Expression analysis of the mouse S100A7/psoriasin gene in skin inflammation and mammary tumorigenesis

BACKGROUND: The human psoriasin (S100A7) gene has been implicated in inflammation and tumor progression. Implementation of a mouse model would facilitate further investigation of its function, however little is known of the murine psoriasin gene. In this study we have cloned the cDNA and characterized the expression of the potential murine ortholog of human S100A7/psoriasin in skin inflammation and mammary tumorigenesis. METHODS: On the basis of chromosomal location, phylogenetic analysis, amino acid sequence similarity, conservation of a putative Jab1-binding motif, and similarities of the patterns of mouse S100A7/psoriasin gene expression (measured by RT-PCR and in-situ hybridization) with those of human S100A7/psoriasin, we propose that mouse S100A7/psoriasin is the murine ortholog of human psoriasin/S100A7. RESULTS: Although mouse S100A7/psoriasin is poorly conserved relative to other S100 family members, its pattern of expression parallels that of the human psoriasin gene. In murine skin S100A7/psoriasin was significantly upregulated in relation to inflammation. In murine mammary gland expression is also upregulated in mammary tumors, where it is localized to areas of squamous differentiation. This mirrors the context of expression in human tumor types where both squamous and glandular differentiation occur, including cervical and lung carcinomas. Additionally, mouse S100A7/psoriasin possesses a putative Jab1 binding motif that mediates many downstream functions of the human S100A7 gene. CONCLUSION: These observations and results support the hypothesis that the mouse S100A7 gene is structurally and functionally similar to human S100A7 and may offer a relevant model system for studying its normal biological function and putative role in tumor progression

Deconjugation of Nedd8 from Cul1 Is Directly Regulated by Skp1-F-box and Substrate, and the COP9 Signalosome Inhibits Deneddylated SCF by a Noncatalytic Mechanism

COP9 signalosome (CSN) mediates deconjugation of the ubiquitin-like protein Nedd8 from the cullin subunits of SCF and other cullin-RING ubiquitin ligases (CRLs). This process is essential to maintain the proper activity of CRLs in cells. Here, we report a detailed kinetic characterization of CSN-mediated deconjugation of Nedd8 from SCF. CSN is an efficient enzyme, with a k_(cat) of ∼1 s^(−1) and K_mfor neddylated Cul1-Rbx1 of ∼200 nm, yielding a k_(cat)/K_m near the anticipated diffusion-controlled limit. Assembly with an F-box-Skp1 complex markedly inhibited deneddylation, although the magnitude varied considerably, with Fbw7-Skp1 inhibiting by ∼5-fold but Skp2-Cks1-Skp1 by only ∼15%. Deneddylation of both SCF^(Fbw7) and SCF^(Skp2-Cks1) was further inhibited ∼2.5-fold by the addition of substrate. Combined, the inhibition by Fbw7-Skp1 plus its substrate cyclin E was greater than 10-fold. Unexpectedly, our results also uncover significant product inhibition by deconjugated Cul1, which results from the ability of Cul1 to bind tightly to CSN. Reciprocally, CSN inhibits the ubiquitin ligase activity of deneddylated Cul1. We propose a model in which assembled CRL complexes engaged with substrate are normally refractory to deneddylation. Upon consumption of substrate and subsequent deneddylation, CSN can remain stably bound to the CRL and hold it in low state of reduced activity

Environmental chemical-induced bone marrow B cell apoptosis: Death receptor-independent activation of a caspase-3 to caspase-8 pathway

ABSTRACT Programmed cell death is a critical process in B lymphocyte development. Premature apoptosis in developing B cells could affect the repertoire and number of mature B cells produced. Of particular concern is the ability of environmentally ubiquitous polycyclic aromatic hydrocarbons (PAH) to induce B cell apoptosis within the bone marrow microenvironment in a clonally nonspecific way. Here, models of bone marrow B cell development were used to assess the role of the "extrinsic" apoptosis pathway in PAH-induced apoptosis and to compare PAH-induced apoptosis with that induced during clonal deletion. A

Fashionable curiosities: extreme footwear as wearable fantasies

This paper considers an aspect of the material culture fashion, focusing on shoes. Like clothes, shoes are used every day: they are essential objects that primarily allow people to perform daily and socially accepted activities, walk comfortably and adorn the body in a fashionable way. Furthermore, shoes are associated with the idea of individuality and can be highly practical or decorative, depending on their design and fashion style. With regard to their style, one phenomenon emerging in high fashion is that of the “impossible-to-wear shoes”: exhibitions and fashion shows staging designers’ bizarre shoes are becoming more frequent. During these shows, the spectators are presented with an unusual variety of footwear (e.g. heelless shoes; shoes without soles; fish-shaped shoes). These shoes are not made to fit the individual. On the contrary, their shape and forms are imposed on the individuals. This paper explores the extreme, impossible-to-wear shoes and considers the visual statements they make about contemporary society, women and femininity. I will argue that impossible-to-wear shoes are puzzling yet charming objects, epitomizing a spectacle-centered society: they are part of unexpected and personal performances, which blend the boundaries of fashion and art and allow the wearers to shift from an ordinary “self” to the extraordinary “other”

Nuclear S100A7 Is Associated with Poor Prognosis in Head and Neck Cancer

Tissue proteomic analysis of head and neck squamous cell carcinoma (HNSCC) and normal oral mucosa using iTRAQ (isobaric tag for relative and absolute quantitation) labeling and liquid chromatography-mass spectrometry, led to the identification of a panel of biomarkers including S100A7. In the multi-step process of head and neck tumorigenesis, the presence of dysplastic areas in the epithelium is proposed to be associated with a likely progression to cancer; however there are no established biomarkers to predict their potential of malignant transformation. This study aimed to determine the clinical significance of S100A7 overexpression in HNSCC.Immunohistochemical analysis of S100A7 expression in HNSCC (100 cases), oral lesions (166 cases) and 100 histologically normal tissues was carried out and correlated with clinicopathological parameters and disease prognosis over 7 years for HNSCC patients. Overexpression of S100A7 protein was significant in oral lesions (squamous cell hyperplasia/dysplasia) and sustained in HNSCC in comparison with oral normal mucosa (p(trend)<0.001). Significant increase in nuclear S100A7 was observed in HNSCC as compared to dysplastic lesions (p = 0.005) and associated with well differentiated squamous cell carcinoma (p = 0.031). Notably, nuclear accumulation of S100A7 also emerged as an independent predictor of reduced disease free survival (p = 0.006, Hazard ratio (HR = 7.6), 95% CI = 1.3-5.1) in multivariate analysis underscoring its relevance as a poor prognosticator of HNSCC patients.Our study demonstrated nuclear accumulation of S100A7 may serve as predictor of poor prognosis in HNSCC patients. Further, increased nuclear accumulation of S100A7 in HNSCC as compared to dysplastic lesions warrants a large-scale longitudinal study of patients with dysplasia to evaluate its potential as a determinant of increased risk of transformation of oral premalignant lesions

Michael Gove’s war on professional historical expertise : conservative curriculum reform, extreme Whig history and the place of imperial heroes in modern multicultural Britain

Six years of continuously baiting his opponents within the history profession eventually amounted to little where it mattered most. UK Secretary of State for Education, Michael Gove, finally backtracked in 2013 on his plans to impose a curriculum for English schools based on a linear chronology of the achievements of British national heroes. His ‘history as celebration’ curriculum was designed to instil pride amongst students in a supposedly shared national past, but would merely have accentuated how many students in modern multicultural Britain fail to recognise themselves in what is taught in school history lessons. Now that the dust has settled on Gove’s tenure as Secretary of State, the time is right for retrospective analysis of how his plans for the history curriculum made it quite so far. How did he construct an ‘ideological’ conception of expertise which allowed him to go toe-to-toe for so long with the ‘professional’ expertise of academic historians and history teachers? What does the content of this ideological expertise tell us about the politics of race within Conservative Party curriculum reforms? This article answers these questions to characterise Gove as a ‘whig historian’ of a wilfully extreme nature in his attachment to imperial heroes as the best way to teach national history in modern multicultural Britain

Epigenetic deregulation of multiple S100 gene family members by differential hypomethylation and hypermethylation events in medulloblastoma

Deregulated expression of genes encoding members of the S100 family of calcium-binding proteins has been associated with the malignant progression of multiple tumour types. Using a pharmacological expression reactivation approach, we screened 16 S100 genes for evidence of epigenetic regulation in medulloblastoma, the most common malignant brain tumour of childhood. Four family members (S100A2, S100A4, S100A6 and S100A10) demonstrated evidence of upregulated expression in multiple medulloblastoma cell lines, following treatment with the DNA methyltransferase inhibitor, 5′-aza-2′-deoxycytidine. Subsequent analysis revealed methylation of critical CpG sites located within these four genes in an extended cell line panel. Assessment of these genes in the non-neoplastic cerebellum (from which medulloblastomas develop) revealed strong somatic methylation affecting S100A2 and S100A4, whereas S100A6 and S100A10 were unmethylated. Assessed against these normal tissue-specific methylation states, S100A6 and S100A10 demonstrated tumour-specific hypermethylation in medulloblastoma primary tumours (5 out of 40 and 4 out of 35, respectively, both 12%) and cell lines (both 7 out of 9, 78%), which was associated with their transcriptional silencing. Moreover, S100A6 hypermethylation was significantly associated with the aggressive large cell/anaplastic morphophenotype (P=0.026). In contrast, pro-metastatic S100A4 displayed evidence of hypomethylation relative to the normal cerebellum in a significant proportion primary tumours (7 out of 41, 17%) and cell lines (3 out of 9, 33%), which was associated with its elevated expression. In summary, these data characterise complex patterns of somatic methylation affecting S100 genes in the normal cerebellum and demonstrate their disruption causing epigenetic deregulation of multiple S100 family members in medulloblastoma development. Epigenetic events affecting S100 genes have potential clinical utility and merit further investigation as molecular biomarkers for this disease

Enhanced deformation of limestone and sandstone in the presence of high pCO2 fluids

International audienceGeological repositories subject to the injection of large amounts of anthropogenic carbon dioxide will undergo chemical and mechanical instabilities for which there are currently little experimental data. This study reports on experiments where low and high pCO2 (8~MPa) aqueous fluids where injected into natural rock samples. The experiments were performed in flow-through triaxial cells, where the vertical and confining stresses, temperature, and pressure and composition of the fluid were separately controlled and monitored. The axial vertical strains of two limestones and one sandstone were continuously measured during separate experiments for several months, with a strain rate resolution of 10^-11 s-1. Fluids exiting the triaxial cells where continuously collected and their compositions analysed. The high pCO2 fluids induced an increase in strain rates of the limestones by up to a factor of 5, compared to the low pCO2 fluids. Injection of high pCO2 fluids into the sandstone resulted in deformation rates one order of magnitude smaller than the limestones. The creep accelerating effect of high pCO2 fluids with respect to the limestones was mainly due to the acidification of the injected fluids, resulting in a significant increase in solubility and reaction kinetics of calcite. Compared to the limestones, the much weaker response of the sandstone was due to the much lower solubility and reactivity of quartz in high pCO2 fluids. In general, all samples showed a positive correlation between fluid flow rate and strain rate. X-ray tomography results revealed significant increases in porosity at the inlet portion of each core; the porosity increases were dependent on the original lithological structure and composition. The overall deformation of the samples is interpreted in terms of simultaneous dissolution reactions in pore spaces and intergranular pressure solution creep