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Item 14-3-3σ regulation of and interaction with YAP1 in acquired gemcitabine resistance via promoting ribonucleotide reductase expression(Impact Journals, LLC, 2016-04-05) Qin, Li; Dong, Zizheng; Zhang, Jian-Ting; Department of Pharmacology and Toxicology, IU School of MedicineGemcitabine is an important anticancer therapeutics approved for treatment of several human cancers including locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Its clinical effectiveness, however, is hindered by existence of intrinsic and development of acquired resistances. Previously, it was found that 14-3-3σ expression associates with poor clinical outcome of PDAC patients. It was also found that 14-3-3σ expression is up-regulated in gemcitabine resistant PDAC cells and contributes to the acquired gemcitabine resistance. In this study, we investigated the molecular mechanism of 14-3-3σ function in gemcitabine resistance and found that 14-3-3σ up-regulates YAP1 expression and then binds to YAP1 to inhibit gemcitabine-induced caspase 8 activation and apoptosis. 14-3-3σ association with YAP1 up-regulates the expression of ribonucleotide reductase M1 and M2, which may mediate 14-3-3σ/YAP1 function in the acquired gemcitabine resistance. These findings suggest a possible role of YAP1 signaling in gemcitabine resistance.Item Are there errors in glycogen biosynthesis and is laforin a repair enzyme?(Elsevier, 2011-10-20) Roach, Peter J.; Department of Biochemistry & Molecular Biology, IU School of MedicineGlycogen, a branched polymer of glucose, is well known as a cellular reserve of metabolic energy and/or biosynthetic precursors. Besides glucose, however, glycogen contains small amounts of covalent phosphate, present as C2 and C3 phosphomonoesters. Current evidence suggests that the phosphate is introduced by the biosynthetic enzyme glycogen synthase as a rare alternative to its normal catalytic addition of glucose units. The phosphate can be removed by the laforin phosphatase, whose mutation causes a fatal myoclonus epilepsy called Lafora disease. The hypothesis is that glycogen phosphorylation can be considered a catalytic error and laforin a repair enzyme.Item Ataxia Telangiectasia Mutated Dysregulation Results in Diabetic Retinopathy(Wiley Blackwell (John Wiley & Sons), 2016-02) Bhatwadekar, Ashay D.; Duan, Yaqian; Chakravarthy, Harshini; Korah, Maria; Caballero, Sergio; Busik, Julia V.; Grant, Maria B.; Department of Ophthalmology, IU School of MedicineAtaxia telangiectasia mutated (ATM) acts as a defense against a variety of bone marrow (BM) stressors. We hypothesized that ATM loss in BM-hematopoietic stem cells (HSCs) would be detrimental to both HSC function and microvascular repair while sustained ATM would be beneficial in disease models of diabetes. Chronic diabetes represents a condition associated with HSC depletion and inadequate vascular repair. Gender mismatched chimeras of ATM(-/-) on wild type background were generated and a cohort were made diabetic using streptozotocin (STZ). HSCs from the STZ-ATM(-/-) chimeras showed (a) reduced self-renewal; (b) decreased long-term repopulation; (c) depletion from the primitive endosteal niche; (d) myeloid bias; and (e) accelerated diabetic retinopathy (DR). To further test the significance of ATM in hematopoiesis and diabetes, we performed microarrays on circulating angiogenic cells, CD34(+) cells, obtained from a unique cohort of human subjects with long-standing (>40 years duration) poorly controlled diabetes that were free of DR. Pathway analysis of microarrays in these individuals revealed DNA repair and cell-cycle regulation as the top networks with marked upregulation of ATM mRNA compared with CD34(+) cells from diabetics with DR. In conclusion, our study highlights using rodent models and human subjects, the critical role of ATM in microvascular repair in DR.Item Critical role of NKT cells in posttransplant alloantibody production(Wiley Blackwell (Blackwell Publishing), 2014-11) Zimmerer, J. M.; Swamy, P.; Sanghavi, P. B.; Wright, C. L.; Abdel-Rasoul, M.; Elzein, S. M.; Brutkiewicz, R. R.; Bumgardner, G. L.; Department of Microbiology & Immunology, IU School of MedicineWe previously reported that posttransplant alloantibody production in CD8-deficient hosts is IL-4+ CD4+ T cell-dependent and IgG1 isotype-dominant. The current studies investigated the hypothesis that IL-4-producing natural killer T cells (NKT cells) contribute to maximal alloantibody production. To investigate this, alloantibody levels were examined in CD8-deficient WT, CD1d KO and Jα18 KO transplant recipients. We found that the magnitude of IgG1 alloantibody production was critically dependent on the presence of type I NKT cells, which are activated by day 1 posttransplant. Unexpectedly, type I NKT cell contribution to enhanced IgG1 alloantibody levels was interferon-γ-dependent and IL-4-independent. Cognate interactions between type I NKT and B cells alone do not stimulate alloantibody production. Instead, NKT cells appear to enhance maturation of IL-4+ CD4+ T cells. To our knowledge, this is the first report to substantiate a critical role for type I NKT cells in enhancing in vivo antibody production in response to endogenous antigenic stimuli.Item Hypoxia Mediated Downregulation of miRNA Biogenesis Promotes Tumor Progression(Nature Publishing Group, 2014-10-29) Rupaimoole, Rajesha; Wu, Sherry Y.; Pradeep, Sunila; Ivan, Cristina; Pecot, Chad V.; Gharpure, Kshipra M.; Nagaraja, Archana S.; Armaiz-Pena, Guillermo N.; McGuire, Michael; Zand, Behrouz; Dalton, Heather J.; Filant, Justyna; Miller, Justin Bottsford; Lu, Chunhua; Sadaoui, Nouara C.; Mangala, Lingegowda S.; Taylor, Morgan; van den Beucken, Twan; Koch, Elizabeth; Rodriguez-Aguayo, Cristian; Huang, Li; Bar-Eli, Menashe; Wouters, Bradly G.; Radovich, Milan; Ivan, Mircea; Calin, George A.; Zhang, Wei; Lopez-Berestein, Gabriel; Sood, Anil K.; Department of Surgery, IU School of MedicineCancer-related deregulation of miRNA biogenesis has been suggested, but the underlying mechanisms remain elusive. Here, we report a previously unrecognized effect of hypoxia in the downregulation of Drosha and Dicer in cancer cells that leads to dysregulation of miRNA biogenesis and increased tumor progression. We show that hypoxia mediated downregulation of Drosha is dependent on ETS1/ELK1 transcription factors. Moreover, mature miRNA array and deep sequencing studies reveal altered miRNA maturation in cells under hypoxic conditions. At a functional level, this phenomenon results in increased cancer progression in vitro and in vivo, and data from patient samples are suggestive of miRNA biogenesis downregulation in hypoxic tumors. Rescue of Drosha by siRNAs targeting ETS1/ELK1 in vivo results in significant tumor regression. These findings provide a new link in the mechanistic understanding of global miRNA downregulation in the tumor microenvironment.Item Interleukin-driven insulin-like growth factor promotes prostatic inflammatory hyperplasia(American Society for Pharmacology & Experimental Therapeutics (ASPET), 2014-12) Hahn, Alana M.; Myers, Jason D.; McFarland, Eliza K.; Lee, Sanghee; Jerde, Travis J.; Department of Pharmacology and Toxicology, IU School of MedicineProstatic inflammation is of considerable importance to urologic research because of its association with benign prostatic hyperplasia and prostate cancer. However, the mechanisms by which inflammation leads to proliferation and growth remain obscure. Here, we show that insulin-like growth factors (IGFs), previously known as critical developmental growth factors during prostate organogenesis, are induced by inflammation as part of the proliferative recovery to inflammation. Using genetic models and in vivo IGF receptor blockade, we demonstrate that the hyperplastic response to inflammation depends on interleukin-1-driven IGF signaling. We show that human prostatic hyperplasia is associated with IGF pathway activation specifically localized to foci of inflammation. This demonstrates that mechanisms of inflammation-induced epithelial proliferation and hyperplasia involve the induction of developmental growth factors, further establishing a link between inflammatory and developmental signals and providing a mechanistic basis for the management of proliferative diseases by IGF pathway modulation.Item Lovastatin enhances adenovirus-mediated TRAIL induced apoptosis by depleting cholesterol of lipid rafts and affecting CAR and death receptor expression of prostate cancer cells(Impact Journals, LLC, 2015-02-20) Liu, Youhong; Chen, Lin; Gong, Zhicheng; Shen, Liangfang; Kao, Chinghai; Hock, Janet M.; Sun, Lunquan; Li, Xiong; Department of Urology, IU school of MedicineOncolytic adenovirus and apoptosis inducer TRAIL are promising cancer therapies. Their antitumor efficacy, when used as single agents, is limited. Oncolytic adenoviruses have low infection activity, and cancer cells develop resistance to TRAIL-induced apoptosis. Here, we explored combining prostate-restricted replication competent adenovirus-mediated TRAIL (PRRA-TRAIL) with lovastatin, a commonly used cholesterol-lowering drug, as a potential therapy for advanced prostate cancer (PCa). Lovastatin significantly enhanced the efficacy of PRRA-TRAIL by promoting the in vivo tumor suppression, and the in vitro cell killing and apoptosis induction, via integration of multiple molecular mechanisms. Lovastatin enhanced PRRA replication and virus-delivered transgene expression by increasing the expression levels of CAR and integrins, which are critical for adenovirus 5 binding and internalization. Lovastatin enhanced TRAIL-induced apoptosis by increasing death receptor DR4 expression. These multiple effects of lovastatin on CAR, integrins and DR4 expression were closely associated with cholesterol-depletion in lipid rafts. These studies, for the first time, show correlations between cholesterol/lipid rafts, oncolytic adenovirus infection efficiency and the antitumor efficacy of TRAIL at the cellular level. This work enhances our understanding of the molecular mechanisms that support use of lovastatin, in combination with PRRA-TRAIL, as a candidate strategy to treat human refractory prostate cancer in the future.Item The MafA transcription factor becomes essential to islet β-cells soon after birth(American Diabetes Association, 2014-06) Hang, Yan; Yamamoto, Tsunehiko; Benninger, Richard K. P.; Brissova, Marcela; Guo, Min; Bush, Will; Piston, David W.; Powers, Alvin C.; Magnuson, Mark; Thurmond, Debbie C.; Stein, Roland; Department of Pediatrics, IU School of MedicineThe large Maf transcription factors, MafA and MafB, are expressed with distinct spatial-temporal patterns in rodent islet cells. Analysis of Mafa(-/-) and pancreas-specific Mafa(∆panc) deletion mutant mice demonstrated a primary role for MafA in adult β-cell activity, different from the embryonic importance of MafB. Our interests here were to precisely define when MafA became functionally significant to β-cells, to determine how this was affected by the brief period of postnatal MafB production, and to identify genes regulated by MafA during this period. We found that islet cell organization, β-cell mass, and β-cell function were influenced by 3 weeks of age in Mafa(Δpanc) mice and compromised earlier in Mafa(Δpanc);Mafb(+/-) mice. A combination of genome-wide microarray profiling, electron microscopy, and metabolic assays were used to reveal mechanisms of MafA control. For example, β-cell replication was produced by actions on cyclin D2 regulation, while effects on granule docking affected first-phase insulin secretion. Moreover, notable differences in the genes regulated by embryonic MafB and postnatal MafA gene expression were found. These results not only clearly define why MafA is an essential transcriptional regulator of islet β-cells, but also why cell maturation involves coordinated actions with MafB.Item MicroRNA Expression Profiling of Human Respiratory Epithelium Affected by Invasive Candida Infection(Public Library of Science, 2015) Muhammad, Syed Aun; Fatima, Nighat; Syed, Nawazish-I.-Husain; Wu, Xiaogang; Yang, X. Frank; Chen, Jake Yue; IU School of Informatics and ComputingInvasive candidiasis is potentially life-threatening systemic fungal infection caused by Candida albicans (C. albicans). Candida enters the blood stream and disseminate throughout the body and it is often observed in hospitalized patients, immunocompromised individuals or those with chronic diseases. This infection is opportunistic and risk starts with the colonization of C. albicans on mucocutaneous surfaces and respiratory epithelium. MicroRNAs (miRNAs) are small non-coding RNAs which are involved in the regulation of virtually every cellular process. They regulate and control the levels of mRNA stability and post-transcriptional gene expression. Aberrant expression of miRNAs has been associated in many disease states, and miRNA-based therapies are in progress. In this study, we investigated possible variations of miRNA expression profiles of respiratory epithelial cells infected by invasive Candida species. For this purpose, respiratory epithelial tissues of infected individuals from hospital laboratory were accessed before their treatment. Invasive Candida infection was confirmed by isolation of Candia albicans from the blood cultures of the same infected individuals. The purity of epithelial tissues was assessed by flow cytometry (FACSCalibur cytometer; BD Biosciences, Heidelberg, Germany) using statin antibody (S-44). TaqMan quantitative real-time PCR (in a TaqMan Low Density Array format) was used for miRNA expression profiling. MiRNAs investigated, the levels of expression of 55 miRNA were significantly altered in infected tissues. Some miRNAs showed dramatic increase (miR-16-1) or decrease of expression (miR-17-3p) as compared to control. Gene ontology enrichment analysis of these miRNA-targeted genes suggests that Candidal infection affect many important biological pathways. In summary, disturbance in miRNA expression levels indicated the change in cascade of pathological processes and the regulation of respiratory epithelial functions following invasive Candidal infection. These findings contribute to our understanding of host cell response to Candidal systemic infections.Item Periostin, a matricellular protein, plays a role in the induction of chemokines in pulmonary fibrosis(American Thoracic Society, 2012-05) Uchida, Masaru; Shiraishi, Hiroshi; Ohta, Shoichiro; Arima, Kazuhiko; Taniguchi, Kazuto; Suzuki, Shoichi; Okamoto, Masaki; Ahlfeld, Shawn K.; Ohshima, Koichi; Kato, Seiya; Toda, Shuji; Sagara, Hironori; Aizawa, Hisamichi; Hoshino, Tomoaki; Conway, Simon J.; Hayashi, Shinichiro; Izuhara, Kenji; Department of Pediatrics, IU School of MedicineIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal form of interstitial lung disease (ILD). The precise molecular mechanisms of IPF remain poorly understood. However, analyses of mice receiving bleomycin (BLM) as a model of IPF established the importance of preceding inflammation for the formation of fibrosis. Periostin is a recently characterized matricellular protein involved in modulating cell functions. We recently found that periostin is highly expressed in the lung tissue of patients with IPF, suggesting that it may play a role in the process of pulmonary fibrosis. To explore this possibility, we administered BLM to periostin-deficient mice, and they subsequently showed a reduction of pulmonary fibrosis. We next determined whether this result was caused by a decrease in the preceding recruitment of neutrophils and macrophages in the lungs because of the lower production of chemokines and proinflammatory cytokines. We performed an in vitro analysis of chemokine production in lung fibroblasts, which indicated that periostin-deficient fibroblasts produced few or no chemokines in response to TNF-α compared with control samples, at least partly explaining the lack of inflammatory response and, therefore, fibrosis after BLM administration to periostin-deficient mice. In addition, we confirmed that periostin is highly expressed in the lung tissue of chemotherapeutic-agent-induced ILD as well as of patients with IPF. Taking these results together, we conclude that periostin plays a unique role as an inducer of chemokines to recruit neutrophils and macrophages important in the process of pulmonary fibrosis in BLM-administered model mice. Our results suggest a therapeutic potential for periostin in IPF and drug-induced ILD.