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Gregory T Jones,
Matthew J Bown,
Solveig Gretarsdottir,
Simon P R Romaine,
Anna Helgadottir,
Grace Yu,
Gerard Tromp,
Paul E Norman,
Cao Jin,
Annette F Baas, [......],
Anne Johnson,
Soroush Sohrabi,
D Julian Scott, David J Carey,
Robert Erdman,
James R Elmore,
Helena Kuivaniemi,
Nilesh J Samani,
Kari Stefansson,
Andre M van Rij
[show abstract]
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ABSTRACT: Abdominal aortic aneurysm (AAA) is a common human disease with a high estimated heritability (0.7), however only a small number of associated genetic loci have been reported to date. In contrast, over 100 loci have now been reproducibly associated with either blood lipid profile and/or coronary artery disease (both risk factors for AAA) in large-scale meta-analyses. This study employed a staged design to investigate if the loci for these two phenotypes are also associated with abdominal aortic aneurysm (AAA). Validated coronary artery disease and dyslipidemia loci underwent screening using the Otago AAA genome-wide association dataset. Putative associations underwent staged secondary validation in ten additional cohorts. A novel association between the SORT1 (1p13.3) locus and AAA was identified. The rs599839 G allele, which has been previously associated with both dyslipidemia and coronary artery disease, reached genome-wide significance in eleven combined independent cohorts (meta-analysis with 7,048 AAA cases and 75,976 controls: G allele OR 0.81, 95% CI 0.76-0.85, p=7.2x10(-14)). Modelling for confounding interactions of concurrent dyslipidemia, heart disease and other risk factors, suggested that this marker is an independent predictor of AAA susceptibility. In conclusion, a genetic marker associated with cardiovascular risk factors, and in particular concurrent vascular disease, appeared to independently contribute to susceptibility for AAA. Given the potential genetic overlap between risk factor and disease phenotypes, the use of well characterized case-control cohorts allowing for modelling of cardiovascular disease risk confounders will be an important component in the future discovery of genetic markers for conditions such as AAA.
Human Molecular Genetics 03/2013; · 7.64 Impact Factor
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Gabor Gäbel,
James R Elmore,
Gerard Tromp,
David J Carey,
Irene Hinterseher,
David P Franklin,
Charles M Schworer,
Helena Kuivaniemi,
Matthew C Pahl, Kimberly Derr,
John L Gray,
Thomas C Peeler
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Christian J Gaffney,
Tsutomu Oka,
Virginia Mazack,
Dror Hilman,
Uri Gat,
Tomoki Muramatsu,
Johji Inazawa,
Alicia Golden, David J Carey,
Amjad Farooq,
Gerard Tromp,
Marius Sudol
[show abstract]
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ABSTRACT: The YAP1 gene encodes a potent new oncogene and stem cell factor. However, in some cancers, the YAP1 gene plays a role of tumor suppressor. At present, the gene and its products are intensely studied and its cDNAs are used as transgenes in cellular and animal models. Here, we report 4 new potential mRNA splicing isoforms of the YAP1 gene, bringing the total number of isoforms to 8. We detected all 8 YAP1 isoforms in a panel of human tissues and evaluated the expression of the longest isoform of YAP1 (YAP1-2δ) using Real Time PCR. All YAP1 isoforms are barely detectable in human leukocytes compared to fair levels of expression found in other human tissues. We analyzed the structure of the genomic region that gave rise to alternatively spliced YAP1 transcripts in different metazoans. We found that YAP1 isoforms, which utilize exon 6 emerged in evolution with the appearance of amniotes. Interestingly, 6 YAP1 isoforms, which contain the exon 5 extension, exon 6 or both would have their leucine zipper region disrupted in the predicted protein product, compared to the intact leucine zipper found in two YAP1 (α) isoforms. This observation has direct functional ramifications for YAP1 signaling. We also propose a normalized nomenclature for the mRNA splice variants of the YAP1 gene, which should aid in the characterization of signaling differences among the potential protein products of the YAP1 gene.
Gene 08/2012; 509(2):215-22. · 2.34 Impact Factor
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Anna Helgadottir,
Solveig Gretarsdottir,
Gudmar Thorleifsson,
Hilma Holm,
Riyaz S Patel,
Thorarinn Gudnason,
Gregory T Jones,
Andre M van Rij,
Danny J Eapen,
Annette F Baas, [......],
Pall T Onundarson,
Einar Valdimarsson,
Stefan E Matthiasson,
Daniel F Gudbjartsson,
Guðmundur Thorgeirsson,
Arshed A Quyyumi,
Hugh Watkins,
Martin Farrall,
Unnur Thorsteinsdottir,
Kari Stefansson
[show abstract]
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ABSTRACT: The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components.
It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis.
The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n(e)] = 9,396); peripheral arterial disease (n(e) = 5,215); abdominal aortic aneurysm (n(e) = 4,572); venous thromboembolism (n(e) = 4,607); intracranial aneurysm (n(e) = 1,328); CAD (n(e) = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588).
LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 × 10(-4)), peripheral artery disease (OR: 1.47; p = 2.9 × 10(-14)), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 × 10(-5)), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 × 10(-12)). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (-1.58 years/allele; p = 8.2 × 10(-8)) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15).
LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.
Journal of the American College of Cardiology 08/2012; 60(8):722-9. · 14.16 Impact Factor
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Irene Hinterseher,
Robert Erdman,
James R Elmore,
Elizabeth Stahl,
Matthew C Pahl,
Kimberly Derr,
Alicia Golden,
John H Lillvis,
Matthew C Cindric,
Kathryn Jackson,
William D Bowen,
Charles M Schworer,
Michael A Chernousov,
David P Franklin,
John L Gray,
Robert P Garvin,
Zoran Gatalica, David J Carey,
Gerard Tromp,
Helena Kuivaniemi
[show abstract]
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ABSTRACT: Abdominal aortic aneurysm (AAA), a dilatation of the infrarenal aorta, typically affects males >65 years. The pathobiological mechanisms of human AAA are poorly understood. The goal of this study was to identify novel pathways involved in the development of AAAs.
A custom-designed 'AAA-chip' was used to assay 43 of the differentially expressed genes identified in a previously published microarray study between AAA (n = 15) and control (n = 15) infrarenal abdominal aorta. Protein analyses were performed on selected genes.
Altogether 38 of the 43 genes on the 'AAA-chip' showed significantly different expression. Novel validated genes in AAA pathobiology included ADCY7, ARL4C, BLNK, FOSB, GATM, LYZ, MFGE8, PRUNE2, PTPRC, SMTN, TMODI and TPM2. These genes represent a wide range of biological functions, such as calcium signaling, development and differentiation, as well as cell adhesion not previously implicated in AAA pathobiology. Protein analyses for GATM, CD4, CXCR4, BLNK, PLEK, LYZ, FOSB, DUSP6, ITGA5 and PTPRC confirmed the mRNA findings.
The results provide new directions for future research into AAA pathogenesis to study the role of novel genes confirmed here. New treatments and diagnostic tools for AAA could potentially be identified by studying these novel pathways.
Pathobiology 07/2012; 80(1):1-10. · 1.18 Impact Factor
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Matthew C Pahl,
Kimberly Derr,
Gabor Gäbel,
Irene Hinterseher,
James R Elmore,
Charles M Schworer,
Thomas C Peeler,
David P Franklin,
John L Gray, David J Carey,
Gerard Tromp,
Helena Kuivaniemi
[show abstract]
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ABSTRACT: BACKGROUND: Abdominal aortic aneurysm (AAA) is a dilatation of the aorta affecting most frequentlyelderly men. Histologically AAAs are characterized by inflammation, vascular smoothmuscle cell apoptosis, and extracellular matrix degradation. The mechanisms of AAAformation, progression, and rupture are currently poorly understood. A previous mRNAexpression study revealed a large number of differentially expressed genes between AAA andnon-aneurysmal control aortas. MicroRNAs (miRNAs), small non-coding RNAs that arepost-transcriptional regulators of gene expression, could provide a mechanism for thedifferential expression of genes in AAA. METHODS: To determine differences in miRNA levels between AAA (n = 5) and control (n = 5) infrarenalaortic tissues, a microarray study was carried out. Results were adjusted using Benjamini-Hochberg correction (adjusted p < 0.05). Real-time quantitative RT-PCR (qRT-PCR) assayswith an independent set of 36 AAA and seven control tissues were used for validation.Potential gene targets were retrieved from miRNA target prediction databases Pictar,TargetScan, and MiRTarget2. Networks from the target gene set were generated andexamined using the network analysis programs, CytoScape® and Ingenuity Pathway CoreAnalysis®. RESULTS: A microarray study identified eight miRNAs with significantly different expression levelsbetween AAA and controls (adjusted p < 0.05). Real-time qRT-PCR assays validated thefindings for five of the eight miRNAs. A total of 222 predicted miRNA target genes knownto be differentially expressed in AAA based on a prior mRNA microarray study wereidentified. Bioinformatic analyses revealed that several target genes are involved in apoptosisand activation of T cells CONCLUSIONS: Our genome-wide approach revealed several differentially expressed miRNAs in humanAAA tissue suggesting that miRNAs play a role in AAA pathogenesis.
BMC Medical Genomics 06/2012; 5(1):25. · 3.69 Impact Factor
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ABSTRACT: Factors that influence long-term weight loss after Roux-en Y gastric bypass (RYGB) surgeries are poorly defined. The melanocortin system plays an important role in regulating energy homeostasis, satiety, and glucose metabolism. Variations of the MC4R comprise the most prevalent monogenetic obesity disorder.
The objective of the study was to examine the role of MC4R variants and diabetic status in long-term weight loss after RYGB.
In 1433 extremely obese patients who underwent RYGB, we sequenced for genetic variants of MC4R. We examined the MC4R genotype and its relationship with weight loss profile, and clinical phenotypes accumulated during a 48-month period before and after surgery.
We found 80 subjects with rare and common variants of MC4R in the RYGB cohort. Among these, 26 and 36 patients carry the I251L and V103I variants, respectively. These common alleles are negatively associated with obesity. Remarkably, after the 12-month presurgery caloric restriction and RYGB, I251L allele carriers lost 9% more weight (∼9 kg) compared with the noncarriers, continued rapid weight loss longer, regained less weight, and had lower presurgery homeostatic model assessment for insulin resistance values. Normoglycemic, I251L allele carriers lost more weight compared with their diabetic and prediabetic counterparts and maintained their weight loss. Among noncarriers, normoglycemic individuals initially lost more weight compared with dysglycemics, but this difference was not maintained in the long term.
Individuals carrying the I251L common allele are predisposed to better clinical outcome, reduced risk of type 2 diabetes, and better weight loss during diet and surgical interventions. Diabetic status has only a small, short-term effect on weight loss after RYGB.
The Journal of clinical endocrinology and metabolism 12/2011; 96(12):E2088-96. · 6.50 Impact Factor
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Irene Hinterseher,
Robert Erdman,
Larry A Donoso,
Tamara R Vrabec,
Charles M Schworer,
John H Lillvis,
Amy M Boddy,
Kimberly Derr,
Alicia Golden,
William D Bowen,
Zoran Gatalica,
Nikos Tapinos,
James R Elmore,
David P Franklin,
John L Gray,
Robert P Garvin,
Glenn S Gerhard, David J Carey,
Gerard Tromp,
Helena Kuivaniemi
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ABSTRACT: The goal of this study was to investigate the role of complement cascade genes in the pathobiology of human abdominal aortic aneurysms (AAAs).
Results of a genome-wide microarray expression profiling revealed 3274 differentially expressed genes between aneurysmal and control aortic tissue. Interestingly, 13 genes in the complement cascade were significantly differentially expressed between AAA and the controls. In silico analysis of the promoters of the 13 complement cascade genes showed enrichment for transcription factor binding sites for signal transducer and activator of transcription (STAT)5A. Chromatin-immunoprecipitation experiments demonstrated binding of transcription factor STAT5A to the promoters of the majority of the complement cascade genes. Immunohistochemical analysis showed strong staining for C2 in AAA tissues.
These results provide strong evidence that the complement cascade plays a role in human AAA. Based on our microarray studies, the pathway is activated in AAA, particularly via the lectin and classical pathways. The overrepresented binding sites of transcription factor STAT5A in the complement cascade gene promoters suggest a role for STAT5A in the coordinated regulation of complement cascade gene expression.
Arteriosclerosis Thrombosis and Vascular Biology 07/2011; 31(7):1653-60. · 6.37 Impact Factor
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John H Lillvis,
Robert Erdman,
Charles M Schworer,
Alicia Golden,
Kimberly Derr,
Zoran Gatalica,
Laura A Cox,
Jianbin Shen,
Richard S Vander Heide,
Guy M Lenk,
Leigh Hlavaty,
Li Li,
James R Elmore,
David P Franklin,
John L Gray,
Robert P Garvin, David J Carey,
Wayne D Lancaster,
Gerard Tromp,
Helena Kuivaniemi
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ABSTRACT: The infrarenal abdominal aorta exhibits increased disease susceptibility relative to other aortic regions. Allograft studies exchanging thoracic and abdominal segments showed that regional susceptibility is maintained regardless of location, suggesting substantial roles for embryological origin, tissue composition and site-specific gene expression.
We analyzed gene expression with microarrays in baboon aortas, and found that members of the HOX gene family exhibited spatial expression differences. HOXA4 was chosen for further study, since it had decreased expression in the abdominal compared to the thoracic aorta. Western blot analysis from 24 human aortas demonstrated significantly higher HOXA4 protein levels in thoracic compared to abdominal tissues (P < 0.001). Immunohistochemical staining for HOXA4 showed nuclear and perinuclear staining in endothelial and smooth muscle cells in aorta. The HOXA4 transcript levels were significantly decreased in human abdominal aortic aneurysms (AAAs) compared to age-matched non-aneurysmal controls (P < 0.00004). Cultured human aortic endothelial and smooth muscle cells stimulated with INF-γ (an important inflammatory cytokine in AAA pathogenesis) showed decreased levels of HOXA4 protein (P < 0.0007).
Our results demonstrated spatial variation in expression of HOXA4 in human aortas that persisted into adulthood and that downregulation of HOXA4 expression was associated with AAAs, an important aortic disease of the ageing population.
BMC Physiology 05/2011; 11:9.
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Christopher D Still,
G Craig Wood,
Xin Chu,
Robert Erdman,
Christina H Manney,
Peter N Benotti,
Anthony T Petrick,
William E Strodel,
Uyenlinh L Mirshahi,
Tooraj Mirshahi, David J Carey,
Glenn S Gerhard
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ABSTRACT: Genome-wide association and linkage studies have identified multiple susceptibility loci for obesity. We hypothesized that such loci may affect weight loss outcomes following dietary or surgical weight loss interventions. A total of 1,001 white individuals with extreme obesity (BMI >35 kg/m(2)) who underwent a preoperative diet/behavioral weight loss intervention and Roux-en-Y gastric bypass surgery were genotyped for single-nucleotide polymorphisms (SNPs) in or near the fat mass and obesity-associated (FTO), insulin induced gene 2 (INSIG2), melanocortin 4 receptor (MC4R), and proprotein convertase subtilisin/kexin type 1 (PCSK1) obesity genes. Association analysis was performed using recessive and additive models with pre- and postoperative weight loss data. An increasing number of obesity SNP alleles or homozygous SNP genotypes was associated with increased BMI (P < 0.0006) and excess body weight (P < 0.0004). No association between the amounts of weight lost from a short-term dietary intervention and any individual obesity SNP or cumulative number of obesity SNP alleles or homozygous SNP genotypes was observed. Linear mixed regression analysis revealed significant differences in postoperative weight loss trajectories across groups with low, intermediate, and high numbers of obesity SNP alleles or numbers of homozygous SNP genotypes (P < 0.0001). Initial BMI interacted with genotype to influence weight loss with initial BMI <50 kg/m(2), with evidence of a dosage effect, which was not present in individuals with initial BMI ≥50 kg/m(2). Differences in metabolic rate, binge eating behavior, and other clinical parameters were not associated with genotype. These data suggest that response to a surgical weight loss intervention is influenced by genetic susceptibility and BMI.
Obesity 02/2011; 19(8):1676-83. · 4.28 Impact Factor
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Solveig Gretarsdottir,
Annette F Baas,
Gudmar Thorleifsson,
Hilma Holm,
Martin den Heijer,
Jean-Paul P M de Vries,
Steef E Kranendonk,
Clark J A M Zeebregts,
Steven M van Sterkenburg,
Robert H Geelkerken, [......],
Janet T Powell, David J Carey,
Helena Kuivaniemi,
Jes S Lindholt,
Gregory T Jones,
Augustine Kong,
Jan D Blankensteijn,
Stefan E Matthiasson,
Unnur Thorsteinsdottir,
Kari Stefansson
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ABSTRACT: We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
Nature Genetics 08/2010; 42(8):692-7. · 35.53 Impact Factor
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ABSTRACT: Aortic aneurysms occur in the thoracic and abdominal sections of the aorta and are a deadly late-age-at-onset disease with complex pathobiology. Currently, the number of published genome-wide analyses including microarray-based expression profiling, DNA linkage studies, and genetic association studies is still limited and it is difficult to make generalizations about the disease pathogenesis or genetic risk factors contributing to aortic aneurysms, but it appears that thoracic aortic aneurysms differ in many ways from abdominal aortic aneurysms. Characterization of diseases at the molecular level is likely to lead to more accurate diagnoses and the use of "genomic nosology" of disease. The biggest future challenge will be to translate the genomic information to the clinic and improve our understanding of the disease processes, help us to develop better diagnostic tools, and lead to the design of new ways to manage aortic aneurysms in the era of personalized medicine.
Current Atherosclerosis Reports 07/2010; 12(4):259-66. · 2.66 Impact Factor
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ABSTRACT: Background: Abdominal Aortic Aneurysm (AAA) rupture is the thirteenth leading cause of death in the U.S. and a major cause of death in the elderly. Since most AAAs are asymptomatic, mortality could be greatly reduced by determining which patients are at risk, then screening those patients prior to a rupture. Our aim was to determine which clinical and genetic risk factors are associated with AAA. Methods: This was a case- control study of patients from the Geisinger Vascular Clinic and the Geisinger MyCode Project (a biobanking project of Geisinger Clinic patients who volunteered to participate in genetic research projects). Clinical and environmental risk factor data was obtained from patient electronic medical records (EMR) and analyzed by multivariate logistic regression. In a subset of participants, we also analyzed three promising genetic polymorphisms, two from a prior genome-wide association study in this population (rs12039875, 1q41; rs7635818, 3p12.3) and one from the recent literature (rs10757278, 9p21). The genetic data was combined with the clinical data using multivariate logistic regression. Results: In the clinical analysis the number of Vascular Clinic and MyCode AAA cases totaled 722, with 11,761 controls. Adjusted OR showed a significant AAA risk for age, gender, smoking, intermittent claudication and peripheral artery disease, while body mass index (BMI) and diabetes were surprisingly protective. The genetic analysis consisted of 502 AAA cases and 295 controls from the Vascular Clinic. The GC genotype of rs7635818 showed an increased risk, but the rs12039875 AA genotype showed a significant protective effect when controlling for the clinical variables. This SNP is located in KCNK2, a gene in the potassium channel protein family. Although this gene has not previously been linked with AAA, our laboratory showed that this gene is expressed in vascular tissue. Conclusions: Our study indicates a significant elevated risk of AAA for individuals who are older, male, ever smoked, have peripheral artery disease and a GC genotype of rs7635818. Higher BMI, diabetes and the AA genotype of rs12039875 in the KCNK2 gene significantly lower AAA risk. This is one of the first studies to utilize the MyCode population in a research study and establish this population source as a valuable and convenient asset of Geisinger Health System for clinical research.
Clinical Medicine & Research 03/2010; 8(1):50.
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ABSTRACT: ACK (activated Cdc42-associated tyrosine kinase) (also Tnk2) is an ubiquitin-binding protein and plays an important role in ligand-induced and ubiquitination-mediated degradation of epidermal growth factor receptor (EGFR). Here we report that ACK is ubiquitinated by HECT E3 ubiquitin ligase Nedd4-1 and degraded along with EGFR in response to EGF stimulation. ACK interacts with Nedd4-1 through a conserved PPXY WW-binding motif. The WW3 domain in Nedd4-1 is critical for binding to ACK. Although ACK binds to both Nedd4-1 and Nedd4-2 (also Nedd4L), Nedd4-1 is the E3 ubiquitin ligase for ubiquitination of ACK in cells. Interestingly, deletion of the sterile alpha motif (SAM) domain at the N terminus dramatically reduced the ubiquitination of ACK by Nedd4-1, while deletion of the Uba domain dramatically enhanced the ubiquitination. Use of proteasomal and lysosomal inhibitors demonstrated that EGF-induced ACK degradation is processed by lysosomes, not proteasomes. RNA interference (RNAi) knockdown of Nedd4-1, not Nedd4-2, inhibited degradation of both EGFR and ACK, and overexpression of ACK mutants that are deficient in either binding to or ubiquitination by Nedd4-1 blocked EGF-induced degradation of EGFR. Our findings suggest an essential role of Nedd4-1 in regulation of EGFR degradation through interaction with and ubiquitination of ACK.
Molecular and cellular biology 03/2010; 30(6):1541-54. · 6.06 Impact Factor
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ABSTRACT: The extracellular matrix of peripheral nerve is formed from a diverse set of macromolecules, including glycoproteins, collagens and proteoglycans. Recent studies using knockout animal models have demonstrated that individual components of the extracellular matrix play a vital role in peripheral nerve development and regeneration. In this study we identified fibrillin-1 and fibrillin-2, large modular structural glycoproteins, as components of the extracellular matrix of peripheral nerve. Previously it was found that fibrillin-2 null mice display joint contractures, suggesting a possible defect of the peripheral nervous system in these animals. Close examination of the peripheral nerves of fibrillin-2 deficient animals described here revealed some structural abnormalities in the perineurium, while general structure of the nerve and molecular composition of nerve extracellular matrix remained unchanged. We also found that in spite of the obvious motor function impairment, fibrillin-2 null mice failed to display changes of nerve conduction properties or nerve regeneration capacity. Based on the data obtained we can conclude that peripheral neuropathy should be excluded as the cause of the impairment of locomotory function and joint contractures observed in fibrillin-2 deficient animals.
Matrix biology: journal of the International Society for Matrix Biology 02/2010; 29(5):357-68. · 3.56 Impact Factor
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ABSTRACT: Nedd4 E3 ligases are members of the HECT E3 ubiquitin ligase family and regulate ubiquitination-mediated protein degradation. In this report, we demonstrate that calcium releases the C2 domain-mediated auto-inhibition in both Nedd4-1 and Nedd4-2. Calcium disrupts binding of the C2 domain to the HECT domain. Consistent with this, calcium activates the E3 ubiquitin ligase activity of Nedd4. Elevation of intracellular calcium by ionomycin treatment, or activation of acetylcholine receptor or epidermal growth factor receptor by carbachol or epidermal growth factor stimulation induced activation of endogenous Nedd4 in vivo evaluated by assays of either Nedd4 E3 ligase activity or ubiquitination of Nedd4 substrate ENaC-beta. The activation effect of calcium on Nedd4 E3 ligase activity was dramatically enhanced by a membrane-rich fraction, suggesting that calcium-mediated membrane translocation through the C2 domain might be an activation mechanism of Nedd4 in vivo. Our studies have revealed an activation mechanism of Nedd4 E3 ubiquitin ligases and established a connection of intracellular calcium signaling to regulation of protein ubiquitination.
Journal of Biological Chemistry 02/2010; 285(16):12279-88. · 4.77 Impact Factor
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ABSTRACT: The goal of this project was to identify genetic variants associated with abdominal aortic aneurysms (AAAs).
A genome wide association study was carried out using pooled DNA samples from 123 AAA cases and 112 controls matched for age, gender, and smoking history using Affymetrix 500K single nucleotide polymorphism (SNP) arrays (Affymetrix, Inc, Santa Clara, Calif). The difference in mean allele frequency between cases and controls was calculated for each SNP and used to identify candidate genomic regions. Association of candidate SNPs with AAA was confirmed by individual TaqMan genotype assays in a total of 2096 cases and controls that included an independent replication sample set.
A genome wide association study of AAA cases and controls identified a candidate AAA-associated haplotype on chromosome 3p12.3. By individual genotype analysis, four SNPs in this region were significantly associated with AAA in cases and controls from the original study population. One SNP in this region (rs7635818) was genotyped in a total of 502 cases and 736 controls from the original study population (P = .017) and 448 cases and 410 controls from an independent replication sample (P = .013; combined P value = .0028; combined odds ratio [OR] = 1.33). An even stronger association with AAA was observed in a subset of smokers (391 cases, 241 controls, P = .00041, OR = 1.80), which represent the highest risk group for AAA. The AAA-associated haplotype is located approximately 200 kbp upstream of the CNTN3 gene transcription start site.
This study identifies a region on chromosome 3 that is significantly associated with AAA in 2 distinct study populations.
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 07/2009; 49(6):1525-31. · 3.52 Impact Factor
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ABSTRACT: Laminins and collagens are extracellular matrix proteins that play essential roles in peripheral nervous system development. Laminin signals regulate Schwann cell proliferation and survival as well as actin cytoskeleton dynamics, which are essential steps for radial sorting and myelination of peripheral axons by Schwann cells. Collagen and their receptors promote Schwann cell adhesion, spreading, and myelination as well as neurite outgrowth. In this article, we will review the recent advances in the studies of laminin and collagen function in Schwann cell development.
Glia 10/2008; 56(14):1498-507. · 4.82 Impact Factor
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ABSTRACT: Renal injury is known to trigger upregulation of many intracellular signal proteins, but those most sensitive in responding to renal injury remain debatable. We used gene microarray analysis to compare gene expression in rat kidneys subjected to early ischemia-reperfusion injury (30 min of renal ischemia and 3 hr of reperfusion) with non-ischemic kidneys as controls. Among 31,100 genes analyzed, microarray analysis revealed 21 genes with >3-fold increase in expression in ischemic kidneys compared to control non-ischemic kidneys. These upregulated genes included heat shock protein 70 (43-fold), heat shock protein 27 (12-fold), heme oxygenase-1 (10-fold), kidney injury molecule-1 (8-fold), and several subtypes of S100 calcium-binding proteins (3.1- to 7.5-fold). Following a prolonged reperfusion period (48 hr) after 30 min of ischemia, acute tubular necrosis was obvious in the S3 segment of proximal tubules of ischemic kidneys. Injured proximal tubules showed upregulated expression of heat shock protein 70 by immunohistochemistry and by Western blotting. These data suggest that heat shock proteins (eg, heat shock protein 70, heat shock protein 27, and heme oxygenase-1) are crucial for renal cell response to ischemic injury and that heat shock protein 70 is a highly sensitive intracellular marker of ischemia-reperfusion injury.
Annals of clinical and laboratory science 02/2008; 38(1):57-64. · 0.96 Impact Factor
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G Craig Wood,
Christopher D Still,
Xin Chu,
Meghan Susek,
Robert Erdman,
Christina Hartman,
Stephanie Yeager,
Mary Ann Blosky,
Wanda Krum, David J Carey,
Kimberly A Skelding,
Peter Benotti,
Walter F Stewart,
Glenn S Gerhard
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ABSTRACT: Genomic medicine research requires substantial time and resources to obtain phenotype data. The electronic health record offers potential efficiencies in addressing these temporal and economic challenges, but few studies have explored the feasibility of using such data for genetics research. The main objective of this study was to determine the association of two genetic variants located on chromosome 9p21 conferring susceptibility to coronary heart disease and type 2 diabetes with a variety of clinical phenotypes derived from the electronic health record in a population of morbidly obese patients. Data on more than 100 clinical measures including diagnoses, laboratory values, and medications were extracted from the electronic health records of a total of 709 morbidly obese (body mass index (BMI) >/= 40 kg/m(2)) patients. Two common single nucleotide polymorphisms located at chromosome 9p21 recently linked to coronary heart disease and type 2 diabetes (McPherson et al. Science 316:1488-1491, 2007; Saxena et al. Science 316:1331-1336, 2007; Scott et al. Science 316:1341-1345, 2007) were genotyped to assess statistical association with clinical phenotypes. Neither the type 2 diabetes variant nor the coronary heart disease variant was related to any expected clinical phenotype, although high-risk type 2 diabetes/coronary heart disease compound genotypes were associated with several coronary heart disease phenotypes. Electronic health records may be efficient sources of data for validation studies of genetic associations.
Genomic Medicine 02/2008; 2(1-2):33-43.
