FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism

A major target of insulin signaling is the FoxO family of Forkhead transcription factors, which translocate from the nucleus to the cytoplasm following insulin-stimulated phosphorylation. Here we show that the Forkhead transcription factors FoxK1 and FoxK2 are also downstream targets of insulin action, but that following insulin stimulation, they translocate from the cytoplasm to nucleus, reciprocal to the translocation of FoxO1. FoxK1/FoxK2 translocation to the nucleus is dependent on the Akt-mTOR pathway, while its localization to the cytoplasm in the basal state is dependent on GSK3. Knockdown of FoxK1 and FoxK2 in liver cells results in upregulation of genes related to apoptosis and down-regulation of genes involved in cell cycle and lipid metabolism. This is associated with decreased cell proliferation and altered mitochondrial fatty acid metabolism. Thus, FoxK1/K2 are reciprocally regulated to FoxO1 following insulin stimulation and play a critical role in the control of apoptosis, metabolism and mitochondrial function

Genome-wide approaches for identification of nuclear receptor target genes

Large-scale genomics analyses have grown by leaps and bounds with the rapid advances in high throughput DNA sequencing and synthesis techniques. Nuclear receptor signaling is ideally suited to genomics studies because receptors function as ligand-regulated gene switches. This review will survey the strengths and limitations of three major classes of high throughput techniques widely used in the nuclear receptor field to characterize ligand-dependent gene regulation: expression profiling studies (microarrays, SAGE and related techniques), chromatin immunoprecipitation followed by microarray (ChIP-on-chip), and genome-wide in silico hormone response element screens. We will discuss each technique, and how each has contributed to our understanding of nuclear receptor signaling

Collecting a set of psoriasis family material through a patient organisation; clinical characterisation and presence of additional disorders

BACKGROUND: The aim of the present study was to describe the clinical characteristics of a population of psoriatics sampled from a patient organisation and not from hospitals or out-patient clinics. Furthermore, we wanted to compare siblings with and without psoriasis regarding the occurrence of other diseases. METHODS: At the end of 1991, we initiated a project which aimed to study genetic factors leading to psoriasis. Firstly, we sent questionnaires to all the members of the Swedish Psoriasis Association. We then examined 1,217 individuals (570 with psoriasis) from 310 families, in their homes in the southern part of Sweden. All the available family members were examined clinically and asked about the course of the skin disease and the occurrence of other diseases. The eight hundred members of the proband generation were divided into two groups, with or without psoriasis, and their clinical features were compared. RESULTS: Most individuals in this study population had a mild form of psoriasis. The siblings with psoriasis had joint complaints significantly more frequently than their siblings without the skin disease and those with joint complaints had more widespread skin disease. Among the other studied concomitant diseases (iritis, heart or hypertension disease, endocrine disease, inflammatory bowel disease and neurological disease), we were not able to find any difference. Seventy-seven of 570 persons were found to be in remission (13.5%). Females had a mean onset 2.5 years earlier than males. We were not able to find any correlation between the extent of the skin disease and age at onset. Twice as many persons with joint complaints were found among those with psoriasis than among those without, 28% versus 13%. Almost half (48%) the psoriatics who also had joint complaints had psoriasis lesions on their nails. Endocrine disorders were found in 9% of those without any allele for Cw6, but only in 1% of those who had Cw6. In fact, none of 183 Cw6 carriers had diabetes, as compared to the population prevalence of 3–5% in Sweden. CONCLUSION: With the exception of joint complaints, persons with psoriasis, collected from a patient organisation, did not have an increased frequency of (studied) co-existing diseases

S100A7 (Psoriasin), highly expressed in Ductal Carcinoma In Situ (DCIS), is regulated by IFN-gamma in mammary epithelial cells

<p>Abstract</p> <p>Background</p> <p>The aim of the present work was to explore signal transduction pathways used in the regulation of S100A7 (psoriasin). Members of the S100 gene family participate in many important cellular functions. Psoriasin, S100A8 (calgranulin A) and S100A9 (calgranulin B) are expressed in ductal carcinoma <it>in situ </it>(DCIS), as well as in the hyperproliferative skin disease, psoriasis. In the latter condition, a disturbance in the STAT pathway has recently been reported. This pathway is implicated in the regulation of IFN-gamma, widely recognized as a key cytokine in psoriasis. IFN-gamma also exerts anti-tumor action in a number of tumor cell types, including breast cancer. We therefore examined the effect of IFN-gamma and STAT-signaling on the psoriasin expression.</p> <p>Methods</p> <p>We established a TAC2 mouse mammary epithelial cell line with tetracycline-inducible psoriasin expression (Tet-Off). Viability in cell culture was estimated using MTS assay. Protein and gene expression were evaluated by Western blotting and quantitative real-time PCR. Statistical analyses were assessed using a one-tailed, paired t-test.</p> <p>Results</p> <p>We report the downregulation of psoriasin by IFN-gamma in the MDA-MB-468 breast cancer cell line, as well as the downregulation of psoriasin induced by anoikis in cell lines derived from different epithelial tissues. In contrast, IFN-gamma had no suppressive effect on calgranulin A or calgranulin B. IFN-gamma is an important activator of the STAT1 pathway and we confirmed an active signaling pathway in the cell lines that responded to IFN-gamma treatment. In contrast, in the SUM190 breast carcinoma cell line, IFN-gamma did not suppress the expression of endogenous psoriasin. Moreover, a reduced phosphorylation of the STAT1 protein was observed. We showed that IFN-gamma treatment and the inhibition of the transcription factor NFkappaB had a synergistic effect on psoriasin levels. Finally, in TAC2 cells with tetracycline-induced psoriasin expression, we observed the increased viability of psoriasin-expressing cells after IFN-gamma treatment.</p> <p>Conclusion</p> <p>Our data support the possibility that psoriasin expression is transcriptionally suppressed by IFN-gamma and that this effect is likely to be mediated by the activation of the STAT1 signaling pathway. The increased viability of psoriasin-expressing cells after IFN-gamma exposure suggests that psoriasin expression leads to the development of an apoptosis-resistant phenotype.</p

S100A7 (psoriasin) expression is associated with aggressive features and alteration of Jab1 in ductal carcinoma in situ of the breast

INTRODUCTION: The S100A7 (psoriasin) gene is highly expressed in ductal carcinoma in situ (DCIS) of the breast and can be downregulated in invasive carcinoma. Persistent S100A7 expression in invasive carcinoma is associated with a worse prognosis, and this effect may be mediated in part through interaction with the multifunctional cell signaling protein Jab1. METHODS: In order to investigate the relationship between S100A7 and progression from DCIS to invasive carcinoma, we studied S100A7 expression in 136 patients with DCIS (including 46 patients with associated invasive carcinoma) by immunohistochemistry. RESULTS: S100A7 expression was present in 63 out of 136 (46%) of DCIS lesions and was associated with estrogen receptor negative status (P = 0.0002), higher nuclear grade (P < 0.0001), necrosis (P < 0.0001) and inflammation (P < 0.0001). S100A7 status was no different between DCIS with and DCIS without an invasive component, but higher levels of S100A7 were present in DCIS associated with invasive carcinoma (P < 0.004). Analysis of a subset of cases showed that S100A7 expression was also associated with an increase in nuclear Jab1 (n = 43; P = 0.0019) and reduced p27(kip1 )(n = 47; P = 0.0168). In cases of DCIS associated with invasive carcinoma, there was also a significant reduction in S100A7 between in situ and invasive components (n = 46; P < 0.0001). In pure DCIS cases treated by local excision, there was no difference in frequency of S100A7 expression between patients with recurrence of DCIS (n = 9) and those without (n = 36). CONCLUSION: The findings reported here suggest that, although S100A7 may not be a marker for recurrence of DCIS, it is associated with poor prognostic markers in DCIS and may influence progression of breast carcinoma through its interaction with and influence on Jab1

Psoriasin (S100A7) expression is altered during skin tumorigenesis

BACKGROUND: Psoriasin (S100A7) expression has previously been associated with psoriasiform hyperplasia as well as with tumor progression in breast cancer. Its expression profile for different stages of skin lesions is unknown. The aim of this study was to determine the relationship between psoriasin (S100A7) and tumor progression in skin. METHODS: Psoriasin was assessed by immunohistochemistry and levels of expression determined by semi-quantitative scoring in skin biopsies from 50 patients. The cohort included normal skin, actinic keratosis, squamous carcinoma in-situ, invasive squamous cell carcinoma, and basal cell carcinoma. RESULTS: In normal skin, psoriasin was rarely detected in epidermis but was expressed in underlying adnexae. In abnormal epidermis psoriasin was frequently expressed in abnormal keratinocytes in actinic keratosis, in-situ and invasive squamous cell carcinoma, but was rarely observed in the basal epidermal layer or in superficial or invasive basal cell carcinoma. The highest levels of expression were seen within squamous carcinoma in-situ. Significantly reduced levels of expression were observed in both unmatched (p = 0.0001) and matched (p < 0.004) invasive squamous cell carcinoma. Psoriasin expression within abnormal squamous lesions correlated with mitotic count (r = 0.54, p = 0.0036), however no significant relation was found with the intensity of dermal inflammatory cell infiltrates assessed within each pathology. CONCLUSION: These results suggest that altered psoriasin expression occurs in abnormal epidermis and that downregulation may be related to the onset of invasion in squamous cell carcinoma in skin

S100A7 and the progression of breast cancer

The S100 gene family comprises more than 20 members whose protein sequences encompass at least one EF-hand Ca(2+ )binding motif. The expression of individual family members is not ubiquitous for all tissues and there appears to be an element of tissue-specific expression. Molecular analysis of breast tumors has revealed that several S100s, including S100A2, S100A4 and S100A7, exhibit altered expression levels during breast tumorigenesis and/or progression. Subsequent studies have started to describe a functional role for these S100 proteins as well as their mechanism of action and the biochemical pathways they modify. The present review outlines what is known about S100A7 in breast cancer and summarizes the need to better understand the importance of this protein in breast cancer

Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants

Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size amp;gt;39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFkB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8(+) T-cells and CD4(+) T-cells including T(H)0, T(H)1 and T(H)17). The identified loci explain similar to 28% of the genetic heritability and generate a discriminatory genetic risk score (AUC = 0.76 in our sample) that is significantly correlated with age at onset (p = 2 x 10(-89)). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis.Funding Agencies|National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183]; Foundation for the National Institutes of Health; Dermatology Foundation; National Psoriasis Foundation; Arthritis National Research Foundation; Ann Arbor Veterans Affairs Hospital; Dawn and Dudley Holmes Foundation; Babcock Memorial Trust; Medical Research Council [MR/L011808/1]; German Ministry of Education and Research (BMBF); Doris Duke Foundation [2013106]; National Institute of Health [K08AR060802, R01AR06907]; Taubman Medical Research Institute; Department of Health via the NIHR comprehensive Biomedical Research Center; Kings College London; KCH NHS Foundation Trust; Barbara and Neal Henschel Charitable Foundation; Heinz Nixdorf Foundation; Estonian Ministry of Education and Research [IUT20-46]; Centre of Translational Genomics of University of Tartu (SP1GVARENG); European Regional Development Fund (Centre of Translational Medicine, University of Tartu); German Federal Ministry of Education and Research (BMBF); National Human Genome Research Institute of the National Institutes of Health [R44HG006981]; International Psoriasis Council</p

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

Gene expression profile of AIDS-related Kaposi's sarcoma

BACKGROUND: Kaposi's Sarcoma (KS) is a proliferation of aberrant vascular structures lined by spindle cells, and is caused by a gammaherpes virus (HHV8/KSHV). Its course is aggravated by co-infection with HIV-1, where the timing of infection with HIV-1 and HHV8 is important for the clinical outcome. METHODS: In order to better understand the pathogenesis of KS, we have analysed tissue from two AIDS-KS lesions, and from normal skin by serial analysis of gene expression (SAGE). Semi-quantitative RT-PCR was then used to validate the results. RESULTS: The expression profile of AIDS-related KS (AIDS-KS) reflects an active process in the skin. Transcripts of HHV8 were found to be very low, and HIV-1 mRNA was not detected by SAGE, although it could be found using RT-PCR. Comparing the expression profile of AIDS-KS tissue with publicly available SAGE libraries suggested that AIDS-KS mRNA levels are most similar to those in an artificially mixed library of endothelial cells and leukocytes, in line with the description of KS lesions as containing spindle cells with endothelial characteristics, and an inflammatory infiltrate. At least 64 transcripts were found to be significantly elevated, and 28 were statistically downregulated in AIDS-KS compared to normal skin. Five of the upregulated mRNAs, including Tie 1 and sialoadhesin/CD169, were confirmed by semi-quantitative PCR to be elevated in additional AIDS-KS biopsies. Antibodies to sialoadhesin/CD169, a known marker of activated macrophages, were shown to specifically label tumour macrophages. CONCLUSION: The expression profile of AIDS-KS showed 64 genes to be significantly upregulated, and 28 genes downregulated, compared with normal skin. One of the genes with increased expression was sialoadhesin (CD169). Antibodies to sialoadhesin/CD169 specifically labelled tumour-associated macrophages, suggesting that macrophages present in AIDS-KS lesions belong to a subset of human CD169+ macrophages