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Adenoviral E1A function through Myc.
Chakraborty AA, Tansey WP
(2009) Cancer Res 69: 6-9
MeSH Terms: Adenoviridae, Adenovirus E1A Proteins, Animals, Cell Transformation, Viral, DNA Tumor Viruses, Humans, Proto-Oncogene Proteins c-myc
Show Abstract · Added March 10, 2014
The study of DNA tumor viruses has been invaluable in uncovering the cellular nodes and pathways that contribute to oncogenesis. Perhaps one of the best-studied oncoproteins encoded by a DNA tumor virus is adenovirus E1A, which modifies the function of key regulatory proteins such as retinoblastoma (Rb) and the chromatin remodeling protein p400. Although the interaction of E1A with Rb has long been known to target regulation of the E2F transcription factors, the downstream target of the E1A-p400 interaction has remained elusive. We have recently reported that a critical downstream link of the E1A-p400 nexus is the oncoprotein transcription factor c-Myc. Through its interaction with p400, E1A stabilizes Myc and promotes formation of Myc-p400 complexes on chromatin, leading to activation of Myc target genes. These findings point to an important role for p400 in Myc function and reveal that E1A drives oncogenesis by tapping into two important transcriptional networks: those of E2F and Myc.
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7 MeSH Terms
Restoration of hepatic glucokinase expression corrects hepatic glucose flux and normalizes plasma glucose in zucker diabetic fatty rats.
Torres TP, Catlin RL, Chan R, Fujimoto Y, Sasaki N, Printz RL, Newgard CB, Shiota M
(2009) Diabetes 58: 78-86
MeSH Terms: Adenoviridae, Aging, Animals, Blood Glucose, Blotting, Western, Body Weight, Carrier Proteins, Diabetes Mellitus, Experimental, Glucagon, Glucokinase, Glucose, Hyperglycemia, Insulin, Liver, Male, Rats, Rats, Zucker
Show Abstract · Added February 19, 2015
OBJECTIVE - We examined in 20-week-old Zucker diabetic fatty (ZDF) rats whether restoration of hepatic glucokinase (GK) expression would alter hepatic glucose flux and improve hyperglycemia.
RESEARCH DESIGN AND METHODS - ZDF rats were treated at various doses with an adenovirus that directs the expression of rat liver GK (AdvCMV-GKL) dose dependently, and various metabolic parameters were compared with those of nondiabetic lean littermates (ZCL rats) before and during a hyperglycemic clamp. Viral infection per se did not affect hepatic GK activity, since expression of a catalytically inactive form of GK did not alter endogenous hepatic GK activity.
RESULTS - ZDF rats compared with ZCL rats have lower hepatic GK activity (11.6 +/- 1.9 vs. 32.5 +/- 3.2 mU/mg protein), marked hyperglycemia (23.9 +/- 1.2 vs. 7.4 +/- 0.3 mmol/l), higher endogenous glucose production (80 +/- 3 vs. 38 +/- 3 micromol x kg(-1) x min(-1)), increased glucose-6-phosphatase flux (150 +/- 11 vs. 58 +/- 8 micromol x kg(-1) x min(-1)), and during a hyperglycemic clamp, a failure to suppress endogenous glucose production (80 +/- 7 vs. -7 +/- 4 micromol x kg(-1) x min(-1)) and promote glucose incorporation into glycogen (15 +/- 5 vs. 43 +/- 3 micromol/g liver). Treatment of ZDF rats with different doses of AdvCMV-GKL, which restored hepatic GK activity to one to two times that of ZCL rats, normalized plasma glucose levels and endogenous glucose production. During a hyperglycemic clamp, glucose production was suppressed and glucose incorporation into glycogen was normal.
CONCLUSIONS - Alteration of hepatic GK activity in ZDF rats has profound effects on plasma glucose and hepatic glucose flux.
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17 MeSH Terms
Interferon-stimulated gene ISG12b1 inhibits adipogenic differentiation and mitochondrial biogenesis in 3T3-L1 cells.
Li B, Shin J, Lee K
(2009) Endocrinology 150: 1217-24
MeSH Terms: 3T3-L1 Cells, Adenoviridae, Adipogenesis, Adipose Tissue, Amino Acid Sequence, Animals, Cell Differentiation, Colforsin, Down-Regulation, Gene Expression Regulation, Interferons, Membrane Proteins, Mice, Mice, Obese, Mitochondria, Molecular Sequence Data, Proteins, Transduction, Genetic
Show Abstract · Added March 3, 2014
Microarray analysis was performed to find a new group of genes or pathways that might be important in adipocyte development and metabolism. Among them, a mouse interferon-stimulated gene 12b1 (ISG12b1) is expressed at a 400-fold higher level in adipocytes compared with stromal-vascular cells. It is predominantly expressed in adipose tissue among other tissues we tested. Developmentally, ISG12b1 mRNA expression was initially inhibited followed by a dramatic induction during both in vivo and in vitro adipogenic differentiation. Adenovirus-mediated overexpression of ISG12b1 inhibited adipogenic differentiation in 3T3-L1 cells as shown by decreased lipid staining with Oil-Red-O and reduction in adipogenic marker proteins including peroxisome proliferator-activated receptor-gamma (PPARgamma), and CCAAT/enhancer-binding protein-alpha (C/EBPalpha). Our bioinformatics analysis for the predicted localization of ISG12b1 protein suggested the mitochondrial localization, which was confirmed by the colocalization of hemagglutinin-tagged ISG12b1 protein with mitochondrial marker MitoTracker. In addition, ISG12b1 protein was exclusively detected in protein extract from the fractionated mitochondria by Western blot analysis. Furthermore, overexpression of ISG12b1 in adipocytes reduced mitochondrial DNA content and gene expression of mitochondrial transcription factor A (mtTFA), nuclear respiratory factor 1 (NRF1), and cytochrome oxidase II, suggesting an inhibitory role of ISG12b1 in mitochondrial biogenesis and function. Activation of mitochondrial biogenesis and function by treatment with PPARgamma and PPARalpha agonists in 3T3-L1 cells and cold exposure in mice induced mitochondrial transcription factors and reduced ISG12 expression. These data demonstrated that mitochondrial-localized ISG12b1 protein inhibits adipocyte differentiation and mitochondrial biogenesis and function, implying the important role of mitochondrial function in adipocyte development and associated diseases.
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18 MeSH Terms
Phase I study of adenovirus p53 administered by bronchoalveolar lavage in patients with bronchioloalveolar cell lung carcinoma: ECOG 6597.
Keedy V, Wang W, Schiller J, Chada S, Slovis B, Coffee K, Worrell J, Thet LA, Johnson DH, Carbone DP
(2008) J Clin Oncol 26: 4166-71
MeSH Terms: Adenocarcinoma, Bronchiolo-Alveolar, Adenoviridae, Adult, Aged, Bronchoalveolar Lavage, Female, Gene Transfer Techniques, Genes, p53, Genetic Therapy, Humans, Lung Neoplasms, Male, Middle Aged, Pilot Projects, Treatment Outcome
Show Abstract · Added March 11, 2014
PURPOSE - This pilot phase I trial evaluated the safety and maximum-tolerated dose of p53 gene transfer using an adenovirus vector (Ad-p53) delivered via bronchoalveolar lavage (BAL) to patients with bronchioloalveolar lung carcinoma (BAC).
PATIENTS AND METHODS - Patients were initially administered two treatments of Ad-p53 to a single involved lobe, beginning at 2 x 10(9) viral particles (vp) per dose and escalated to a maximum of 2 x 10(12) vp. If a clinical benefit was seen and the treatment was well tolerated, additional doses could be administered to additional lobes.
RESULTS - Twenty-five patients were treated at doses between 2 x 10(9) and 2 x 10(12) vp. At 2 x 10(12) vp, one patient experienced grade 4 pulmonary toxicity, and one patient died 25 days after his second cycle; therefore, a cohort of 10 patients was treated at the recommended phase II dose of 5 x 10(11) vp, with no grade 4 toxicity observed. The most frequent toxicities included low-grade fever, hypoxia, and dyspnea. Of the 23 assessable patients, 16 had stable disease as their best response. Subjective improvement in breathing was noted in eight patients. Limited distribution of vector was observed, with transient detection in patient sputum for 1 to 2 days after administration.
CONCLUSION - Ad-p53 can be administered safely by BAL at 5 x 10(11) vp with repeated dosing. Stabilization of disease and symptomatic improvement may warrant further studies of Ad-p53 or other adenoviruses administered by BAL in patients with BAC.
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15 MeSH Terms
Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets.
Kato T, Shimano H, Yamamoto T, Ishikawa M, Kumadaki S, Matsuzaka T, Nakagawa Y, Yahagi N, Nakakuki M, Hasty AH, Takeuchi Y, Kobayashi K, Takahashi A, Yatoh S, Suzuki H, Sone H, Yamada N
(2008) Diabetes 57: 2382-92
MeSH Terms: Adenoviridae, Animals, Eicosapentaenoic Acid, Gene Expression, Gene Silencing, Insulin, Insulin Receptor Substrate Proteins, Insulin Secretion, Intracellular Signaling Peptides and Proteins, Ion Channels, Islets of Langerhans, Lipogenesis, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mitochondrial Proteins, Organ Culture Techniques, Palmitates, Phosphoproteins, Proto-Oncogene Proteins c-akt, RNA, Messenger, Signal Transduction, Sterol Regulatory Element Binding Protein 1, Uncoupling Protein 2
Show Abstract · Added March 27, 2013
OBJECTIVE - Chronic exposure to fatty acids causes beta-cell failure, often referred to as lipotoxicity. We investigated its mechanisms, focusing on contribution of SREBP-1c, a key transcription factor for lipogenesis.
RESEARCH DESIGN AND METHODS - We studied in vitro and in vivo effects of saturated and polyunsaturated acids on insulin secretion, insulin signaling, and expression of genes involved in beta-cell functions. Pancreatic islets isolated from C57BL/6 control and SREBP-1-null mice and adenoviral gene delivery or knockdown systems of related genes were used.
RESULTS - Incubation of C57BL/6 islets with palmitate caused inhibition of both glucose- and potassium-stimulated insulin secretion, but addition of eicosapentaenoate (EPA) restored both inhibitions. Concomitantly, palmitate activated and EPA abolished both mRNA and nuclear protein of SREBP-1c, accompanied by reciprocal changes of SREBP-1c target genes such as insulin receptor substrate-2 (IRS-2) and granuphilin. These palmitate-EPA effects on insulin secretion were abolished in SREBP-1-null islets. Suppression of IRS-2/Akt pathway could be a part of the downstream mechanism for the SREBP-1c-mediated insulin secretion defect because adenoviral constitutively active Akt compensated it. Uncoupling protein-2 (UCP-2) also plays a crucial role in the palmitate inhibition of insulin secretion, as confirmed by knockdown experiments, but SREBP-1c contribution to UCP-2 regulation was partial. The palmitate-EPA regulation of insulin secretion was similarly observed in islets from C57BL/6 mice pretreated with dietary manipulations. Furthermore, administration of EPA to diabetic KK-Ay mice ameliorated impairment of insulin secretion in their islets.
CONCLUSIONS - SREBP-1c plays a dominant role in palmitate-mediated insulin secretion defect, and EPA prevents it through SREBP-1c inhibition, implicating a therapeutic potential for treating diabetes related to lipotoxicity.
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25 MeSH Terms
Virus-mediated gene delivery to neuronal progenitors.
Rex TS
(2008) Adv Exp Med Biol 613: 147-53
MeSH Terms: Adenoviridae, Animals, Dependovirus, Forecasting, Gene Transfer Techniques, Genetic Therapy, Genetic Vectors, Humans, Lentivirus, Neurons, Stem Cells
Added January 20, 2015
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11 MeSH Terms
IP3 receptor-dependent Ca2+ release modulates excitation-contraction coupling in rabbit ventricular myocytes.
Domeier TL, Zima AV, Maxwell JT, Huke S, Mignery GA, Blatter LA
(2008) Am J Physiol Heart Circ Physiol 294: H596-604
MeSH Terms: Adenoviridae, Animals, Blotting, Western, Calcium, Calcium Signaling, Cats, Cell Separation, Heart Ventricles, In Vitro Techniques, Inositol 1,4,5-Trisphosphate Receptors, Lipid Bilayers, Microscopy, Confocal, Myocardial Contraction, Myocytes, Cardiac, RNA, Rabbits, Ryanodine Receptor Calcium Release Channel, Sarcoplasmic Reticulum, Signal Transduction
Show Abstract · Added May 27, 2014
Inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R)-dependent Ca(2+) signaling exerts positive inotropic, but also arrhythmogenic, effects on excitation-contraction coupling (ECC) in the atrial myocardium. The role of IP(3)R-dependent sarcoplasmic reticulum (SR) Ca(2+) release in ECC in the ventricular myocardium remains controversial. Here we investigated the role of this signaling pathway during ECC in isolated rabbit ventricular myocytes. Immunoblotting of proteins from ventricular myocytes showed expression of both type 2 and type 3 IP(3)R at levels approximately 3.5-fold less than in atrial myocytes. In permeabilized myocytes, direct application of IP(3) (10 microM) produced a transient 21% increase in the frequency of Ca(2+) sparks (P < 0.05). This increase was accompanied by a 13% decrease in spark amplitude (P < 0.05) and a 7% decrease in SR Ca(2+) load (P < 0.05) and was inhibited by IP(3)R antagonists 2-aminoethoxydiphenylborate (2-APB; 20 microM) and heparin (0.5 mg/ml). In intact myocytes endothelin-1 (100 nM) was used to stimulate IP(3) production and caused a 38% (P < 0.05) increase in the amplitude of action potential-induced (0.5 Hz, field stimulation) Ca(2+) transients. This effect was abolished by the IP(3)R antagonist 2-APB (2 microM) or by using adenoviral expression of an IP(3) affinity trap that buffers cellular IP(3). Together, these data suggest that in rabbit ventricular myocytes IP(3)R-dependent Ca(2+) release has positive inotropic effects on ECC by facilitating Ca(2+) release through ryanodine receptor clusters.
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19 MeSH Terms
15(S)-HETE production in human retinal microvascular endothelial cells by hypoxia: Novel role for MEK1 in 15(S)-HETE induced angiogenesis.
Bajpai AK, Blaskova E, Pakala SB, Zhao T, Glasgow WC, Penn JS, Johnson DA, Rao GN
(2007) Invest Ophthalmol Vis Sci 48: 4930-8
MeSH Terms: Adenoviridae, Arachidonate 15-Lipoxygenase, Basement Membrane, Cell Movement, Cells, Cultured, Chromatography, High Pressure Liquid, Endothelium, Vascular, Enzyme Inhibitors, Genetic Vectors, Humans, Hydroxyeicosatetraenoic Acids, Hypoxia, MAP Kinase Kinase 1, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase 8, Phosphorylation, Retinal Neovascularization, Retinal Vessels, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added October 9, 2013
PURPOSE - To examine for the expression of 15-lipoxygenase 1 (15-LOX1) and 15-LOX2 in human retinal microvascular endothelial cells (HRMVECs) and study the role of arachidonic acid metabolites of these enzymes in angiogenesis.
METHODS - Quantitative RT-PCR and reverse-phase HPLC analyses were used to determine 15-LOX1/2 expression and their arachidonic acid metabolites in HRMVECs. The role of MEK1 in 15(S)-HETE-induced angiogenesis was studied using HRMVEC migration, tube formation, and basement membrane matrix plug angiogenesis.
RESULTS - HRMVECs expressed both 15-LOX1 and 15-LOX2. Hypoxia induced the expression of 15-LOX1 and the production of its arachidonic acid metabolites 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) and 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). 15(S)-HETE stimulated HRMVEC migration and tube formation as potently as 20 ng/mL fibroblast growth factor-2 (FGF-2). In addition, 15(S)-HETE stimulated the phosphorylation of ERK1/2, JNK1, p38 MAPK, and MEK1 in a time-dependent manner in these cells. Inhibition of MEK1 by pharmacologic and dominant-negative mutant approaches attenuated 15(S)-HETE-induced phosphorylation of ERK1/2 and JNK1 but not p38 MAPK. Blockade of ERK1/2 and JNK1 activation suppressed 15(S)-HETE-induced HRMVEC migration and tube formation and basement membrane matrix plug angiogenesis. Inhibition of p38 MAPK attenuated 15(S)-HETE-induced HRMVEC migration only. Inhibition of MEK1 also blocked 15(S)-HETE-induced HRMVEC migration and tube formation and basement membrane matrix plug angiogenesis.
CONCLUSIONS - These results suggest that hypoxia, through the induction of 15-LOX1 expression, leads to the production of 15(S)-HETE in HRMVECs. In addition, 15(S)-HETE, through MEK1-dependent activation of ERK1/2 and JNK1, stimulates the angiogenic differentiation of HRMVECs and basement membrane matrix plug angiogenesis.
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22 MeSH Terms
Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance.
Nagle CA, An J, Shiota M, Torres TP, Cline GW, Liu ZX, Wang S, Catlin RL, Shulman GI, Newgard CB, Coleman RA
(2007) J Biol Chem 282: 14807-15
MeSH Terms: Adenoviridae, Animals, Deoxyglucose, Fatty Liver, Gene Expression, Glycerol-3-Phosphate O-Acyltransferase, Glycogen, Hyperlipidemias, Insulin Resistance, Interleukin-1beta, Lipid Metabolism, Liver, Male, Muscle, Skeletal, NF-kappa B, Protein Kinase C-epsilon, Rats, Rats, Wistar, Transduction, Genetic, Triglycerides, Tumor Necrosis Factor-alpha
Show Abstract · Added February 19, 2015
Fatty liver is commonly associated with insulin resistance and type 2 diabetes, but it is unclear whether triacylglycerol accumulation or an excess flux of lipid intermediates in the pathway of triacyglycerol synthesis are sufficient to cause insulin resistance in the absence of genetic or diet-induced obesity. To determine whether increased glycerolipid flux can, by itself, cause hepatic insulin resistance, we used an adenoviral construct to overexpress glycerol-sn-3-phosphate acyltransferase-1 (Ad-GPAT1), the committed step in de novo triacylglycerol synthesis. After 5-7 days, food intake, body weight, and fat pad weight did not differ between Ad-GPAT1 and Ad-enhanced green fluorescent protein control rats, but the chow-fed Ad-GPAT1 rats developed fatty liver, hyperlipidemia, and insulin resistance. Liver was the predominant site of insulin resistance; Ad-GPAT1 rats had 2.5-fold higher hepatic glucose output than controls during a hyperinsulinemic-euglycemic clamp. Hepatic diacylglycerol and lysophosphatidate were elevated in Ad-GPAT1 rats, suggesting a role for these lipid metabolites in the development of hepatic insulin resistance, and hepatic protein kinase Cepsilon was activated, providing a potential mechanism for insulin resistance. Ad-GPAT1-treated rats had 50% lower hepatic NF-kappaB activity and no difference in expression of tumor necrosis factor-alpha and interleukin-beta, consistent with hepatic insulin resistance in the absence of increased hepatic inflammation. Glycogen synthesis and uptake of 2-deoxyglucose were reduced in skeletal muscle, suggesting mild peripheral insulin resistance associated with a higher content of skeletal muscle triacylglycerol. These results indicate that increased flux through the pathway of hepatic de novo triacylglycerol synthesis can cause hepatic and systemic insulin resistance in the absence of obesity or a lipogenic diet.
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21 MeSH Terms
Novel approaches for understanding the mechanisms of wound repair.
Nanney LB, Caldwell RL, Pollins AC, Cardwell NL, Opalenik SR, Davidson JM
(2006) J Investig Dermatol Symp Proc 11: 132-9
MeSH Terms: Adenoviridae, Animals, Burns, Epidermal Growth Factor, ErbB Receptors, Humans, Microdissection, Receptor, ErbB-4, Regeneration, Signal Transduction, Skin Physiological Phenomena, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Wound Healing
Show Abstract · Added December 10, 2013
Mechanisms that drive wound repair are complex and have challenged wound-healing investigators for many years. In this review, we present four examples of new tools that are being utilized to discover events that drive wound repair and regeneration. Laser capture microdissection facilitates the focused collection of tissue for purposes of genomic or proteomic analysis from specific cell populations within the wound bed. Tissue profiling and protein imaging by matrix-assisted laser desorption ionization mass spectrometry are two proteomic-based tools that permit rapid analysis with spatial orientation and relative abundance of hundreds to thousands of molecules from intact tissues. Another approach uses an in vivo porcine model to harness a strategy of adenoviral-driven receptor overexpression. This biological model closely mimics the human setting and permits transient stimulation along a specific cytokine pathway to tip the balance in favor of accelerated repair. The advent of new approaches that collect cell samples from within their in vivo circumstance while preserving discrete cellular localizations is likely to move the field of wound repair forward.
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13 MeSH Terms