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 197

Publication Record

Connections

Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.
Tian J, Teuscher KB, Aho ER, Alvarado JR, Mills JJ, Meyers KM, Gogliotti RD, Han C, Macdonald JD, Sai J, Shaw JG, Sensintaffar JL, Zhao B, Rietz TA, Thomas LR, Payne WG, Moore WJ, Stott GM, Kondo J, Inoue M, Coffey RJ, Tansey WP, Stauffer SR, Lee T, Fesik SW
(2020) J Med Chem 63: 656-675
MeSH Terms: Antineoplastic Agents, Bridged Bicyclo Compounds, Heterocyclic, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Chromatin, Crystallography, X-Ray, Drug Design, Drug Discovery, Epigenetic Repression, Genes, myc, Humans, Intracellular Signaling Peptides and Proteins, Quinolones, Structure-Activity Relationship, WD40 Repeats
Show Abstract · Added March 3, 2020
WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using a structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent antiproliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site binders inhibit proliferation in MYC-driven cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Normal Saline solutions cause endothelial dysfunction through loss of membrane integrity, ATP release, and inflammatory responses mediated by P2X7R/p38 MAPK/MK2 signaling pathways.
Cheung-Flynn J, Alvis BD, Hocking KM, Guth CM, Luo W, McCallister R, Chadalavada K, Polcz M, Komalavilas P, Brophy CM
(2019) PLoS One 14: e0220893
MeSH Terms: Adenosine Triphosphate, Animals, Aorta, Cell Membrane, Endothelial Cells, Humans, Inflammation, Intracellular Signaling Peptides and Proteins, Phosphorylation, Protein-Serine-Threonine Kinases, Rats, Receptors, Purinergic P2X7, Saline Solution, Saphenous Vein, Signal Transduction, Swine, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added March 3, 2020
Resuscitation with 0.9% Normal Saline (NS), a non-buffered acidic solution, leads to increased morbidity and mortality in the critically ill. The goal of this study was to determine the molecular mechanisms of endothelial injury after exposure to NS. The hypothesis of this investigation is that exposure of endothelium to NS would lead to loss of cell membrane integrity, resulting in release of ATP, activation of the purinergic receptor (P2X7R), and subsequent activation of stress activated signaling pathways and inflammation. Human saphenous vein endothelial cells (HSVEC) incubated in NS, but not buffered electrolyte solution (Plasma-Lyte, PL), exhibited abnormal morphology and increased release of lactate dehydrogenase (LDH), adenosine triphosphate (ATP), and decreased transendothelial resistance (TEER), suggesting loss of membrane integrity. Incubation of intact rat aorta (RA) or human saphenous vein in NS but not PL led to impaired endothelial-dependent relaxation which was ameliorated by apyrase (hydrolyzes ATP) or SB203580 (p38 MAPK inhibitor). Exposure of HSVEC to NS but not PL led to activation of p38 MAPK and its downstream substrate, MAPKAP kinase 2 (MK2). Treatment of HSVEC with exogenous ATP led to interleukin 1β (IL-1β) release and increased vascular cell adhesion molecule (VCAM) expression. Treatment of RA with IL-1β led to impaired endothelial relaxation. IL-1β treatment of HSVEC led to increases in p38 MAPK and MK2 phosphorylation, and increased levels of arginase II. Incubation of porcine saphenous vein (PSV) in PL with pH adjusted to 6.0 or less also led to impaired endothelial function, suggesting that the acidic nature of NS is what contributes to endothelial dysfunction. Volume overload resuscitation in a porcine model after hemorrhage with NS, but not PL, led to acidosis and impaired endothelial function. These data suggest that endothelial dysfunction caused by exposure to acidic, non-buffered NS is associated with loss of membrane integrity, release of ATP, and is modulated by P2X7R-mediated inflammatory responses.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations.
Ahmed IA, Farooqi MS, Vander Lugt MT, Boklan J, Rose M, Friehling ED, Triplett B, Lieuw K, Saldana BD, Smith CM, Schwartz JR, Goyal RK
(2019) Biol Blood Marrow Transplant 25: 2186-2196
MeSH Terms: Allografts, Child, Preschool, Disease-Free Survival, Female, Genetic Diseases, Inborn, Germ-Line Mutation, Hematopoietic Stem Cell Transplantation, Humans, Infant, Intracellular Signaling Peptides and Proteins, Male, Myelodysplastic Syndromes, Retrospective Studies, Survival Rate, Syndrome, Tumor Suppressor Proteins
Show Abstract · Added September 19, 2019
Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n = 10), congenital amegakaryocytic thrombocytopenia (n = 1), and dyskeratosis congenita (n = 1). Exome sequencing revealed heterozygous mutations in SAMD9 (n = 6) or SAMD9L (n = 6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L-associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.
Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity.
Aho ER, Wang J, Gogliotti RD, Howard GC, Phan J, Acharya P, Macdonald JD, Cheng K, Lorey SL, Lu B, Wenzel S, Foshage AM, Alvarado J, Wang F, Shaw JG, Zhao B, Weissmiller AM, Thomas LR, Vakoc CR, Hall MD, Hiebert SW, Liu Q, Stauffer SR, Fesik SW, Tansey WP
(2019) Cell Rep 26: 2916-2928.e13
MeSH Terms: Binding Sites, Cell Line, Tumor, Chromatin, Enzyme Inhibitors, Female, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Male, Protein Binding
Show Abstract · Added March 26, 2019
The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the "WIN site" of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Direct reprogramming to human nephron progenitor-like cells using inducible piggyBac transposon expression of SNAI2-EYA1-SIX1.
Vanslambrouck JM, Woodard LE, Suhaimi N, Williams FM, Howden SE, Wilson SB, Lonsdale A, Er PX, Li J, Maksimovic J, Oshlack A, Wilson MH, Little MH
(2019) Kidney Int 95: 1153-1166
MeSH Terms: Cells, Cultured, Cellular Reprogramming, DNA Transposable Elements, Gene Transfer Techniques, Genetic Engineering, Homeodomain Proteins, Humans, Intracellular Signaling Peptides and Proteins, Nephrons, Nuclear Proteins, Primary Cell Culture, Protein Tyrosine Phosphatases, Regeneration, Snail Family Transcription Factors
Show Abstract · Added March 28, 2019
All nephrons in the mammalian kidney arise from a transient nephron progenitor population that is lost close to the time of birth. The generation of new nephron progenitors and their maintenance in culture are central to the success of kidney regenerative strategies. Using a lentiviral screening approach, we previously generated a human induced nephron progenitor-like state in vitro using a pool of six transcription factors. Here, we sought to develop a more efficient approach for direct reprogramming of human cells that could be applied in vivo. PiggyBac transposons are a non-viral integrating gene delivery system that is suitable for in vivo use and allows for simultaneous delivery of multiple genes. Using an inducible piggyBac transposon system, we optimized a protocol for the direct reprogramming of HK2 cells to induced nephron progenitor-like cells with expression of only 3 transcription factors (SNAI2, EYA1, and SIX1). Culture in conditions supportive of the nephron progenitor state further increased the expression of nephron progenitor genes. The refined protocol was then applied to primary human renal epithelial cells, which integrated into developing nephron structures in vitro and in vivo. Such inducible reprogramming to nephron progenitor-like cells could facilitate direct cellular reprogramming for kidney regeneration.
Copyright © 2019 International Society of Nephrology. All rights reserved.
0 Communities
2 Members
0 Resources
14 MeSH Terms
Treating Nonalcoholic Fatty Liver Disease From the Outside In?
Flynn CR
(2019) Cell Mol Gastroenterol Hepatol 7: 682-683
MeSH Terms: Animals, Hepatocytes, Intracellular Signaling Peptides and Proteins, Mice, Non-alcoholic Fatty Liver Disease, Oligonucleotides, Antisense, Protein-Serine-Threonine Kinases
Added April 15, 2019
0 Communities
1 Members
0 Resources
7 MeSH Terms
Excipients for the lyoprotection of MAPKAP kinase 2 inhibitory peptide nano-polyplexes.
Mukalel AJ, Evans BC, Kilchrist KV, Dailing EA, Burdette B, Cheung-Flynn J, Brophy CM, Duvall CL
(2018) J Control Release 282: 110-119
MeSH Terms: Cell Line, Drug Stability, Enzyme Inhibitors, Excipients, Freeze Drying, Humans, Intracellular Signaling Peptides and Proteins, Nanoparticles, Peptides, Protein-Serine-Threonine Kinases, Sucrose, Trehalose, Trisaccharides
Show Abstract · Added May 22, 2018
Herein, excipients are investigated to ameliorate the deleterious effects of lyophilization on peptide-polymer nano-polyplex (NP) morphology, cellular uptake, and bioactivity. The NPs are a previously-described platform technology for intracellular peptide delivery and are formulated from a cationic therapeutic peptide and the anionic, pH-responsive, endosomolytic polymer poly(propylacrylic acid) (PPAA). These NPs are effective when formulated and immediately used for delivery into cells and tissue, but they are not amenable to reconstitution following storage as a lyophilized powder due to aggregation. To develop a lyophilized NP format that facilitates longer-term storage and ease of use, MAPKAP kinase 2 inhibitory peptide-based NPs (MK2i-NPs) were prepared in the presence of a range of concentrations of the excipients sucrose, trehalose, and lactosucrose prior to lyophilization and storage. All excipients improved particle morphology post-lyophilization and significantly improved MK2i-NP uptake in human coronary artery smooth muscle cells relative to lyophilized NPs without excipient. In particular, MK2i-NPs lyophilized with 300 mM lactosucrose as an excipient demonstrated a 5.23 fold increase in cellular uptake (p < 0.001), a 2.52 fold increase in endosomal disruption (p < 0.05), and a 2.39 fold increase in ex vivo bioactivity (p < 0.01) compared to MK2i-NPs lyophilized without excipients. In sum, these data suggest that addition of excipients, particularly lactosucrose, maintains and even improves the uptake and therapeutic efficacy of peptide-polymer NPs post-lyophilization relative to freshly-made formulations. Thus, the use of excipients as lyoprotectants is a promising approach for the long-term storage of biotherapeutic NPs and poises this NP platform for clinical translation.
Copyright © 2018 Elsevier B.V. All rights reserved.
0 Communities
2 Members
0 Resources
13 MeSH Terms
Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling.
Ng VH, Hang BI, Sawyer LM, Neitzel LR, Crispi EE, Rose KL, Popay TM, Zhong A, Lee LA, Tansey WP, Huppert S, Lee E
(2018) J Cell Sci 131:
MeSH Terms: Amino Acid Motifs, Animals, Apoptosis Regulatory Proteins, Cell Line, Glycogen Synthase Kinase 3, Humans, Intracellular Signaling Peptides and Proteins, Mitochondrial Proteins, Phosphorylation, Protein Binding, Threonine, Wnt Signaling Pathway, Wnt3A Protein, X-Linked Inhibitor of Apoptosis Protein, Xenopus
Show Abstract · Added July 6, 2018
X-linked inhibitor of apoptosis (XIAP) plays an important role in preventing apoptotic cell death. XIAP has been shown to participate in signaling pathways, including Wnt signaling. XIAP regulates Wnt signaling by promoting the monoubiquitylation of the co-repressor Groucho/TLE family proteins, decreasing its affinity for the TCF/Lef family of transcription factors and allowing assembly of transcriptionally active β-catenin-TCF/Lef complexes. We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAP) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in embryos. Although XIAP ubiquitylates TLE3 at wild-type levels , it exhibits a reduced capacity to ubiquitylate and bind TLE3 in human cells. XIAP binds Smac (also known as DIABLO) and inhibits Fas-induced apoptosis to a similar degree to wild-type XIAP. Our studies uncover a new mechanism by which XIAP is specifically directed towards a Wnt signaling function versus its anti-apoptotic function. These findings have implications for development of anti-XIAP therapeutics for human cancers.
© 2018. Published by The Company of Biologists Ltd.
0 Communities
2 Members
0 Resources
15 MeSH Terms
The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ.
Edwards DN, Ngwa VM, Wang S, Shiuan E, Brantley-Sieders DM, Kim LC, Reynolds AB, Chen J
(2017) Sci Signal 10:
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Transport System ASC, Animals, Biomarkers, Tumor, Breast Neoplasms, DNA-Binding Proteins, Disease Models, Animal, Ephrin-A2, Female, Glutaminase, Glutamine, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Knockout, Minor Histocompatibility Antigens, Muscle Proteins, Phosphoproteins, Transcription Factors, Tumor Cells, Cultured
Show Abstract · Added April 2, 2019
Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Glutamine transporters and glutaminase activity are critical for glutamine metabolism in tumor cells. We found that the receptor tyrosine kinase EphA2 activated the TEAD family transcriptional coactivators YAP and TAZ (YAP/TAZ), likely in a ligand-independent manner, to promote glutamine metabolism in cells and mouse models of HER2-positive breast cancer. Overexpression of EphA2 induced the nuclear accumulation of YAP and TAZ and increased the expression of YAP/TAZ target genes. Inhibition of the GTPase Rho or the kinase ROCK abolished EphA2-dependent YAP/TAZ nuclear localization. Silencing or substantially reduced the amount of intracellular glutamate through decreased expression of and , respectively, genes that encode proteins that promote glutamine uptake and metabolism. The regulatory DNA elements of both and contain TEAD binding sites and were bound by TEAD4 in an EphA2-dependent manner. In patient breast cancer tissues, expression positively correlated with that of and , as well as that of and Although high expression of predicted enhanced metastatic potential and poor patient survival, it also rendered HER2-positive breast cancer cells more sensitive to glutaminase inhibition. The findings define a previously unknown mechanism of EphA2-mediated glutaminolysis through YAP/TAZ activation in HER2-positive breast cancer and identify potential therapeutic targets in patients.
Copyright © 2017 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
UNC-45a promotes myosin folding and stress fiber assembly.
Lehtimäki JI, Fenix AM, Kotila TM, Balistreri G, Paavolainen L, Varjosalo M, Burnette DT, Lappalainen P
(2017) J Cell Biol 216: 4053-4072
MeSH Terms: Actomyosin, Cell Adhesion, Cell Line, Tumor, Cell Movement, Cell Polarity, Gene Expression, Humans, Intracellular Signaling Peptides and Proteins, Myosin Type II, Osteoblasts, Proteasome Endopeptidase Complex, Protein Folding, Protein Isoforms, Stress Fibers, Tetratricopeptide Repeat
Show Abstract · Added March 14, 2018
Contractile actomyosin bundles, stress fibers, are crucial for adhesion, morphogenesis, and mechanosensing in nonmuscle cells. However, the mechanisms by which nonmuscle myosin II (NM-II) is recruited to those structures and assembled into functional bipolar filaments have remained elusive. We report that UNC-45a is a dynamic component of actin stress fibers and functions as a myosin chaperone in vivo. UNC-45a knockout cells display severe defects in stress fiber assembly and consequent abnormalities in cell morphogenesis, polarity, and migration. Experiments combining structured-illumination microscopy, gradient centrifugation, and proteasome inhibition approaches revealed that a large fraction of NM-II and myosin-1c molecules fail to fold in the absence of UNC-45a. The remaining properly folded NM-II molecules display defects in forming functional bipolar filaments. The C-terminal UNC-45/Cro1/She4p domain of UNC-45a is critical for NM-II folding, whereas the N-terminal tetratricopeptide repeat domain contributes to the assembly of functional stress fibers. Thus, UNC-45a promotes generation of contractile actomyosin bundles through synchronized NM-II folding and filament-assembly activities.
© 2017 Lehtimäki et al.
0 Communities
1 Members
0 Resources
15 MeSH Terms