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p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton.
Fuertes-Alvarez S, Maeso-Alonso L, Villoch-Fernandez J, Wildung M, Martin-Lopez M, Marshall C, Villena-Cortes AJ, Diez-Prieto I, Pietenpol JA, Tissir F, Lizé M, Marques MM, Marin MC
(2018) Cell Death Dis 9: 1183
MeSH Terms: Animals, Carrier Proteins, Cell Polarity, Cilia, Cytoskeleton, Ependyma, Female, Frizzled Receptors, Gene Expression Regulation, Gene Ontology, HCT116 Cells, Humans, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Microtubules, Molecular Sequence Annotation, Nerve Tissue Proteins, Nonmuscle Myosin Type IIA, Pluripotent Stem Cells, Signal Transduction, Tumor Protein p73
Show Abstract · Added March 27, 2019
Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct cerebrospinal fluid circulation. Thus, PCP disruption results in ciliopathies and hydrocephalus. PCP establishment depends on the polarization of cytoskeleton and requires the asymmetric localization of core and global regulatory modules, including membrane proteins like Vangl1/2 or Frizzled. We analyzed the subcellular localization of select proteins that make up these modules in ependymal cells and the effect of Trp73 loss on their localization. We identify a novel function of the Trp73 tumor suppressor gene, the TAp73 isoform in particular, as an essential regulator of PCP through the modulation of actin and microtubule cytoskeleton dynamics, demonstrating that Trp73 is a key player in the organization of ependymal ciliated epithelia. Mechanistically, we show that p73 regulates translational PCP and actin dynamics through TAp73-dependent modulation of non-musclemyosin-II activity. In addition, TAp73 is required for the asymmetric localization of PCP-core and global signaling modules and regulates polarized microtubule dynamics, which in turn set up the rotational PCP. Therefore, TAp73 modulates, directly and/or indirectly, transcriptional programs regulating actin and microtubules dynamics and Golgi organization signaling pathways. These results shed light into the mechanism of ependymal cell planar polarization and reveal p73 as an epithelial architect during development regulating the cellular cytoskeleton.
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24 MeSH Terms
Carcinogenic Strains Selectively Dysregulate the Gastric Proteome, Which May Be Associated with Stomach Cancer Progression.
Noto JM, Rose KL, Hachey AJ, Delgado AG, Romero-Gallo J, Wroblewski LE, Schneider BG, Shah SC, Cover TL, Wilson KT, Israel DA, Roa JC, Schey KL, Zavros Y, Piazuelo MB, Peek RM
(2019) Mol Cell Proteomics 18: 352-371
MeSH Terms: Animals, Carrier Proteins, Cell Line, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, Intestinal Mucosa, Male, Protein Interaction Maps, Proteomics, Stomach Neoplasms, Up-Regulation, Vesicular Transport Proteins
Show Abstract · Added December 16, 2018
is the strongest risk factor for gastric cancer. Initial interactions between and its host originate at the microbial-gastric epithelial cell interface, and contact between and gastric epithelium activates signaling pathways that drive oncogenesis. One microbial constituent that increases gastric cancer risk is the pathogenicity island, which encodes a type IV secretion system that translocates the effector protein, CagA, into host cells. We previously demonstrated that infection of Mongolian gerbils with a carcinogenic strain, 7.13, recapitulates many features of -induced gastric cancer in humans. Therefore, we sought to define gastric proteomic changes induced by that are critical for initiation of the gastric carcinogenic cascade. Gastric cell scrapings were harvested from -infected and uninfected gerbils for quantitative proteomic analyses using isobaric tags for relative and absolute quantitation (iTRAQ). Quantitative proteomic analysis of samples from two biological replicate experiments quantified a total of 2764 proteins, 166 of which were significantly altered in abundance by infection. Pathway mapping identified significantly altered inflammatory and cancer-signaling pathways that included Rab/Ras signaling proteins. Consistent with the iTRAQ results, RABEP2 and G3BP2 were significantly up-regulated , in primary human gastric monolayers, and in gerbil gastric epithelium following infection with strain 7.13 in a -dependent manner. Within human stomachs, RABEP2 and G3BP2 expression in gastric epithelium increased in parallel with the severity of premalignant and malignant lesions and was significantly elevated in intestinal metaplasia and dysplasia, as well as gastric adenocarcinoma, compared with gastritis alone. These results indicate that carcinogenic strains of induce dramatic and specific changes within the gastric proteome and that a subset of altered proteins within pathways with oncogenic potential may facilitate the progression of gastric carcinogenesis in humans.
© 2019 Noto et al.
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16 MeSH Terms
Rif1 inhibits replication fork progression and controls DNA copy number in Drosophila.
Munden A, Rong Z, Sun A, Gangula R, Mallal S, Nordman JT
(2018) Elife 7:
MeSH Terms: Amino Acid Sequence, Animals, Carrier Proteins, DNA, DNA Replication, DNA-Binding Proteins, Drosophila Proteins, Drosophila melanogaster, Gene Dosage, Genome, Insect, Heat-Shock Response, Heterochromatin, Mutation, Protein Binding, Protein Domains, Reproducibility of Results, Salivary Glands
Show Abstract · Added March 3, 2020
Control of DNA copy number is essential to maintain genome stability and ensure proper cell and tissue function. In polyploid cells, the SNF2-domain-containing SUUR protein inhibits replication fork progression within specific regions of the genome to promote DNA underreplication. While dissecting the function of SUUR's SNF2 domain, we identified an interaction between SUUR and Rif1. Rif1 has many roles in DNA metabolism and regulates the replication timing program. We demonstrate that repression of DNA replication is dependent on Rif1. Rif1 localizes to active replication forks in a partially SUUR-dependent manner and directly regulates replication fork progression. Importantly, SUUR associates with replication forks in the absence of Rif1, indicating that Rif1 acts downstream of SUUR to inhibit fork progression. Our findings uncover an unrecognized function of the Rif1 protein as a regulator of replication fork progression.
© 2018, Munden et al.
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Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS).
Gao C, Tabb KL, Dimitrov LM, Taylor KD, Wang N, Guo X, Long J, Rotter JI, Watanabe RM, Curran JE, Blangero J, Langefeld CD, Bowden DW, Palmer ND
(2018) Sci Rep 8: 5603
MeSH Terms: Adult, Apolipoprotein A-V, Atherosclerosis, Carrier Proteins, Female, Genetic Linkage, Genetic Variation, Genome-Wide Association Study, Humans, Insulin Resistance, Lipids, Lipoproteins, HDL, Mexican Americans, Middle Aged, Polymorphism, Single Nucleotide, Triglycerides, Whole Exome Sequencing
Show Abstract · Added April 10, 2018
Genome-wide association studies have identified numerous variants associated with lipid levels; yet, the majority are located in non-coding regions with unclear mechanisms. In the Insulin Resistance Atherosclerosis Family Study (IRASFS), heritability estimates suggest a strong genetic basis: low-density lipoprotein (LDL, h = 0.50), high-density lipoprotein (HDL, h = 0.57), total cholesterol (TC, h = 0.53), and triglyceride (TG, h = 0.42) levels. Exome sequencing of 1,205 Mexican Americans (90 pedigrees) from the IRASFS identified 548,889 variants and association and linkage analyses with lipid levels were performed. One genome-wide significant signal was detected in APOA5 with TG (rs651821, P = 3.67 × 10, LOD = 2.36, MAF = 14.2%). In addition, two correlated SNPs (r = 1.0) rs189547099 (P = 6.31 × 10, LOD = 3.13, MAF = 0.50%) and chr4:157997598 (P = 6.31 × 10, LOD = 3.13, MAF = 0.50%) reached exome-wide significance (P < 9.11 × 10). rs189547099 is an intronic SNP in FNIP2 and SNP chr4:157997598 is intronic in GLRB. Linkage analysis revealed 46 SNPs with a LOD > 3 with the strongest signal at rs1141070 (LOD = 4.30, P = 0.33, MAF = 21.6%) in DFFB. A total of 53 nominally associated variants (P < 5.00 × 10, MAF ≥ 1.0%) were selected for replication in six Mexican-American cohorts (N = 3,280). The strongest signal observed was a synonymous variant (rs1160983, P = 4.44 × 10, MAF = 2.7%) in TOMM40. Beyond primary findings, previously reported lipid loci were fine-mapped using exome sequencing in IRASFS. These results support that exome sequencing complements and extends insights into the genetics of lipid levels.
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17 MeSH Terms
MAGI2 is an independent predictor of biochemical recurrence in prostate cancer.
David SN, Arnold Egloff SA, Goyal R, Clark PE, Phillips S, Gellert LL, Hameed O, Giannico GA
(2018) Prostate 78: 616-622
MeSH Terms: Adenocarcinoma, Aged, Carrier Proteins, Disease Progression, Gene Expression, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Predictive Value of Tests, Prognosis, Prostate-Specific Antigen, Prostatic Neoplasms
Show Abstract · Added March 30, 2020
BACKGROUND - Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI2) promotes the activity of phosphatase and tensin homolog (PTEN). Recent studies suggest that dysregulation of this signaling pathway has a role in prostate carcinogenesis. Our study aims to determine the prognostic significance of MAGI2 expression in prostate cancer.
METHODS - Tissue microarrays from 51 radical prostatectomy cases including benign prostatic tissue, high grade prostatic intraepithelial neoplasia (HGPIN), and adenocarcinoma were constructed. Immunohistochemistry with double staining for MAGI2 and p63 was performed and analyzed by image analysis as percent of analyzed area (%AREA). Multivariable logistic regression was used to correlate MAGI2 expression with clinical outcomes. Generalized Estimating Equations (GEE) with linear and logistic regression was used to correlate MAGI2 with intrapatient histology.
RESULTS - MAGI2 %AREA was inversely associated with progression from HGPIN to adenocarcinoma of low to high Gleason score (OR, 0.980; slope, -0.02; P = 0.005) and HGPIN to cancer of any Gleason score (OR, 0.969; P = 0.007). After adjusting for grade, stage, and margin status, MAGI2 %AREA was a significant independent predictor of biochemical recurrence (BCR) (OR, 0.936; 95%CI, 0.880-0.996; P = 0.037; bootstrap P = 0.017). The addition of MAGI2 %AREA to these standard clinical parameters improved accuracy of predicting BCR by 2.9% (91.0% vs 88.1%).
CONCLUSIONS - These results reveal that MAGI2 expression is reduced during prostate cancer progression and that retention of MAGI2 signal reduces odds of BCR. The study results further suggest a possible role of MAGI2 in prostate neoplasia. Decreased MAGI2 expression may help predict prostate cancer aggressiveness and provide new insight for treatment decisions and post-operative surveillance intervals.
© 2018 Wiley Periodicals, Inc.
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The Marburgvirus-Neutralizing Human Monoclonal Antibody MR191 Targets a Conserved Site to Block Virus Receptor Binding.
King LB, Fusco ML, Flyak AI, Ilinykh PA, Huang K, Gunn B, Kirchdoerfer RN, Hastie KM, Sangha AK, Meiler J, Alter G, Bukreyev A, Crowe JE, Saphire EO
(2018) Cell Host Microbe 23: 101-109.e4
MeSH Terms: Agrobacterium tumefaciens, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Binding Sites, Carrier Proteins, Cell Line, Chlorocebus aethiops, Crystallography, X-Ray, Drosophila melanogaster, Humans, Marburgvirus, Membrane Glycoproteins, Receptors, Virus, Tobacco, Vero Cells, Viral Envelope Proteins, Viral Fusion Proteins, Virus Attachment
Show Abstract · Added March 17, 2018
Since their first identification 50 years ago, marburgviruses have emerged several times, with 83%-90% lethality in the largest outbreaks. Although no vaccines or therapeutics are available for human use, the human antibody MR191 provides complete protection in non-human primates when delivered several days after inoculation of a lethal marburgvirus dose. The detailed neutralization mechanism of MR191 remains outstanding. Here we present a 3.2 Å crystal structure of MR191 complexed with a trimeric marburgvirus surface glycoprotein (GP). MR191 neutralizes by occupying the conserved receptor-binding site and competing with the host receptor Niemann-Pick C1. The structure illuminates previously disordered regions of GP including the stalk, fusion loop, CXCC switch, and an N-terminal region of GP2 that wraps about the outside of GP1 to anchor a marburgvirus-specific "wing" antibody epitope. Virus escape mutations mapped far outside the MR191 receptor-binding site footprint suggest a role for these other regions in the GP quaternary structure.
Copyright © 2017 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Microsomal triglyceride transfer protein contributes to lipid droplet maturation in adipocytes.
Swift LL, Love JD, Harris CM, Chang BH, Jerome WG
(2017) PLoS One 12: e0181046
MeSH Terms: 3T3-L1 Cells, Adipocytes, Adipose Tissue, Brown, Adipose Tissue, White, Animals, Body Composition, Carrier Proteins, Diet, High-Fat, Gene Knockdown Techniques, Lipid Droplets, Mice, Mice, Transgenic, Weight Gain
Show Abstract · Added March 3, 2020
Previous studies in our laboratory have established the presence of MTP in both white and brown adipose tissue in mice as well as in 3T3-L1 cells. Additional studies demonstrated an increase in MTP levels as 3T3-L1 cells differentiate into adipocytes concurrent with the movement of MTP from the juxtanuclear region of the cell to the surface of lipid droplets. This suggested a role for MTP in lipid droplet biogenesis and/or maturation. To probe the role of MTP in adipocytes, we used a Cre-Lox approach with aP2-Cre and Adipoq-Cre recombinase transgenic mice to knock down MTP expression in brown and white fat of mice. MTP expression was reduced approximately 55% in white fat and 65-80% in brown fat. Reducing MTP expression in adipose tissue had no effect on weight gain or body composition, whether the mice were fed a regular rodent or high fat diet. In addition, serum lipids and unesterified fatty acid levels were not altered in the knockdown mice. Importantly, decreased MTP expression in adipose tissue was associated with smaller lipid droplets in brown fat and smaller adipocytes in white fat. These results combined with our previous studies showing MTP lipid transfer activity is not necessary for lipid droplet initiation or growth in the early stages of differentiation, suggest that a structural feature of the MTP protein is important in lipid droplet maturation. We conclude that MTP protein plays a critical role in lipid droplet maturation, but does not regulate total body fat accumulation.
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MeSH Terms
Prp40 Homolog A Is a Novel Centrin Target.
Díaz Casas A, Chazin WJ, Pastrana-Ríos B
(2017) Biophys J 112: 2529-2539
MeSH Terms: Binding Sites, Calorimetry, Carrier Proteins, Chlamydomonas reinhardtii, Circular Dichroism, Humans, Hydrophobic and Hydrophilic Interactions, Protein Unfolding, Recombinant Proteins, Sequence Homology, Amino Acid, Spectroscopy, Fourier Transform Infrared, Thermodynamics, Trimethoprim, Sulfamethoxazole Drug Combination, Two-Hybrid System Techniques
Show Abstract · Added March 24, 2018
Pre-mRNA processing protein 40 (Prp40) is a nuclear protein that has a role in pre-mRNA splicing. Prp40 possesses two leucine-rich nuclear export signals, but little is known about the function of Prp40 in the export process. Another protein that has a role in protein export is centrin, a member of the EF-hand superfamily of Ca-binding proteins. Prp40 was found to be a centrin target by yeast-two-hybrid screening using both Homo sapiens centrin 2 (Hscen2) and Chlamydomonas reinhardtii centrin (Crcen). We identified a centrin-binding site within H. sapiens Prp40 homolog A (HsPrp40A), which contains a hydrophobic triad WLL that is known to be important in the interaction with centrin. This centrin-binding site is highly conserved within the first nuclear export signal consensus sequence identified in Saccharomyces cerevisiae Prp40. Here, we examine the interaction of HsPrp40A peptide (HsPrp40Ap) with both Hscen2 and Crcen by isothermal titration calorimetry. We employed the thermodynamic parameterization to estimate the polar and apolar surface area of the interface. In addition, we have defined the molecular mechanism of thermally induced unfolding and dissociation of the Crcen-HsPrp40Ap complex using two-dimensional infrared correlation spectroscopy. These complementary techniques showed for the first time, to our knowledge, that HsPrp40Ap interacts with centrin in vitro, supporting a coupled functional role for these proteins in pre-mRNA splicing.
Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.
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14 MeSH Terms
Next-generation sequencing identifies pathogenic and modifier mutations in a consanguineous Chinese family with hypertrophic cardiomyopathy.
Zhang X, Xie J, Zhu S, Chen Y, Wang L, Xu B
(2017) Medicine (Baltimore) 96: e7010
MeSH Terms: Adolescent, Adult, Aged, Asian Continental Ancestry Group, Calcium Channels, L-Type, Cardiac Myosins, Cardiomyopathy, Hypertrophic, Familial, Carrier Proteins, Child, China, Consanguinity, Echocardiography, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotyping Techniques, Humans, Male, Middle Aged, Mutation, Myosin Heavy Chains, Sequence Analysis, Young Adult
Show Abstract · Added September 11, 2017
Hypertrophic cardiomyopathy (HCM) is a highly heterogeneous disease displaying considerable interfamilial and intrafamilial phenotypic variation, including disease severity, age of onset, and disease progression. This poorly understood variance raises the possibility of genetic modifier effects, particularly in MYBPC3-associated HCM.In a large consanguineous Chinese HCM family, we identified 8 members harboring the MYBPC3 c.3624delC (p.Lys1209Serfs) disease-causing mutation, but with very disparate phenotypes. Genotyping ruled out the modifying effect of previously described variants in renin-angiotensin-aldosterone system. Afterwards, we screened for modifying variants in all known causing genes and closely related genes for cardiomyopathy and channelopathy by performing targeted next-generation sequencing. For first time, we showed that a c.1598C>T (p.Ser533Leu) mutation in voltage-dependent l-type calcium channel subunit beta-2 (CACNB2) was present in all severely affected HCM patients, but not in those moderately affected or genotype-positive phenotype-negative patients. This CACNB2 p.Ser533Leu mutation is extremely conserved in evolution, and was not found in 550 healthy controls.Our results suggest that CACNB2 is a possible candidate genetic modifier of MYBPC3-associated familial HCM, but more genetic evidence and functional experiments are needed to confirm.
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23 MeSH Terms
Interaction of phosphorylated Rab11-FIP2 with Eps15 regulates apical junction composition.
Lapierre LA, Manning EH, Mitchell KM, Caldwell CM, Goldenring JR
(2017) Mol Biol Cell 28: 1088-1100
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Cadherins, Carrier Proteins, Cell Polarity, Dogs, Endosomes, Epithelial Cells, Gene Knockout Techniques, HEK293 Cells, Humans, Intercellular Junctions, Madin Darby Canine Kidney Cells, Membrane Proteins, Occludin, Phosphorylation, Protein Binding, Protein Transport, rab GTP-Binding Proteins
Show Abstract · Added April 18, 2017
MARK2 regulates the establishment of polarity in Madin-Darby canine kidney (MDCK) cells in part through phosphorylation of serine 227 of Rab11-FIP2. We identified Eps15 as an interacting partner of phospho-S227-Rab11-FIP2 (pS227-FIP2). During recovery from low calcium, Eps15 localized to the lateral membrane before pS227-FIP2 arrival. Later in recovery, Eps15 and pS227-FIP2 colocalized at the lateral membrane. In MDCK cells expressing the pseudophosphorylated FIP2 mutant FIP2(S227E), during recovery from low calcium, Eps15 was trapped and never localized to the lateral membrane. Mutation of any of the three NPF domains within GFP-FIP2(S227E) rescued Eps15 localization at the lateral membrane and reestablished single-lumen cyst formation in GFP-FIP2(S227E)-expressing cells in three-dimensional (3D) culture. Whereas expression of GFP-FIP2(S227E) induced the loss of E-cadherin and occludin, mutation of any of the NPF domains of GFP-FIP2(S227E) reestablished both proteins at the apical junctions. Knockdown of Eps15 altered the spatial and temporal localization of pS227-FIP2 and also elicited formation of multiple lumens in MDCK 3D cysts. Thus an interaction of Eps15 and pS227-FIP2 at the appropriate time and location in polarizing cells is necessary for proper establishment of epithelial polarity.
© 2017 Lapierre et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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19 MeSH Terms