- Browse by Author
Browsing by Author "Department of Dermatology, IU School of Medicine"
Now showing 1 - 10 of 21
Results Per Page
Sort Options
Item Autophagy dysregulation in cell culture and animals models of Spinal Muscular Atrophy(Elsevier, 2014-07) Custer, Sara K.; Androphy, Elliot J.; Department of Dermatology, IU School of MedicineAbnormal autophagy has become a central thread linking neurodegenerative diseases, particularly of the motor neuron. One such disease is spinal muscular atrophy (SMA), a genetic neuromuscular disorder caused by mutations in the SMN1 gene resulting in low levels of Survival Motor Neuron (SMN) protein. Despite knowing the causal protein, the exact intracellular processes that are involved in the selective loss of motor neurons remains unclear. Autophagy induction can be helpful or harmful depending on the situation, and we sought to understand the state of the autophagic response in SMA. We show that cell culture and animal models demonstrate induction of autophagy accompanied by attenuated autophagic flux, resulting in the accumulation of autophagosomes and their associated cargo. Expression of the SMN-binding protein a-COP, a known modulator of autophagic flux, can ameliorate this autophagic traffic jam.Item Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor(American Association for Cancer Research, 2014-12-01) Sahu, Ravi P.; Ocana, Jesus A.; Harrison, Kathleen A.; Ferracini, Matheus; Touloukian, Christopher E.; Al-Hassani, Mohammed; Sun, Louis; Loesch, Mathew; Murphy, Robert C.; Althouse, Sandra K.; Perkins, Susan M.; Speicher, Paul J.; Tyler, Douglas S.; Konger, Raymond L.; Travers, Jeffrey B.; Department of Dermatology, IU School of MedicineOxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation.Item Cross-generational impact of a male murine pheromone 2-sec-butyl-4,5- dihydrothiazole in female mice(The Royal Society, 2015-07-22) Koyama, Sachiko; Soini, Helena A.; Wager-Miller, James; Alley, William R.; Pizzo, Matthew J.; Rodda, Cathleen; Alberts, Jeffrey; Crystal, Jonathon D.; Lai, Cary; Foley, John; Novotny, Milos V.; Department of Dermatology, IU School of MedicineThe current understanding of the activity of mammalian pheromones is that endocrine and behavioural effects are limited to the exposed individuals. Here, we demonstrate that the nasal exposure of female mice to a male murine pheromone stimulates expansion of mammary glands, leading to prolonged nursing of pups. Subsequent behavioural testing of the pups from pheromone-exposed dams exhibited enhanced learning. Sialic acid components in the milk are known to be involved in brain development. We hypothesized that the offspring might have received more of this key nutrient that promotes brain development. The mRNA for polysialyltransferase, which produces polysialylated neural cell adhesion molecules related to brain development,was increased in the brain of offspring of pheromone-exposed dams at post-natal day 10, while it was not different at embryonic stages, indicating possible differential brain development during early post-natal life.Item Eruptive Disseminated Porokeratosis Associated with Corticosteroid-Induced Immunosuppression(Wiley, 2015-10) Bednarek, Robert; Ezra, Navid; Toubin, Yulianna; Linos, Konstantinos; Mousdicas, Nico; Department of Dermatology, IU School of MedicineEruptive disseminated porokeratosis (EDP) is a disease that presents clinically with sudden onset of erythematous papules and plaques, with a ridge-like border histologically represented by a cornoid lamella. We report a case of EDP occurring in a 39-year-old woman 3 days after completion of a 2-week course of oral corticosteroid therapy for an acute asthma exacerbation. The patient was treated with emollients and sun protection. Unlike the more chronic disseminated superficial (actinic) porokeratosis, EDP secondary to immunosuppression from corticosteroid therapy has very rarely been reported in the dermatological literature.Item Ferroxitosis: a cell death from modulation of oxidative phosphorylation and PKM2-dependent glycolysis in melanoma(Impact Journals, LLC, 2014-12-30) Lakhter, Alexander J.; Hamilton, James; Dagher, Pierre C.; Mukkamala, Suresh; Hato, Takashi; Dong, X. Charlie; Mayo, Lindsey D.; Harris, Robert A.; Shekhar, Anantha; Ivan, Mircea; Brustovetsky, Nickolay; Naidu, Samisubbu R.; Department of Dermatology, IU School of MedicineReliance on glycolysis is a characteristic of malignancy, yet the development of resistance to BRAF inhibitors in melanoma is associated with gain of mitochondrial function. Concurrent attenuation of oxidative phosphorylation and HIF-1α/PKM2-dependent glycolysis promotes a non-apoptotic, iron- and oxygen-dependent cell death that we term ferroxitosis. The redox cycling agent menadione causes a robust increase in oxygen consumption, accompanied by significant loss of intracellular ATP and rapid cell death. Conversely, either hypoxic adaptation or iron chelation prevents menadione-induced ferroxitosis. Ectopic expression of K213Q HIF-1α mutant blunts the effects of menadione. However, knockdown of HIF-1α or PKM2 restores menadione-induced cytotoxicity in hypoxia. Similarly, exposure of melanoma cells to shikonin, a menadione analog and a potential PKM2 inhibitor, is sufficient to induce ferroxitosis under hypoxic conditions. Collectively, our findings reveal that ferroxitosis curtails metabolic plasticity in melanoma.Item Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility(Nature Publishing Group, 2015-04-23) Yin, Xianyong; Low, Hui Qi; Wang, Ling; Li, Yonghong; Ellinghaus, Eva; Han, Jiali; Estivill, Xavier; Sun, Liangdan; Zuo, Xianbo; Shen, Changbing; Zhu, Caihong; Zhang, Anping; Sanchez, Fabio; Padyukov, Leonid; Catanese, Joseph J.; Krueger, Gerald G.; Duffin, Kristina Callis; Mucha, Sören; Weichenthal, Michael; Weidinger, Stephan; Lieb, Wolfgang; Foo, Jia Nee; Li, Yi; Sim, Karseng; Liany, Herty; Irwan, Ishak; Teo, Yikying; Theng, Colin T. S.; Gupta, Rashmi; Bowcock, Anne; De Jager, Philip L.; Qureshi, Abrar A.; de Bakker, Paul I. W.; Seielstad, Mark; Liao, Wilson; Ståhle, Mona; Franke, Andre; Zhang, Xuejun; Liu, Jianjun; Department of Dermatology, IU School of MedicinePsoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations.Item Human keratinocyte differentiation requires translational control by the eIF2α kinase GCN2(Elsevier, 2017) Collier, Ann E.; Wek, Ronald C.; Spandau, Dan F.; Department of Dermatology, IU School of MedicineAppropriate and sequential differentiation of keratinocytes is essential for all functions of the human epidermis. While transcriptional regulation has proven to be important for keratinocyte differentiation, little is known about the role of translational control. A key mechanism for modulating translation is through phosphorylation of the α subunit of eIF2. A family of different eIF2α kinases function in the integrative stress response to inhibit general protein synthesis coincident with preferential translation of select mRNAs that participate in stress alleviation. Here we demonstrate that translational control through eIF2α phosphorylation is required for normal keratinocyte differentiation. Analyses of polysome profiles revealed that key differentiation genes, including involucrin, are bound to heavy polysomes during differentiation, despite decreased general protein synthesis. Induced eIF2α phosphorylation by the GCN2 protein kinase facilitated translational control and differentiation-specific protein expression during keratinocyte differentiation. Furthermore, loss of GCN2 thwarted translational control, normal epidermal differentiation, and differentiation gene expression in organotypic skin culture. These findings underscore a previously unknown function for GCN2 phosphorylation of eIF2α and translational control in the formation of an intact human epidermis.Item Human papillomavirus oncogenic E6 protein regulates human β-defensin 3 (hBD3) expression via the tumor suppressor protein p53.(Impact Journals, 2016-05-10) DasGupta, Twishasri; Nweze, Emeka I.; Yue, Hong; Wang, Liming; Jin, Jessica; Ghosh, Santosh K.; Kawsar, Hameem I.; Zender, Chad; Androphy, Elliot J.; Weinberg, Aaron; McCormick, Thomas S.; Jin, Ge; Department of Dermatology, IU School of MedicineHuman β-defensin-3 (hBD3) is an epithelial cell-derived innate immune regulatory molecule overexpressed in oral dysplastic lesions and fosters a tumor-promoting microenvironment. Expression of hBD3 is induced by the epidermal growth factor receptor signaling pathway. Here we describe a novel pathway through which the high-risk human papillomavirus type-16 (HPV-16) oncoprotein E6 induces hBD3 expression in mucosal keratinocytes. Ablation of E6 by siRNA induces the tumor suppressor p53 and diminishes hBD3 in HPV-16 positive CaSki cervical cancer cells and UM-SCC-104 head and neck cancer cells. Malignant cells in HPV-16-associated oropharyngeal cancer overexpress hBD3. HPV-16 E6 induces hBD3 mRNA expression, peptide production and gene promoter activity in mucosal keratinocytes. Reduction of cellular levels of p53 stimulates hBD3 expression, while activation of p53 by doxorubicin inhibits its expression in primary oral keratinocytes and CaSki cells, suggesting that p53 represses hBD3 expression. A p53 binding site in the hBD3 gene promoter has been identified by using electrophoretic mobility shift assays and chromatin immunoprecipitation (ChIP). In addition, the p63 protein isoform ΔNp63α, but not TAp63, stimulated transactivation of the hBD3 gene and was co-expressed with hBD3 in head and neck cancer specimens. Therefore, high-risk HPV E6 oncoproteins may stimulate hBD3 expression in tumor cells to facilitate tumorigenesis of HPV-associated head and neck cancer.Item Levels of the E2 interacting protein TopBP1 modulate papillomavirus maintenance stage replication(Elsevier, 2015-04) Kanginakudru, Sriramana; DeSmet, Marsha; Thomas, Yanique; Morgan, Iain M.; Androphy, Elliot J.; Department of Dermatology, IU School of MedicineThe evolutionarily conserved DNA topoisomerase II beta-binding protein 1 (TopBP1) functions in DNA replication, DNA damage response, and cell survival. We analyzed the role of TopBP1 in human and bovine papillomavirus genome replication. Consistent with prior reports, TopBP1 co-localized in discrete nuclear foci and was in complex with papillomavirus E2 protein. Similar to E2, TopBP1 is recruited to the region of the viral origin of replication during G1/S and early S phase. TopBP1 knockdown increased, while over-expression decreased transient virus replication, without affecting cell cycle. Similarly, using cell lines harboring HPV-16 or HPV-31 genome, TopBP1 knockdown increased while over-expression reduced viral copy number relative to genomic DNA. We propose a model in which TopBP1 serves dual roles in viral replication: it is essential for initiation of replication yet it restricts viral copy number.Item Pediatric positional sitting dermatitis: a new form of pediatric contact dermatitis(Wiley, 2016-05) Isaacs, Michael J.; Strausburg, Matthew B.; Mousdicas, Nico; Department of Dermatology, IU School of MedicineWe report on four pediatric patients who presented with localized dermatitis in areas subject to repetitive friction due to their sitting positions. We propose that the cause of the eruption was irritant contact dermatitis due to frequently sitting in a crossed-leg sitting position, an entity for which we have coined the term pediatric positional sitting dermatitis (PPSD). The goal of this report is to raise clinicians' awareness of PPSD, which to our knowledge has not been previously described, and to discuss management of these patients.
- «
- 1 (current)
- 2
- 3
- »