Comparison of the Transcriptional Profiles of Melanocytes from Dark and Light Skinned Individuals under Basal Conditions and Following Ultraviolet-B Irradiation

López, Saioa; Zubiaga, Isabel Smith; Galdeano, Alicia García de; Boyano, María Dolores; Garcı́a, Oscar; Gardeazábal, Jesús; Martínez-Cadenas, Conrado; Izagirre, Neskuts; Rúa, Concepción de la; Alonso, Santos

doi:10.1371/journal.pone.0134911

Cited by 15 publications

(14 citation statements)

References 61 publications

(60 reference statements)

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“…keratinocytes, immune cells, and melanocytes, to be taken into account. We note that in a study of UVR-treated cultured melanocytes, ribosome metabolism was the most significantly altered pathway at 6, 12, and 24h after UVR (39), as in our whole skin studies. To gain a better sense of changes in skin correlated with RRP15 expression we constructed a network of genes correlated with RRP15 expression across the sun-exposed anatomical site human skin GTEx cohort (Fig 5B).…”

Section: Skin Gene Expression Changes After Neonatal Uvrsupporting

confidence: 70%

Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma

Walker

Ferguson

Handoko

et al. 2018

Preprint

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wordsGenetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this to melanoma using the collaborative cross (CC), a resource of mouse strains designed to discover genes for complex diseases. We studied melanomaprone transgenic progeny across seventy CC genetic backgrounds. We mapped a strong quantitative trait locus for rapid onset spontaneous melanoma onset to Prkdc, a gene involved in detection and repair of DNA damage. In contrast, rapid onset UVR-induced melanoma was linked to the ribosomal subunit gene Rrp15. Ribosome biogenesis was upregulated in skin shortly after UVR exposure, Mechanistically, variation in the "usual suspects" by which UVR may exacerbate melanoma, defective DNA repair, melanocyte proliferation, or inflammatory cell infiltration, did not explain melanoma susceptibility or resistance across the CC. Instead, events occurring soon after exposure, such as dysregulation of ribosome function, which alters many aspects of cellular metabolism, may be important.neutrophil monoclonal antibody Abcam ab2557: NIMP-R14 (Cambridge, UK) at a concentration of 1:100. Neutrophil depletion:Each NOD/Cdk4 R24C/+ ::NRAS pup was injected intraperitoneally, with either 100ug InVivo MAb antimouse Ly6G (Bio C Cell, Beverly, MA, USA) or PBS (as a control) at P2, P3 and P5. At P3, all pups were also given UVR treatment. As the depletion was done using anti-Ly6G, staining to differentiate between depleted and non-depleted skin was done using Myeloperoxidase staining (Abnova rabbit anti-MPO, Taipei, Taiwan) at a concentration of 1:75. Statistical Analysis:One-way Anova tests were used to determine the significant difference between means, using R. The survival of mice in each treatment group was estimated using Kaplan-Meier analysis (PRISM TM ), and the Log-Rank (Mantel-Cox) test was used to test for differences between the groups. For correlation comparisons Pearson correlation r value was calculated in PRISM along with the p-value for significant correlation.

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Section: Skin Gene Expression Changes After Neonatal Uvrsupporting

confidence: 70%

Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma

Walker

Ferguson

Handoko

et al. 2018

Preprint

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“…ROS have been shown to activate proinflammatory and MAPK signaling cascades, subsequently leading to various biological responses including cell death or dysfunction [43–45]. López et al, reported that paracrine protective effects of CM from UVB-irradiated KC on MC involved regulation of various signaling pathways including proinflammatory and p53-dependent apoptotic pathways [42]. Our study demonstrated that the microenvironment created by KC reversed damaging effects of UVB on MC by reducing activation of caspase-3 and p53 that play a crucial role in UVR-mediated apoptosis associated with DNA damage [25,26], and by downregulating inflammatory markers including NF-κB activation and TNF-α levels implicated in photodamaged skin [46,47].…”

Section: Discussionmentioning

confidence: 99%

Nrf2 in keratinocytes modulates UVB-induced DNA damage and apoptosis in melanocytes through MAPK signaling

Jeayeng

Wongkajornsilp

Slominski

et al. 2017

Free Radical Biology and Medicine

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Responses of melanocytes (MC) to ultraviolet (UV) irradiation can be influenced by their neighbouring keratinocytes (KC). We investigated the role of Nrf2 in regulating paracrine effects of KC on UVB-induced MC responses through phosphorylation of MAPKs in association with oxidative stress in primary human MC cocultured with primary human KC using a transwell co-culture system and small-interfering RNA-mediated silencing of Nrf2 (siNrf2). The mechanisms by which Nrf2 modulated paracrine factors including α-melanocyte-stimulating hormone (α-MSH) and paracrine effects of KC on UVB-mediated apoptosis were also assessed. Our findings showed that co-culture of MC with siNrf2-transfected KC enhanced UVB-mediated cyclobutane pyrimidine dimer (CPD) formation, apoptosis and oxidant formation, together with phosphorylation of ERK, JNK and p38 in MC. Treatment of MC with conditioned medium (CM) from Nrf2-depleted KC also increased UVB-mediated MC damage, suggesting that KC modulated UVB-mediated MC responses via paracrine effects. Additionally, depletion of Nrf2 in KC suppressed UVB-induced α-MSH levels as early as 30 min post-irradiation, although pretreatment with N-acetylcysteine (NAC) elevated its levels in CM from siNrf2-transfected KC. Furthermore, NAC reversed the effect of CM from Nrf2-depleted KC on UVB-induced apoptosis and inflammatory response in MC. Our study demonstrates for the first time that KC provided a rescue effect on UVB-mediated MC damage, although depletion of Nrf2 in KC reversed its protective effects on MC in a paracrine fashion in association with elevation of ROS levels and activation of MAPK pathways in MC. Nrf2 may indirectly regulate the paracrine effects of KC probably by affecting levels of the paracrine factor α-MSH via a ROS-dependent mechanism.

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“…In 2015, López et al conducted a time-series analysis to compare the transcriptional profile of dark and light melanocyte lines under basal conditions and after UVB radiation, finding that ribosomal proteins can interact with the p53 signaling pathway in response to UVB [28]. This study identified a total of 151 up-regulated and 64 down-regulated genes in skin in response to UVB irradiation, which probably remained increased after repetitive exposure for approximately 2–3 weeks [11].…”

Section: Discussionmentioning

confidence: 99%

Potential molecular characteristics in situ in response to repetitive UVB irradiation

Chen

Zhang

2016

Diagn Pathol

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BackgroundTo identify molecular characteristics in situ in response to repetitive UVB (ultraviolet-B) irradiation.MethodsMicroarray data from the Gene Expression Omnibus were re-analyzed to identify DEGs (differentially expressed genes) between UVB-irradiated and non-irradiated skin biopsies. Enrichment and annotation analyses were performed respectively using DAVID, and TSGene and TAG databases. PPIs (protein-protein interactions) were analyzed using STRING, and miRNAs (microRNAs) and TFs (transcription factors) were predicted separately by miRNA-related databases and ENCODE. Accordingly, the PPI network and regulatory networks were visualized using Cytoscape, and they were merged together to obtain an integrated network for mining densely connected modules.ResultsAltogether, 151 up- and 64 down-regulated genes were identified between UVB-irradiated and non-irradiated skin biopsies, among which down-regulated DNAJB4 and SLIT2 were annotated as tumor-suppressors and up-regulated KIT was annotated as an oncogene. The up-regulated DEGs were significantly enriched in biological processes related to pigmentation (DCT, SOX10, TYRP1, TYR, MLPH, KIT and GPR143), while the down-regulated DEGs were dramatically related to haemopoiesis and the immune system (GPR183, INHBA, PTPRC, PLEK, CD8A and IKZF1). Furthermore, many miRNAs were screened for the DEGs, including miR-206 and miR-496 targeting KIT, miR-184 targeting DCT, and highly significant miR-337-5p, miR-21 and miR-16. Additionally, TFs were identified for the DEGs, among which PAX5 and HNF4A targeted MLPH and GPR143, respectively, while BATF, SPI1 and EP300 jointly target GPR183, PTPRC and PLEK.ConclusionsThe pigmentation and immune system implicated by DEGs, miRNAs and TFs might be important molecular mechanisms in response to UVB irradiation.

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Comparison of the Transcriptional Profiles of Melanocytes from Dark and Light Skinned Individuals under Basal Conditions and Following Ultraviolet-B Irradiation

Cited by 15 publications

References 61 publications

Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma

Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma

Nrf2 in keratinocytes modulates UVB-induced DNA damage and apoptosis in melanocytes through MAPK signaling

Potential molecular characteristics in situ in response to repetitive UVB irradiation

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