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Molecular and epidemiologic characterization of Wilms tumor from Baghdad, Iraq.
Phelps HM, Al-Jadiry MF, Corbitt NM, Pierce JM, Li B, Wei Q, Flores RR, Correa H, Uccini S, Frangoul H, Alsaadawi AR, Al-Badri SAF, Al-Darraji AF, Al-Saeed RM, Al-Hadad SA, Lovvorn Iii HN
(2018) World J Pediatr 14: 585-593
MeSH Terms: Adaptor Proteins, Signal Transducing, Child, Preschool, DNA Topoisomerases, Type II, Female, Homeodomain Proteins, Humans, Immunohistochemistry, Infant, Insulin-Like Growth Factor II, Iraq, Kidney Neoplasms, Male, Multiplex Polymerase Chain Reaction, Mutation, N-Myc Proto-Oncogene Protein, Nerve Tissue Proteins, Neural Cell Adhesion Molecules, Nuclear Proteins, Poly-ADP-Ribose Binding Proteins, Receptors, Retinoic Acid, Sequence Analysis, DNA, Transcription Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, WT1 Proteins, Wilms Tumor, beta Catenin
Show Abstract · Added January 28, 2019
BACKGROUND - Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population.
METHODS - Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled.
RESULTS - Mutations were detected in previously described WT "hot spots" (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6-78 months).
CONCLUSIONS - These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.
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27 MeSH Terms
Identifying the substrate proteins of U-box E3s E4B and CHIP by orthogonal ubiquitin transfer.
Bhuripanyo K, Wang Y, Liu X, Zhou L, Liu R, Duong D, Zhao B, Bi Y, Zhou H, Chen G, Seyfried NT, Chazin WJ, Kiyokawa H, Yin J
(2018) Sci Adv 4: e1701393
MeSH Terms: Amino Acid Sequence, Bacteriophages, Biocatalysis, Cyclin-Dependent Kinase 4, Endoplasmic Reticulum Stress, HEK293 Cells, Humans, Mutant Proteins, Mutation, Peptides, Proteolysis, Reproducibility of Results, Signal Transduction, Substrate Specificity, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases, Ubiquitination
Show Abstract · Added March 24, 2018
E3 ubiquitin (UB) ligases E4B and carboxyl terminus of Hsc70-interacting protein (CHIP) use a common U-box motif to transfer UB from E1 and E2 enzymes to their substrate proteins and regulate diverse cellular processes. To profile their ubiquitination targets in the cell, we used phage display to engineer E2-E4B and E2-CHIP pairs that were free of cross-reactivity with the native UB transfer cascades. We then used the engineered E2-E3 pairs to construct "orthogonal UB transfer (OUT)" cascades so that a mutant UB (xUB) could be exclusively used by the engineered E4B or CHIP to label their substrate proteins. Purification of xUB-conjugated proteins followed by proteomics analysis enabled the identification of hundreds of potential substrates of E4B and CHIP in human embryonic kidney 293 cells. Kinase MAPK3 (mitogen-activated protein kinase 3), methyltransferase PRMT1 (protein arginine -methyltransferase 1), and phosphatase PPP3CA (protein phosphatase 3 catalytic subunit alpha) were identified as the shared substrates of the two E3s. Phosphatase PGAM5 (phosphoglycerate mutase 5) and deubiquitinase OTUB1 (ovarian tumor domain containing ubiquitin aldehyde binding protein 1) were confirmed as E4B substrates, and β-catenin and CDK4 (cyclin-dependent kinase 4) were confirmed as CHIP substrates. On the basis of the CHIP-CDK4 circuit identified by OUT, we revealed that CHIP signals CDK4 degradation in response to endoplasmic reticulum stress.
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20 MeSH Terms
Development of Erasin: a chromone-based STAT3 inhibitor which induces apoptosis in Erlotinib-resistant lung cancer cells.
Lis C, Rubner S, Roatsch M, Berg A, Gilcrest T, Fu D, Nguyen E, Schmidt AM, Krautscheid H, Meiler J, Berg T
(2017) Sci Rep 7: 17390
MeSH Terms: Antineoplastic Agents, Apoptosis, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Humans, Lung Neoplasms, Molecular Docking Simulation, Phosphorylation, Protein Processing, Post-Translational, STAT1 Transcription Factor, STAT3 Transcription Factor, STAT5 Transcription Factor, Structure-Activity Relationship, Tumor Suppressor Proteins, src Homology Domains
Show Abstract · Added March 17, 2018
Inhibition of protein-protein interactions by small molecules offers tremendous opportunities for basic research and drug development. One of the fundamental challenges of this research field is the broad lack of available lead structures from nature. Here, we demonstrate that modifications of a chromone-based inhibitor of the Src homology 2 (SH2) domain of the transcription factor STAT5 confer inhibitory activity against STAT3. The binding mode of the most potent STAT3 inhibitor Erasin was analyzed by the investigation of structure-activity relationships, which was facilitated by chemical synthesis and biochemical activity analysis, in combination with molecular docking studies. Erasin inhibits tyrosine phosphorylation of STAT3 with selectivity over STAT5 and STAT1 in cell-based assays, and increases the apoptotic rate of cultured NSCLC cells in a STAT3-dependent manner. This ability of Erasin also extends to HCC-827 cells with acquired resistance against Erlotinib, a clinically used inhibitor of the EGF receptor. Our work validates chromone-based acylhydrazones as privileged structures for antagonizing STAT SH2 domains, and demonstrates that apoptosis can be induced in NSCLC cells with acquired Erlotinib resistance by direct inhibition of STAT3.
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15 MeSH Terms
Heterozygous loss of TSC2 alters p53 signaling and human stem cell reprogramming.
Armstrong LC, Westlake G, Snow JP, Cawthon B, Armour E, Bowman AB, Ess KC
(2017) Hum Mol Genet 26: 4629-4641
MeSH Terms: Adolescent, Adult, Alleles, Cellular Reprogramming, Child, Child, Preschool, Female, Fibroblasts, Genes, p53, Heterozygote, Humans, Induced Pluripotent Stem Cells, Infant, Loss of Heterozygosity, Male, Mutation, RNA, Small Interfering, Signal Transduction, TOR Serine-Threonine Kinases, Tuberous Sclerosis, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
Show Abstract · Added April 11, 2018
Tuberous sclerosis complex (TSC) is a pediatric disorder of dysregulated growth and differentiation caused by loss of function mutations in either the TSC1 or TSC2 genes, which regulate mTOR kinase activity. To study aberrations of early development in TSC, we generated induced pluripotent stem cells using dermal fibroblasts obtained from patients with TSC. During validation, we found that stem cells generated from TSC patients had a very high rate of integration of the reprogramming plasmid containing a shRNA against TP53. We also found that loss of one allele of TSC2 in human fibroblasts is sufficient to increase p53 levels and impair stem cell reprogramming. Increased p53 was also observed in TSC2 heterozygous and homozygous mutant human stem cells, suggesting that the interactions between TSC2 and p53 are consistent across cell types and gene dosage. These results support important contributions of TSC2 heterozygous and homozygous mutant cells to the pathogenesis of TSC and the important role of p53 during reprogramming.
© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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24 MeSH Terms
The major miR-31 target genes STK40 and LATS2 and their implications in the regulation of keratinocyte growth and hair differentiation.
Luan L, Shi J, Yu Z, Andl T
(2017) Exp Dermatol 26: 497-504
MeSH Terms: 3' Untranslated Regions, Adaptor Proteins, Signal Transducing, Animals, Apoptosis, Carcinoma, Basal Cell, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Cell Survival, Hair Follicle, Homeodomain Proteins, Humans, Intracellular Signaling Peptides and Proteins, Keratinocytes, Mice, Mice, Transgenic, MicroRNAs, Protein-Serine-Threonine Kinases, Skin, Skin Neoplasms, Transcription Factors, Tumor Suppressor Proteins
Show Abstract · Added June 21, 2017
Emerging evidence indicates that even subtle changes in the expression of key genes of signalling pathways can have profound effects. MicroRNAs (miRNAs) are masters of subtlety and generally have only mild effects on their target genes. The microRNA miR-31 is one of the major microRNAs in many cutaneous conditions associated with activated keratinocytes, such as the hyperproliferative diseases psoriasis, non-melanoma skin cancer and hair follicle growth. miR-31 is a marker of the hair growth phase, and in our miR-31 transgenic mouse model it impairs the function of keratinocytes. This leads to aberrant proliferation, apoptosis, and differentiation that results in altered hair growth, while the loss of miR-31 leads to increased hair growth. Through in vitro and in vivo studies, we have defined a set of conserved miR-31 target genes, including LATS2 and STK40, which serve as new players in the regulation of keratinocyte growth and hair follicle biology. LATS2 can regulate growth of keratinocytes and we have identified a function of STK40 that can promote the expression of key hair follicle programme regulators such as HR, DLX3 and HOXC13.
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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22 MeSH Terms
Loss of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition.
Zhu L, Giunzioni I, Tavori H, Covarrubias R, Ding L, Zhang Y, Ormseth M, Major AS, Stafford JM, Linton MF, Fazio S
(2016) Arterioscler Thromb Vasc Biol 36: 1483-95
MeSH Terms: Adalimumab, Animals, Anti-Inflammatory Agents, Antigens, Ly, Aorta, Aortic Diseases, Apolipoproteins E, Apoptosis, Atherosclerosis, Bone Marrow Transplantation, Cell Movement, Diet, High-Fat, Disease Models, Animal, Drug Resistance, Female, Genetic Predisposition to Disease, Macrophages, Mice, Knockout, Monocytes, Necrosis, Phenotype, Plaque, Atherosclerotic, Receptors, LDL, Signal Transduction, Tumor Necrosis Factor-alpha, Tumor Suppressor Proteins, Whole-Body Irradiation
Show Abstract · Added April 10, 2018
OBJECTIVE - Antiatherosclerotic effects of tumor necrosis factor-α (TNF-α) blockade in patients with systemic inflammatory states are not conclusively demonstrated, which suggests that effects depend on the cause of inflammation. Macrophage LRP1 (low-density lipoprotein receptor-related protein 1) and apoE contribute to inflammation through different pathways. We studied the antiatherosclerosis effects of TNF-α blockade in hyperlipidemic mice lacking either LRP1 (MΦLRP1(-/-)) or apoE from macrophages.
APPROACH AND RESULTS - Lethally irradiated low-density lipoprotein receptor (LDLR)(-/-) mice were reconstituted with bone marrow from either wild-type, MΦLRP1(-/-), apoE(-/-) or apoE(-/-)/MΦLRP1(-/-)(DKO) mice, and then treated with the TNF-α inhibitor adalimumab while fed a Western-type diet. Adalimumab reduced plasma TNF-α concentration, suppressed blood ly6C(hi) monocyte levels and their migration into the lesion, and reduced lesion cellularity and inflammation in both wild-type→LDLR(-/-) and apoE(-/-)→LDLR(-/-) mice. Overall, adalimumab reduced lesion burden by 52% to 57% in these mice. Adalimumab reduced TNF-α and blood ly6C(hi) monocyte levels in MΦLRP1(-/-)→LDLR(-/-) and DKO→LDLR(-/-) mice, but it did not suppress ly6C(hi) monocyte migration into the lesion or atherosclerosis progression.
CONCLUSIONS - Our results show that TNF-α blockade exerts antiatherosclerotic effects that are dependent on the presence of macrophage LRP1.
© 2016 American Heart Association, Inc.
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MeSH Terms
Myeloid translocation genes differentially regulate colorectal cancer programs.
Parang B, Bradley AM, Mittal MK, Short SP, Thompson JJ, Barrett CW, Naik RD, Bilotta AJ, Washington MK, Revetta FL, Smith JJ, Chen X, Wilson KT, Hiebert SW, Williams CS
(2016) Oncogene 35: 6341-6349
MeSH Terms: Animals, Colorectal Neoplasms, Female, Humans, Male, Mice, Mice, Inbred C57BL, Nuclear Proteins, Repressor Proteins, Signal Transduction, Transcription Factors, Translocation, Genetic, Tumor Suppressor Proteins
Show Abstract · Added June 23, 2016
Myeloid translocation genes (MTGs), originally identified as chromosomal translocations in acute myelogenous leukemia, are transcriptional corepressors that regulate hematopoietic stem cell programs. Analysis of The Cancer Genome Atlas (TCGA) database revealed that MTGs were mutated in epithelial malignancy and suggested that loss of function might promote tumorigenesis. Genetic deletion of MTGR1 and MTG16 in the mouse has revealed unexpected and unique roles within the intestinal epithelium. Mtgr1 mice have progressive depletion of all intestinal secretory cells, and Mtg16 mice have a decrease in goblet cells. Furthermore, both Mtgr1 and Mtg16 mice have increased intestinal epithelial cell proliferation. We thus hypothesized that loss of MTGR1 or MTG16 would modify Apc-dependent intestinal tumorigenesis. Mtgr1 mice, but not Mtg16 mice, had a 10-fold increase in tumor multiplicity. This was associated with more advanced dysplasia, including progression to invasive adenocarcinoma, and augmented intratumoral proliferation. Analysis of chromatin immunoprecipitation sequencing data sets for MTGR1 and MTG16 targets indicated that MTGR1 can regulate Wnt and Notch signaling. In support of this, immunohistochemistry and gene expression analysis revealed that both Wnt and Notch signaling pathways were hyperactive in Mtgr1 tumors. Furthermore, in human colorectal cancer (CRC) samples MTGR1 was downregulated at both the transcript and protein level. Overall our data indicates that MTGR1 has a context-dependent effect on intestinal tumorigenesis.
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13 MeSH Terms
Prox1-Heterozygosis Sensitizes the Pancreas to Oncogenic Kras-Induced Neoplastic Transformation.
Drosos Y, Neale G, Ye J, Paul L, Kuliyev E, Maitra A, Means AL, Washington MK, Rehg J, Finkelstein DB, Sosa-Pineda B
(2016) Neoplasia 18: 172-84
MeSH Terms: Acinar Cells, Animals, Cell Transformation, Neoplastic, Ceruletide, Heterozygote, Homeodomain Proteins, Humans, Inflammation, Metaplasia, Mice, Pancreas, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Tumor Suppressor Proteins
Show Abstract · Added April 11, 2016
The current paradigm of pancreatic neoplastic transformation proposes an initial step whereby acinar cells convert into acinar-to-ductal metaplasias, followed by progression of these lesions into neoplasias under sustained oncogenic activity and inflammation. Understanding the molecular mechanisms driving these processes is crucial to the early diagnostic and prevention of pancreatic cancer. Emerging evidence indicates that transcription factors that control exocrine pancreatic development could have either, protective or facilitating roles in the formation of preneoplasias and neoplasias in the pancreas. We previously identified that the homeodomain transcription factor Prox1 is a novel regulator of mouse exocrine pancreas development. Here we investigated whether Prox1 function participates in early neoplastic transformation using in vivo, in vitro and in silico approaches. We found that Prox1 expression is transiently re-activated in acinar cells undergoing dedifferentiation and acinar-to-ductal metaplastic conversion. In contrast, Prox1 expression is largely absent in neoplasias and tumors in the pancreas of mice and humans. We also uncovered that Prox1-heterozygosis markedly increases the formation of acinar-to-ductal-metaplasias and early neoplasias, and enhances features associated with inflammation, in mouse pancreatic tissues expressing oncogenic Kras. Furthermore, we discovered that Prox1-heterozygosis increases tissue damage and delays recovery from inflammation in pancreata of mice injected with caerulein. These results are the first demonstration that Prox1 activity protects pancreatic cells from acute tissue damage and early neoplastic transformation. Additional data in our study indicate that this novel role of Prox1 involves suppression of pathways associated with inflammatory responses and cell invasiveness.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
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14 MeSH Terms
MAGI-2 in prostate cancer: an immunohistochemical study.
Goldstein J, Borowsky AD, Goyal R, Roland JT, Arnold SA, Gellert LL, Clark PE, Hameed O, Giannico GA
(2016) Hum Pathol 52: 83-91
MeSH Terms: Adenocarcinoma, Adult, Aged, Aged, 80 and over, Area Under Curve, Biomarkers, Tumor, Biopsy, Carrier Proteins, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Male, Middle Aged, Neoplasm Grading, PTEN Phosphohydrolase, Predictive Value of Tests, Prostatic Hyperplasia, Prostatic Intraepithelial Neoplasia, Prostatic Neoplasms, ROC Curve, Tissue Array Analysis, Transcription Factors, Tumor Suppressor Proteins, Up-Regulation
Show Abstract · Added April 18, 2017
Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI-2) is a scaffolding protein that links cell adhesion molecules, receptors, and signaling molecules to the cytoskeleton and maintains the architecture of cell junctions. MAGI-2 gene rearrangements have recently been described in prostate cancer. We studied the immunohistochemical expression of MAGI-2 protein in prostate tissue. Seventy-eight radical prostatectomies were used to construct 3 tissue microarrays consisting of 512 cores, including benign tissue, benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia (HGPIN), and adenocarcinoma, Gleason patterns 3 to 5. Immunohistochemistry for phosphatase and tensin homologue (PTEN) and double-stain MAGI-2/p63 was performed and analyzed by visual and image analysis, the latter as percent of analyzed area (%AREA), and mean optical density multiplied by %AREA (STAIN). By visual and image analysis, MAGI-2 was significantly higher in adenocarcinoma and HGPIN compared with benign (benign versus HGPIN P < .001; benign versus adenocarcinoma, P < .001). HGPIN and adenocarcinoma did not significantly differ by either modality. Using visual intensity to distinguish benign tissue and adenocarcinoma, a receiver operating curve yielded an area under the curve of 0.902. A STAIN threshold of 1470 yielded a sensitivity of 0.66 and specificity of 0.96. There was a significant correlation between PTEN and MAGI-2 staining for normal and benign prostatic hyperplasia, but this was lost in HGPIN and cancer. We conclude that MAGI-2 immunoreactivity is elevated in prostate cancer and HGPIN compared with normal tissue, and suggest that MAGI-2 may contribute to prostate carcinogenesis. This is the first report of MAGI-2 staining by immunohistochemistry in prostate cancer.
Copyright © 2016 Elsevier Inc. All rights reserved.
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24 MeSH Terms
Lack of Prox1 Downregulation Disrupts the Expansion and Maturation of Postnatal Murine β-Cells.
Paul L, Walker EM, Drosos Y, Cyphert HA, Neale G, Stein R, South J, Grosveld G, Herrera PL, Sosa-Pineda B
(2016) Diabetes 65: 687-98
MeSH Terms: Animals, Animals, Newborn, Cell Differentiation, Cell Line, Cell Proliferation, Chromatin Immunoprecipitation, Computer Simulation, Down-Regulation, Enzyme-Linked Immunosorbent Assay, Gene Expression Profiling, Gene Knockdown Techniques, Glucose Tolerance Test, Homeodomain Proteins, Humans, Hyperglycemia, Insulin, Insulin-Secreting Cells, Maf Transcription Factors, Large, Mice, Mice, Transgenic, RNA, Messenger, Real-Time Polymerase Chain Reaction, Tumor Suppressor Proteins
Show Abstract · Added September 19, 2016
Transcription factor expression fluctuates during β-cell ontogeny, and disruptions in this pattern can affect the development or function of those cells. Here we uncovered that murine endocrine pancreatic progenitors express high levels of the homeodomain transcription factor Prox1, whereas both immature and mature β-cells scarcely express this protein. We also investigated if sustained Prox1 expression is incompatible with β-cell development or maintenance using transgenic mouse approaches. We discovered that Prox1 upregulation in mature β-cells has no functional consequences; in contrast, Prox1 overexpression in immature β-cells promotes acute fasting hyperglycemia. Using a combination of immunostaining and quantitative and comparative gene expression analyses, we determined that Prox1 upregulation reduces proliferation, impairs maturation, and enables apoptosis in postnatal β-cells. Also, we uncovered substantial deficiency in β-cells that overexpress Prox1 of the key regulator of β-cell maturation MafA, several MafA downstream targets required for glucose-stimulated insulin secretion, and genes encoding important components of FGF signaling. Moreover, knocking down PROX1 in human EndoC-βH1 β-cells caused increased expression of many of these same gene products. These and other results in our study indicate that reducing the expression of Prox1 is beneficial for the expansion and maturation of postnatal β-cells.
© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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23 MeSH Terms