockout of p21 (i.e. Cyclin Dependent Kinase Inhibitor 1A, CDKN1A) in colorectal carcinoma samples and its association with of epithelial-mesenchymal transition (EMT). We analysed and compared three independent cultures of HCT116 p21 wt cells and three HCT116 p21-/- ko cells.
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Project description:The p21 protein, encoded by CDKN1A, plays a vital role in the induction of senescence, and its transcriptional control by p53 tumour supressor is well-established. However, p21 can also be regulated in a p53-independent manner, by mechanisms that remain poorly understood. Therefore, we here used a chromatin-directed proteomic approach and identified ZNF84 as a novel regulator of p21 in various p53-deficient cell lines.
2021-09-07 | PXD022542 | Pride
Project description:Skin barrier dysfunction initiates or deteriorates various cutaneous problems, such as atopic dermatitis (AD). In high concentrations, the nonreducing disaccharide α-d-glucopyranosyl α-d-glucopyranoside (trehalose) can induce transient senescence-like state in fibroblasts and promote wound repair. Here we have investigated the direct effect of a high concentration of trehalose on primary human keratinocytes (KCs) and demonstrated its specific role in the skin barrier. RNA-seq analysis revealed that trehalose regulates many skin-barrier-associated genes in T helper 2 (Th2) cytokines interleukin (IL)-4/IL-13-treated and -untreated KCs. Using monolayer-cultured post-confluent normal human KCs and living skin equivalent (LSE), we identified IL-4/IL-13-downregulated differentiation markers and various epidermal antimicrobial proteins, all of which were significantly upregulated or restored by trehalose (60 mg/mL). Trehalose inhibited IL-33 expression and reduced nuclear IL-33 by activating MEK5- extracellular signal-regulated kinase (ERK)-5 and suppressing MEK1/2-ERK pathways. It also increased nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase 1 (HMOX1) activation via c-Jun N-terminal kinase (JNK), thus, neutralizing IL-4/IL-13-mediated oxidative stress. Trehalose prevented IL-4/IL-13-mediated signal transducer and activator of transcription (STAT)3 and STAT6 activation and restored various skin barrier molecules reduced by IL-4/IL-13 via IL-33 downregulation and Nrf2-HMOX1 activation. This study demonstrates that trehalose might play salubrious roles as skin barrier repair in AD.
2024-09-30 | GSE244738 | GEO
Project description:TAF15 (formerly TAFII68) is a member of the TET family of RNA and DNA binding proteins whose genes are frequently translocated in sarcomas. Consistent with a functional role in cell viability, TAF15 depletion had a growth-inhibitory effect and increased apoptosis. Interestingly, one of the genes affected by TAF15 depletion is CDKN1A/p21, a key regulator of cell cycle. Here we show that TAF15 down-regulates CDKN1A/p21 expression through a pathway involving miRNAs.
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Project description:Normal development requires tight regulation of cell proliferation and cell death. Here, we investigated these control mechanisms in the hyaloid vessels, a temporary vascular network in the mammalian eye that requires a Wnt/β-catenin response for scheduled regression. Transcriptome analysis of the postnatal day 5 mouse hyaloid showed expression of several Wnt pathway proteins. We investigated whether the hyaloid Wnt response was linked to the oncogene Myc, and the cyclin-dependent kinase inhibitor P21 (CDKN1A), both established regulators of cell cycle progression and cell death. Our analysis showed that the Wnt pathway coreceptors LRP5 and LRP6 have overlapping activities mediating the Wnt/β-catenin signaling in hyaloid vascular endothelial cells (VECs). We also showed that both Myc and Cdkn1a are downstream of the Wnt response and are required for hyaloid regression but for different reasons. Conditional deletion of Myc in VECs suppressed both proliferation and cell death. By contrast, conditional deletion of Cdkn1a resulted in VEC over-proliferation that countered the effects of cell death on regression. When combined with analysis of MYC, and P21 protein levels, this analysis suggests that a Wnt/β-catenin, MYC-P21 pathway regulates scheduled hyaloid vessel regression.
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Project description:Analysis of gene expression changes associated with KLF4 expression in the AML cell lines THP1 cells. Resutls demonstrate KLF4 promotes myeloid differentiation in these cells via gene signatures. We also identified KLF4 downstream regulators that are modified in miR-150 and p21 (CDKN1A) CRISPR knockdown cells.
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Project description:microRNAs in the miR-106b family are overexpressed in multiple tumor types and are correlated with the expression of genes that regulate the cell cycle. Consistent with these observations, miR-106b family gain of function promotes cell cycle progression, whereas loss of function reverses this phenotype. Microarray profiling uncovers multiple targets of the family, including the cyclin-dependent kinase inhibitor p21/CDKN1A. We show that p21 is a direct target of miR-106b and that its silencing plays a key role in miR-106b-induced cell cycle phenotypes. We also show that miR-106b overrides a doxorubicin-induced DNA damage checkpoint. Thus, miR-106b family members contribute to tumor cell proliferation in part by regulating cell cycle progression and by modulating checkpoint functions.
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