The development of the epidermis, a stratified squamous epithelium, is dependent on the regulated differentiation of keratinocytes. Differentiation begins with the initiation of stratification, a process tightly controlled through proper gene expression. AP-2 is expressed in skin and previous research suggested a pathway where p63 gene induction results in increased expression of AP-2 which in turn is responsible for induction of K14. This study uses a conditional gene ablation model to further explore the role of AP-2 in skin development. Mice deficient for AP-2 exhibited delayed expression of p63, K14, and K1, key genes required for development and differentiation of the epidermis. In addition, microarray analysis of E16.5 skin revealed delayed expression of additional late epidermal differentiation genes: filaggrin, repetin and secreted Ly6/Plaur domain containing 1, in mutant mice. The genetic delay in skin development was further confirmed by a functional delay in the formation of an epidermal barrier. These results document an important role for AP-2 in skin development, and reveal the existence of regulatory factors that can compensate for AP-2 in its absence.
Disruption of epidermal specific gene expression and delayed skin development in AP-2 gamma mutant mice.
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Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility.
Specimen part
View SamplesWe obtained peripheral blood samples for women from Utah (USA) and Ontario (Canada) who had a family history of breast cancer (or did not), who carried a BRCA1/2 mutation (or did not), and who had developed breast cancer (or had not).
Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility.
Specimen part
View SamplesWe obtained peripheral blood samples for women from Utah (USA) and Ontario (Canada) who had a family history of breast cancer (or did not), who carried a BRCA1/2 mutation (or did not), and who had developed breast cancer (or had not).
Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility.
Specimen part
View SamplesDrug resistance is a major obstacle in cancer therapy. The molecular mechanisms of drug resistance still remain largely elusive. Microarray analyses on paired primary myeloma samples at baseline and after therapy or at relapse showed that NEK2 was one of the most up-regulated genes in myeloma cells after high-dose chemotherapy or at relapse. By analyzing the published (> 2,500) microarrays and clinical datasets, we found that NEK2 expression is increased in many malignancies, and that high expression of NEK2 was associated with a shorter event-free and overall survival. Moreover, NEK2 expression was typically increased in tumors with aggressive subtype and advanced TNM stage. Our studies indicate that over-expressing NEK2 in cancer cells resulted in enhanced cell proliferation and drug resistance, whereas knockdown of NEK2 induced significant cancer cell death and growth inhibition. We found that NEK2 over-expression activates cell cycle progression and cell division through the stimulation of cell cycling genes CDC2/CCNB1 and PBK. Interestingly, NEK2-overexpression also activated the Wnt/-catenin signaling pathway. We conclude that NEK2 represents a predictor for drug resistance and poor prognosis in cancers and could be a potential target for cancer therapy.
NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers.
Specimen part, Subject
View SamplesHighlighting the gene expression characteristics of a large panel of lung cancer cell lines.
No associated publication
Specimen part, Cell line
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Dietary Selenium Levels Affect Selenoprotein Expression and Support the Interferon-γ and IL-6 Immune Response Pathways in Mice.
Sex, Specimen part
View SamplesTo date, no published reports (human or animal) have examined the impact of acute liver failure on global gene expression profiles in remote organ systems like the kidney. In this study, we have characterized a model of acute kidney injury (AKI) using two highly-accurate techniques for assessing renal function in a mouse. In this model, mice developed massive hepatocyte necrosis, disordered hepatosplanchnic hemodynamics, and alterations consistent with ALF. Simultaneously, acute renal insufficiency developed, manifesting as oliguria, azotemia, and decreased glomerular filtration. In this paper, renal function is corroborated using two independent methodologies. These techniques are used in addition to hemodynamic, biochemical, and histologic analyses to demonstrate that acute hepatic injury promulgates renal dysfunction in a mouse. Similar to network-based analyses conducted in other models of human disease, we present a comprehensive, genome-wide assessment of the differentially-regulated, renal transcriptome in the setting of massive hepatic necrosis. Using this approach, mice receiving the select hepatotoxin D-(+)-Galactosamine HCl (GalN) were found to have significant perturbations in renal pathways related to lipid metabolism, small molecule biochemistry, the cell cycle, molecular transport, and amino acid metabolism, despite normal renal histology. By combining data obtained from clinical, physiologic, and molecular investigations, our findings have direct implications for exploring potential pharmacological approaches to the prevention of AKI in this setting.
No associated publication
Specimen part, Time
View SamplesMice were fed Se-deficient or Se-adequate diets for 6 weeks. Liver and lung tissue were harvested and processed for RNA-Seq, ribosome profiling, and microarray analysis. From these studies, we identified changes in mRNA levels and translation of selenoprotein genes and genes regulated by interferon-gamma. Cytokine profiles of serum indicated that interferon-gamma and IL-6 levels were increased in the Se-adequate mice relative to Se-deficient mice.
Dietary Selenium Levels Affect Selenoprotein Expression and Support the Interferon-γ and IL-6 Immune Response Pathways in Mice.
Sex, Specimen part
View SamplesWe show that dHNF4 null mutant larvae are sensitive to starvation. Starved mutant larvae consume glycogen normally, but retain lipids in their midgut and fat body, and have increased levels of long chain fatty acids, suggesting that they are unable to efficiently mobilize stored fat for energy. HNF4 dependent transcripts were identified under fed and starved conditions. Microarray studies indicate reduced expression of genes that control lipid catabolism and beta-oxidation. Late second instar control and HNF4 mutant larvae were collected and fed or starved for 24 hours, and then RNA was isolated for analysis. Taken together, our results support a feed-forward model for dHNF4, in which fatty acids released from triglycerides activate the receptor, inducing enzymes that drive fatty acid oxidation for energy production.
No associated publication
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