Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 191

Publication Record

Connections

Examining How the MAFB Transcription Factor Affects Islet β-Cell Function Postnatally.
Cyphert HA, Walker EM, Hang Y, Dhawan S, Haliyur R, Bonatakis L, Avrahami D, Brissova M, Kaestner KH, Bhushan A, Powers AC, Stein R
(2019) Diabetes 68: 337-348
MeSH Terms: Animals, Cells, Cultured, Chromatin Immunoprecipitation, Chromosomes, Artificial, Bacterial, DNA Methylation, Female, Humans, In Vitro Techniques, Insulin-Secreting Cells, Maf Transcription Factors, Large, MafB Transcription Factor, Mice, Mice, Transgenic, Pregnancy, Tryptophan Hydroxylase
Show Abstract · Added January 8, 2019
The sustained expression of the MAFB transcription factor in human islet β-cells represents a distinct difference in mice. Moreover, mRNA expression of closely related and islet β-cell-enriched MAFA does not peak in humans until after 9 years of age. We show that the MAFA protein also is weakly produced within the juvenile human islet β-cell population and that expression is postnatally restricted in mouse β-cells by de novo DNA methylation. To gain insight into how MAFB affects human β-cells, we developed a mouse model to ectopically express in adult mouse β-cells using transcriptional control sequences. Coexpression of MafB with MafA had no overt impact on mouse β-cells, suggesting that the human adult β-cell MAFA/MAFB heterodimer is functionally equivalent to the mouse MafA homodimer. However, MafB alone was unable to rescue the islet β-cell defects in a mouse mutant lacking MafA in β-cells. Of note, transgenic production of MafB in β-cells elevated tryptophan hydroxylase 1 mRNA production during pregnancy, which drives the serotonin biosynthesis critical for adaptive maternal β-cell responses. Together, these studies provide novel insight into the role of MAFB in human islet β-cells.
© 2018 by the American Diabetes Association.
1 Communities
0 Members
0 Resources
15 MeSH Terms
Activated CaMKII Binds to the mGlu Metabotropic Glutamate Receptor and Modulates Calcium Mobilization.
Marks CR, Shonesy BC, Wang X, Stephenson JR, Niswender CM, Colbran RJ
(2018) Mol Pharmacol 94: 1352-1362
MeSH Terms: Animals, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calmodulin, Cell Line, Cell Membrane, Female, HEK293 Cells, Humans, Immunoprecipitation, Male, Mice, Mice, Knockout, Protein Binding, Receptor, Metabotropic Glutamate 5, Signal Transduction
Show Abstract · Added November 8, 2018
Ca/calmodulin-dependent protein kinase II (CaMKII) and metabotropic glutamate receptor 5 (mGlu) are critical signaling molecules in synaptic plasticity and learning/memory. Here, we demonstrate that mGlu is present in CaMKII complexes isolated from mouse forebrain. Further in vitro characterization showed that the membrane-proximal region of the C-terminal domain (CTD) of mGlu directly interacts with purified Thr286-autophosphorylated (activated) CaMKII However, the binding of CaMKII to this CTD fragment is reduced by the addition of excess Ca/calmodulin or by additional CaMKII autophosphorylation at non-Thr286 sites. Furthermore, in vitro binding of CaMKII is dependent on a tribasic residue motif Lys-Arg-Arg (KRR) at residues 866-868 of the mGlu-CTD, and mutation of this motif decreases the coimmunoprecipitation of CaMKII with full-length mGlu expressed in heterologous cells by about 50%. The KRR motif is required for two novel functional effects of coexpressing constitutively active CaMKII with mGlu in heterologous cells. First, cell-surface biotinylation studies showed that CaMKII increases the surface expression of mGlu Second, using Ca fluorimetry and single-cell Ca imaging, we found that CaMKII reduces the initial peak of mGlu-mediated Ca mobilization by about 25% while doubling the relative duration of the Ca signal. These findings provide new insights into the physical and functional coupling of these key regulators of postsynaptic signaling.
Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
1 Communities
1 Members
0 Resources
16 MeSH Terms
VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma.
Zhang J, Wu T, Simon J, Takada M, Saito R, Fan C, Liu XD, Jonasch E, Xie L, Chen X, Yao X, Teh BT, Tan P, Zheng X, Li M, Lawrence C, Fan J, Geng J, Liu X, Hu L, Wang J, Liao C, Hong K, Zurlo G, Parker JS, Auman JT, Perou CM, Rathmell WK, Kim WY, Kirschner MW, Kaelin WG, Baldwin AS, Zhang Q
(2018) Science 361: 290-295
MeSH Terms: Animals, Carcinoma, Renal Cell, Chromatin Immunoprecipitation, Female, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Hydroxylation, Kidney Neoplasms, Mice, Mice, SCID, Molecular Targeted Therapy, Mutation, NF-kappa B, Oncogenes, Substrate Specificity, Transcription Factors, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added October 30, 2019
Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
0 Communities
1 Members
0 Resources
MeSH Terms
Tuning Hsf1 levels drives distinct fungal morphogenetic programs with depletion impairing Hsp90 function and overexpression expanding the target space.
Veri AO, Miao Z, Shapiro RS, Tebbji F, O'Meara TR, Kim SH, Colazo J, Tan K, Vyas VK, Whiteway M, Robbins N, Wong KH, Cowen LE
(2018) PLoS Genet 14: e1007270
MeSH Terms: Blotting, Western, Candida albicans, Chromatin Immunoprecipitation, Genes, Fungal, HSP90 Heat-Shock Proteins, Heat Shock Transcription Factors, Morphogenesis, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, RNA, Temperature, Virulence
Show Abstract · Added November 7, 2019
The capacity to respond to temperature fluctuations is critical for microorganisms to survive within mammalian hosts, and temperature modulates virulence traits of diverse pathogens. One key temperature-dependent virulence trait of the fungal pathogen Candida albicans is its ability to transition from yeast to filamentous growth, which is induced by environmental cues at host physiological temperature. A key regulator of temperature-dependent morphogenesis is the molecular chaperone Hsp90, which has complex functional relationships with the transcription factor Hsf1. Although Hsf1 controls global transcriptional remodeling in response to heat shock, its impact on morphogenesis remains unknown. Here, we establish an intriguing paradigm whereby overexpression or depletion of C. albicans HSF1 induces morphogenesis in the absence of external cues. HSF1 depletion compromises Hsp90 function, thereby driving filamentation. HSF1 overexpression does not impact Hsp90 function, but rather induces a dose-dependent expansion of Hsf1 direct targets that drives overexpression of positive regulators of filamentation, including Brg1 and Ume6, thereby bypassing the requirement for elevated temperature during morphogenesis. This work provides new insight into Hsf1-mediated environmentally contingent transcriptional control, implicates Hsf1 in regulation of a key virulence trait, and highlights fascinating biology whereby either overexpression or depletion of a single cellular regulator induces a profound developmental transition.
0 Communities
1 Members
0 Resources
MeSH Terms
Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus.
Karimy JK, Zhang J, Kurland DB, Theriault BC, Duran D, Stokum JA, Furey CG, Zhou X, Mansuri MS, Montejo J, Vera A, DiLuna ML, Delpire E, Alper SL, Gunel M, Gerzanich V, Medzhitov R, Simard JM, Kahle KT
(2017) Nat Med 23: 997-1003
MeSH Terms: Acetazolamide, Animals, Antioxidants, Blotting, Western, Bumetanide, Cerebral Hemorrhage, Cerebral Ventricles, Cerebrospinal Fluid, Choroid Plexus, Diuretics, Gene Knockdown Techniques, Gene Knockout Techniques, Hydrocephalus, Immunoblotting, Immunohistochemistry, Immunoprecipitation, Inflammation, NF-kappa B, Proline, Protein-Serine-Threonine Kinases, Rats, Rats, Wistar, Salicylanilides, Solute Carrier Family 12, Member 2, Sulfonamides, Thiocarbamates, Toll-Like Receptor 4
Show Abstract · Added April 3, 2018
The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.
0 Communities
1 Members
0 Resources
MeSH Terms
Power and sample size calculations for high-throughput sequencing-based experiments.
Li CI, Samuels DC, Zhao YY, Shyr Y, Guo Y
(2018) Brief Bioinform 19: 1247-1255
MeSH Terms: Chromatin Immunoprecipitation, Genome-Wide Association Study, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Microbiota, Mutation, Poisson Distribution, Sequence Analysis, RNA
Show Abstract · Added April 3, 2018
Power/sample size (power) analysis estimates the likelihood of successfully finding the statistical significance in a data set. There has been a growing recognition of the importance of power analysis in the proper design of experiments. Power analysis is complex, yet necessary for the success of large studies. It is important to design a study that produces statistically accurate and reliable results. Power computation methods have been well established for both microarray-based gene expression studies and genotyping microarray-based genome-wide association studies. High-throughput sequencing (HTS) has greatly enhanced our ability to conduct biomedical studies at the highest possible resolution (per nucleotide). However, the complexity of power computations is much greater for sequencing data than for the simpler genotyping array data. Research on methods of power computations for HTS-based studies has been recently conducted but is not yet well known or widely used. In this article, we describe the power computation methods that are currently available for a range of HTS-based studies, including DNA sequencing, RNA-sequencing, microbiome sequencing and chromatin immunoprecipitation sequencing. Most importantly, we review the methods of power analysis for several types of sequencing data and guide the reader to the relevant methods for each data type.
0 Communities
1 Members
0 Resources
9 MeSH Terms
Prominin-1 Is a Novel Regulator of Autophagy in the Human Retinal Pigment Epithelium.
Bhattacharya S, Yin J, Winborn CS, Zhang Q, Yue J, Chaum E
(2017) Invest Ophthalmol Vis Sci 58: 2366-2387
MeSH Terms: AC133 Antigen, Adult, Aged, Animals, Autophagy, Blotting, Western, Cells, Cultured, Female, Flow Cytometry, Gene Expression Regulation, Humans, Immunoprecipitation, Macular Degeneration, Male, Microscopy, Confocal, Middle Aged, RNA, Rabbits, Real-Time Polymerase Chain Reaction, Retinal Pigment Epithelium, Signal Transduction, Young Adult
Show Abstract · Added June 11, 2018
Purpose - Prominin-1 (Prom1) is a transmembrane glycoprotein, which is expressed in stem cell lineages, and has recently been implicated in cancer stem cell survival. Mutations in the Prom1 gene have been shown to disrupt photoreceptor disk morphogenesis and cause an autosomal dominant form of Stargardt-like macular dystrophy (STGD4). Despite the apparent structural role of Prom1 in photoreceptors, its role in other cells of the retina is unknown. The purpose of this study is to investigate the role of Prom1 in the highly metabolically active cells of the retinal pigment epithelium (RPE).
Methods - Lentiviral siRNA and the genome editing CRISPR/Cas9 system were used to knockout Prom1 in primary RPE and ARPE-19 cells, respectively. Western blotting, confocal microscopy, and flow sight imaging cytometry assays were used to quantify autophagy flux. Immunoprecipitation was used to detect Prom1 interacting proteins.
Results - Our studies demonstrate that Prom1 is primarily a cytosolic protein in the RPE. Stress signals and physiological aging robustly increase autophagy with concomitant upregulation of Prom1 expression. Knockout of Prom1 increased mTORC1 and mTORC2 signaling, decreased autophagosome trafficking to the lysosome, increased p62 accumulation, and inhibited autophagic puncta induced by activators of autophagy. Conversely, ectopic overexpression of Prom1 inhibited mTORC1 and mTORC2 activities, and potentiated autophagy flux. Through interactions with p62 and HDAC6, Prom1 regulates autophagosome maturation and trafficking, suggesting a new cytoplasmic role of Prom1 in RPE function.
Conclusions - Our results demonstrate that Prom1 plays a key role in the regulation of autophagy via upstream suppression of mTOR signaling and also acting as a component of a macromolecular scaffold involving p62 and HDAC6.
0 Communities
1 Members
0 Resources
MeSH Terms
Determination of the CD148-Interacting Region in Thrombospondin-1.
Takahashi K, Sumarriva K, Kim R, Jiang R, Brantley-Sieders DM, Chen J, Mernaugh RL, Takahashi T
(2016) PLoS One 11: e0154916
MeSH Terms: Animals, Binding Sites, Cell Proliferation, Cells, Cultured, Endothelial Cells, Gene Knockdown Techniques, Humans, Immunoblotting, Immunoprecipitation, Mice, Inbred C57BL, Neovascularization, Physiologic, Peptide Fragments, Protein Tyrosine Phosphatases, Receptor-Like Protein Tyrosine Phosphatases, Class 3, Thrombospondin 1
Show Abstract · Added April 26, 2017
CD148 is a transmembrane protein tyrosine phosphatase that is expressed in multiple cell types, including vascular endothelial cells and duct epithelial cells. Previous studies have shown a prominent role of CD148 to reduce growth factor signals and suppress cell proliferation and transformation. Further, we have recently shown that thrombospondin-1 (TSP1) serves as a functionally important ligand for CD148. TSP1 has multiple structural elements and interacts with various cell surface receptors that exhibit differing effects. In order to create the CD148-specific TSP1 fragment, here we investigated the CD148-interacting region in TSP1 using a series of TSP1 fragments and biochemical and biological assays. Our results demonstrate that: 1) CD148 binds to the 1st type 1 repeat in TSP1; 2) Trimeric TSP1 fragments that contain the 1st type repeat inhibit cell proliferation in A431D cells that stably express wild-type CD148 (A431D/CD148wt cells), while they show no effects in A431D cells that lack CD148 or express a catalytically inactive form of CD148. The anti-proliferative effect of the TSP1 fragment in A431D/CD148wt cells was largely abolished by CD148 knockdown and antagonized by the 1st, but not the 2nd and 3rd, type 1 repeat fragment. Furthermore, the trimeric TSP1 fragments containing the 1st type repeat increased the catalytic activity of CD148 and reduced phospho-tyrosine contents of EGFR and ERK1/2, defined CD148 substrates. These effects were not observed in the TSP1 fragments that lack the 1st type 1 repeat. Last, we demonstrate that the trimeric TSP1 fragment containing the 1st type 1 repeat inhibits endothelial cell proliferation in culture and angiogenesis in vivo. These effects were largely abolished by CD148 knockdown or deficiency. Collectively, these findings indicate that the 1st type 1 repeat interacts with CD148, reducing growth factor signals and inhibiting epithelial or endothelial cell proliferation and angiogenesis.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function.
Arda HE, Li L, Tsai J, Torre EA, Rosli Y, Peiris H, Spitale RC, Dai C, Gu X, Qu K, Wang P, Wang J, Grompe M, Scharfmann R, Snyder MS, Bottino R, Powers AC, Chang HY, Kim SK
(2016) Cell Metab 23: 909-20
MeSH Terms: Adult, Aging, Cell Differentiation, Cell Separation, Child, Child, Preschool, Chromatin, Chromatin Immunoprecipitation, Diabetes Mellitus, Gene Expression Regulation, Developmental, Histone Code, Homeodomain Proteins, Humans, Infant, Insulin-Secreting Cells, Middle Aged, Transcription Factors, Transcriptome, Young Adult
Show Abstract · Added July 16, 2016
Intensive efforts are focused on identifying regulators of human pancreatic islet cell growth and maturation to accelerate development of therapies for diabetes. After birth, islet cell growth and function are dynamically regulated; however, establishing these age-dependent changes in humans has been challenging. Here, we describe a multimodal strategy for isolating pancreatic endocrine and exocrine cells from children and adults to identify age-dependent gene expression and chromatin changes on a genomic scale. These profiles revealed distinct proliferative and functional states of islet α cells or β cells and histone modifications underlying age-dependent gene expression changes. Expression of SIX2 and SIX3, transcription factors without prior known functions in the pancreas and linked to fasting hyperglycemia risk, increased with age specifically in human islet β cells. SIX2 and SIX3 were sufficient to enhance insulin content or secretion in immature β cells. Our work provides a unique resource to study human-specific regulators of islet cell maturation and function.
Copyright © 2016 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
19 MeSH Terms
Transthyretin Suppresses Amyloid-β Secretion by Interfering with Processing of the Amyloid-β Protein Precursor.
Li X, Song Y, Sanders CR, Buxbaum JN
(2016) J Alzheimers Dis 52: 1263-75
MeSH Terms: Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Brain, CHO Cells, Cricetulus, Enzyme-Linked Immunosorbent Assay, Female, Immunoprecipitation, Male, Mice, Mice, Transgenic, Prealbumin
Show Abstract · Added November 21, 2018
In Alzheimer's disease (AD), most hippocampal and cortical neurons show increased staining with anti-transthyretin (TTR) antibodies. Genetically programmed overexpression of wild type human TTR suppressed the neuropathologic and behavioral abnormalities in APP23 AD model mice and TTR-Aβ complexes have been isolated from some human AD brains and those of APP23 transgenic mice. In the present study, in vitro NMR analysis showed interaction between the hydrophobic thyroxine binding pocket of TTR and the cytoplasmic loop of the C99 fragment released by β-secretase cleavage of AβPP, with Kd = 86±9 μM. In cultured cells expressing both proteins, the interaction reduced phosphorylation of C99 (at T668) and suppressed its cleavage by γ-secretase, significantly decreasing Aβ secretion. Coupled with its previously demonstrated capacity to inhibit Aβ aggregation (with the resultant cytotoxicity in tissue culture) and its regulation by HSF1, these findings indicate that TTR can behave as a stress responsive multimodal suppressor of AD pathogenesis.
0 Communities
1 Members
0 Resources
MeSH Terms