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Results: 1 to 10 of 96

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APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway.
Saito-Diaz K, Benchabane H, Tiwari A, Tian A, Li B, Thompson JJ, Hyde AS, Sawyer LM, Jodoin JN, Santos E, Lee LA, Coffey RJ, Beauchamp RD, Williams CS, Kenworthy AK, Robbins DJ, Ahmed Y, Lee E
(2018) Dev Cell 44: 566-581.e8
MeSH Terms: Adenomatous Polyposis Coli Protein, Animals, Cells, Cultured, Clathrin, Drosophila melanogaster, Endocytosis, Female, Humans, Infant, Ligands, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Wnt Proteins, Wnt Signaling Pathway, beta Catenin
Show Abstract · Added March 14, 2018
Adenomatous polyposis coli (APC) mutations cause Wnt pathway activation in human cancers. Current models for APC action emphasize its role in promoting β-catenin degradation downstream of Wnt receptors. Unexpectedly, we find that blocking Wnt receptor activity in APC-deficient cells inhibits Wnt signaling independently of Wnt ligand. We also show that inducible loss of APC is rapidly followed by Wnt receptor activation and increased β-catenin levels. In contrast, APC2 loss does not promote receptor activation. We show that APC exists in a complex with clathrin and that Wnt pathway activation in APC-deficient cells requires clathrin-mediated endocytosis. Finally, we demonstrate conservation of this mechanism in Drosophila intestinal stem cells. We propose a model in which APC and APC2 function to promote β-catenin degradation, and APC also acts as a molecular "gatekeeper" to block receptor activation via the clathrin pathway.
Copyright © 2018 Elsevier Inc. All rights reserved.
0 Communities
4 Members
0 Resources
18 MeSH Terms
Wnt6 maintains anterior escort cells as an integral component of the germline stem cell niche.
Wang X, Page-McCaw A
(2018) Development 145:
MeSH Terms: Animals, Animals, Genetically Modified, Bone Morphogenetic Proteins, Cadherins, Cell Count, Cell Differentiation, Cell Lineage, Cell Survival, Drosophila Proteins, Drosophila melanogaster, Female, Germ Cells, Ligands, Models, Biological, Ovary, Signal Transduction, Stem Cell Niche, Wnt Proteins
Show Abstract · Added March 20, 2018
Stem cells reside in a niche, a local environment whose cellular and molecular complexity is still being elucidated. In ovaries, germline stem cells depend on cap cells for self-renewing signals and physical attachment. Germline stem cells also contact the anterior escort cells, and here we report that anterior escort cells are absolutely required for germline stem cell maintenance. When escort cells die from impaired Wnt signaling or expression, the loss of anterior escort cells causes loss of germline stem cells. Anterior escort cells function as an integral niche component by promoting DE-cadherin anchorage and by transiently expressing the Dpp ligand to promote full-strength BMP signaling in germline stem cells. Anterior escort cells are maintained by Wnt6 ligands produced by cap cells; without Wnt6 signaling, anterior escort cells die leaving vacancies in the niche, leading to loss of germline stem cells. Our data identify anterior escort cells as constituents of the germline stem cell niche, maintained by a cap cell-produced Wnt6 survival signal.
© 2018. Published by The Company of Biologists Ltd.
0 Communities
1 Members
0 Resources
18 MeSH Terms
lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling.
Lu Y, Zhao X, Liu Q, Li C, Graves-Deal R, Cao Z, Singh B, Franklin JL, Wang J, Hu H, Wei T, Yang M, Yeatman TJ, Lee E, Saito-Diaz K, Hinger S, Patton JG, Chung CH, Emmrich S, Klusmann JH, Fan D, Coffey RJ
(2017) Nat Med 23: 1331-1341
MeSH Terms: Antineoplastic Agents, Immunological, Cell Line, Tumor, Cetuximab, Disease Progression, Drug Resistance, Neoplasm, Epigenesis, Genetic, GATA6 Transcription Factor, Humans, MicroRNAs, RNA, Long Noncoding, Signal Transduction, Wnt Proteins, beta Catenin
Show Abstract · Added April 3, 2018
De novo and acquired resistance, which are largely attributed to genetic alterations, are barriers to effective anti-epidermal-growth-factor-receptor (EGFR) therapy. To generate cetuximab-resistant cells, we exposed cetuximab-sensitive colorectal cancer cells to cetuximab in three-dimensional culture. Using whole-exome sequencing and transcriptional profiling, we found that the long non-coding RNA MIR100HG and two embedded microRNAs, miR-100 and miR-125b, were overexpressed in the absence of known genetic events linked to cetuximab resistance. MIR100HG, miR-100 and miR-125b overexpression was also observed in cetuximab-resistant colorectal cancer and head and neck squamous cell cancer cell lines and in tumors from colorectal cancer patients that progressed on cetuximab. miR-100 and miR-125b coordinately repressed five Wnt/β-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness. Our results describe a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby GATA6 represses MIR100HG, but this repression is relieved by miR-125b targeting of GATA6. These findings identify a clinically actionable, epigenetic cause of cetuximab resistance.
0 Communities
2 Members
0 Resources
MeSH Terms
Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells.
Jacob A, Morley M, Hawkins F, McCauley KB, Jean JC, Heins H, Na CL, Weaver TE, Vedaie M, Hurley K, Hinds A, Russo SJ, Kook S, Zacharias W, Ochs M, Traber K, Quinton LJ, Crane A, Davis BR, White FV, Wambach J, Whitsett JA, Cole FS, Morrisey EE, Guttentag SH, Beers MF, Kotton DN
(2017) Cell Stem Cell 21: 472-488.e10
MeSH Terms: Base Sequence, Cell Differentiation, Cell Line, Cell Proliferation, Cell Self Renewal, Cell Separation, Epithelial Cells, Gene Expression Profiling, Genes, Reporter, Humans, Lung Diseases, Models, Biological, Pluripotent Stem Cells, Pulmonary Alveoli, Pulmonary Surfactants, Thyroid Nuclear Factor 1, Time Factors, Wnt Proteins, Wnt Signaling Pathway
Show Abstract · Added April 1, 2019
Lung alveoli, which are unique to air-breathing organisms, have been challenging to generate from pluripotent stem cells (PSCs) in part because there are limited model systems available to provide the necessary developmental roadmaps for in vitro differentiation. Here we report the generation of alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of lung alveoli, from human PSCs. Using multicolored fluorescent reporter lines, we track and purify human SFTPC+ alveolar progenitors as they emerge from endodermal precursors in response to stimulation of Wnt and FGF signaling. Purified PSC-derived SFTPC+ cells form monolayered epithelial "alveolospheres" in 3D cultures without the need for mesenchymal support, exhibit self-renewal capacity, and display additional AEC2 functional capacities. Footprint-free CRISPR-based gene correction of PSCs derived from patients carrying a homozygous surfactant mutation (SFTPB) restores surfactant processing in AEC2s. Thus, PSC-derived AEC2s provide a platform for disease modeling and future functional regeneration of the distal lung.
Copyright © 2017 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
MeSH Terms
Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma.
Rodriguez-Blanco J, Pednekar L, Penas C, Li B, Martin V, Long J, Lee E, Weiss WA, Rodriguez C, Mehrdad N, Nguyen DM, Ayad NG, Rai P, Capobianco AJ, Robbins DJ
(2017) Oncogene 36: 6306-6314
MeSH Terms: Anilides, Animals, Cell Line, Tumor, Cerebellar Neoplasms, Disease Models, Animal, HEK293 Cells, Hedgehog Proteins, Humans, Male, Medulloblastoma, Mice, Mice, Transgenic, Pyridines, Random Allocation, SOXB1 Transcription Factors, Small Molecule Libraries, TRPC Cation Channels, Transfection, Tumor Suppressor Protein p53, Veratrum Alkaloids, Wnt Proteins, Wnt Signaling Pathway
Show Abstract · Added July 18, 2017
The SMOOTHENED inhibitor vismodegib is FDA approved for advanced basal cell carcinoma (BCC), and shows promise in clinical trials for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma (MB) patients. Clinical experience with BCC patients shows that continuous exposure to vismodegib is necessary to prevent tumor recurrence, suggesting the existence of a vismodegib-resistant reservoir of tumor-propagating cells. We isolated such tumor-propagating cells from a mouse model of SHH-subgroup MB and grew them as sphere cultures. These cultures were enriched for the MB progenitor marker SOX2 and formed tumors in vivo. Moreover, while their ability to self-renew was resistant to SHH inhibitors, as has been previously suggested, this self-renewal was instead WNT-dependent. We show here that loss of Trp53 activates canonical WNT signaling in these SOX2-enriched cultures. Importantly, a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup MB in vivo, in an on-target manner, leading to increased survival. Our results imply that the tumor-propagating cells driving the growth of bulk SHH-dependent MB are themselves WNT dependent. Further, our data suggest combination therapy with WNT and SHH inhibitors as a therapeutic strategy in patients with SHH-subgroup MB, in order to decrease the tumor recurrence commonly observed in patients treated with vismodegib.
0 Communities
1 Members
0 Resources
22 MeSH Terms
Blocking TGF- and -Catenin Epithelial Crosstalk Exacerbates CKD.
Nlandu-Khodo S, Neelisetty S, Phillips M, Manolopoulou M, Bhave G, May L, Clark PE, Yang H, Fogo AB, Harris RC, Taketo MM, Lee E, Gewin LS
(2017) J Am Soc Nephrol 28: 3490-3503
MeSH Terms: Animals, Aristolochic Acids, Cell Nucleus, Collagen, Crosses, Genetic, Epithelium, Female, Gene Deletion, Kidney Failure, Chronic, Kidney Tubules, Proximal, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, Transforming Growth Factor beta1, Wnt Proteins, beta Catenin
Show Abstract · Added July 18, 2017
The TGF- and Wnt/-catenin pathways have important roles in modulating CKD, but how these growth factors affect the epithelial response to CKD is not well studied. TGF- has strong profibrotic effects, but this pleiotropic factor has many different cellular effects depending on the target cell type. To investigate how TGF- signaling in the proximal tubule, a key target and mediator of CKD, alters the response to CKD, we injured mice lacking the TGF- type 2 receptor specifically in this epithelial segment. Compared with littermate controls, mice lacking the proximal tubular TGF- receptor had significantly increased tubular injury and tubulointerstitial fibrosis in two different models of CKD. RNA sequencing indicated that deleting the TGF- receptor in proximal tubule cells modulated many growth factor pathways, but Wnt/-catenin signaling was the pathway most affected. We validated that deleting the proximal tubular TGF- receptor impaired -catenin activity and Genetically restoring -catenin activity in proximal tubules lacking the TGF- receptor dramatically improved the tubular response to CKD in mice. Deleting the TGF- receptor alters many growth factors, and therefore, this ameliorated response may be a direct effect of -catenin activity or an indirect effect of -catenin interacting with other growth factors. In conclusion, blocking TGF- and -catenin crosstalk in proximal tubules exacerbates tubular injury in two models of CKD.
Copyright © 2017 by the American Society of Nephrology.
0 Communities
3 Members
0 Resources
22 MeSH Terms
Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors.
Li B, Orton D, Neitzel LR, Astudillo L, Shen C, Long J, Chen X, Kirkbride KC, Doundoulakis T, Guerra ML, Zaias J, Fei DL, Rodriguez-Blanco J, Thorne C, Wang Z, Jin K, Nguyen DM, Sands LR, Marchetti F, Abreu MT, Cobb MH, Capobianco AJ, Lee E, Robbins DJ
(2017) Sci Signal 10:
MeSH Terms: Animals, Antineoplastic Agents, Benzoates, Casein Kinase Ialpha, Enzyme Activation, Enzyme Activators, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Neoplasm Metastasis, Neoplasms, Organ Culture Techniques, Phosphorylation, Pyrvinium Compounds, Signal Transduction, Surface Plasmon Resonance, Wnt Proteins, Wnt Signaling Pathway, Xenograft Model Antitumor Assays, Xenopus laevis
Show Abstract · Added July 18, 2017
Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no WNT inhibitor is currently approved for use in the clinic largely due to the small number of druggable signaling components in the WNT pathway and the substantial toxicity to normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1α (CK1α), is a potent inhibitor of WNT signaling. However, its poor bioavailability limited the ability to test this first-in-class WNT inhibitor in vivo. We characterized a novel small-molecule CK1α activator called SSTC3, which has better pharmacokinetic properties than pyrvinium, and found that it inhibited the growth of CRC xenografts in mice. SSTC3 also attenuated the growth of a patient-derived metastatic CRC xenograft, for which few therapies exist. SSTC3 exhibited minimal gastrointestinal toxicity compared to other classes of WNT inhibitors. Consistent with this observation, we showed that the abundance of the SSTC3 target, CK1α, was decreased in WNT-driven tumors relative to normal gastrointestinal tissue, and knocking down CK1α increased cellular sensitivity to SSTC3. Thus, we propose that distinct CK1α abundance provides an enhanced therapeutic index for pharmacological CK1α activators to target WNT-driven tumors.
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
24 MeSH Terms
Comparative genetic screens in human cells reveal new regulatory mechanisms in WNT signaling.
Lebensohn AM, Dubey R, Neitzel LR, Tacchelly-Benites O, Yang E, Marceau CD, Davis EM, Patel BB, Bahrami-Nejad Z, Travaglini KJ, Ahmed Y, Lee E, Carette JE, Rohatgi R
(2016) Elife 5:
MeSH Terms: Casein Kinase I, Cytoskeletal Proteins, Gene Expression Regulation, Gene Regulatory Networks, Genes, Reporter, Genetic Testing, Haploidy, Humans, Wnt Proteins, Wnt Signaling Pathway
Show Abstract · Added February 13, 2017
The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers of regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted a systematic forward genetic analysis through reporter-based screens in haploid human cells. Comparison of screens for negative, attenuating and positive regulators of WNT signaling, mediators of R-spondin-dependent signaling and suppressors of constitutive signaling induced by loss of the tumor suppressor adenomatous polyposis coli or casein kinase 1α uncovered new regulatory features at most levels of the pathway. These include a requirement for the transcription factor AP-4, a role for the DAX domain of AXIN2 in controlling β-catenin transcriptional activity, a contribution of glycophosphatidylinositol anchor biosynthesis and glypicans to R-spondin-potentiated WNT signaling, and two different mechanisms that regulate signaling when distinct components of the β-catenin destruction complex are lost. The conceptual and methodological framework we describe should enable the comprehensive understanding of other signaling systems.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Reconstitution of the Cytoplasmic Regulation of the Wnt Signaling Pathway Using Xenopus Egg Extracts.
Hyde AS, Hang BI, Lee E
(2016) Methods Mol Biol 1481: 101-9
MeSH Terms: Animals, Cell Cycle, Chromatin Assembly and Disassembly, DNA Replication, Embryonic Development, Microtubules, Molecular Biology, Oocytes, Proteolysis, Wnt Proteins, Wnt Signaling Pathway, Xenopus laevis, beta Catenin
Show Abstract · Added February 13, 2017
The regulation of β-catenin turnover is the central mechanism governing activation of the Wnt signaling pathway. All components of the pathway are present in the early embryo of Xenopus laevis, and Xenopus egg extracts have been used to recapitulate complex biological reactions such as microtubule dynamics, DNA replication, chromatin assembly, and phases of the cell cycle. Herein, we describe a biochemical method for analyzing β-catenin degradation using radiolabeled and luciferase-fusion proteins in Xenopus egg extracts. We show that in such a biochemical system, cytoplasmic β-catenin degradation is regulated by soluble components of the Wnt pathway as well as small molecules.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Wnt/Wingless Pathway Activation Is Promoted by a Critical Threshold of Axin Maintained by the Tumor Suppressor APC and the ADP-Ribose Polymerase Tankyrase.
Wang Z, Tacchelly-Benites O, Yang E, Thorne CA, Nojima H, Lee E, Ahmed Y
(2016) Genetics 203: 269-81
MeSH Terms: Adenomatous Polyposis Coli Protein, Animals, Axin Protein, Drosophila, Genotype, Mitosis, Protein Interaction Domains and Motifs, Protein Stability, Tankyrases, Wnt Proteins, Wnt Signaling Pathway, Xenopus
Show Abstract · Added February 13, 2017
Wnt/β-catenin signal transduction directs metazoan development and is deregulated in numerous human congenital disorders and cancers. In the absence of Wnt stimulation, a multiprotein "destruction complex," assembled by the scaffold protein Axin, targets the key transcriptional activator β-catenin for proteolysis. Axin is maintained at very low levels that limit destruction complex activity, a property that is currently being exploited in the development of novel therapeutics for Wnt-driven cancers. Here, we use an in vivo approach in Drosophila to determine how tightly basal Axin levels must be controlled for Wnt/Wingless pathway activation, and how Axin stability is regulated. We find that for nearly all Wingless-driven developmental processes, a three- to fourfold increase in Axin is insufficient to inhibit signaling, setting a lower-limit for the threshold level of Axin in the majority of in vivo contexts. Further, we find that both the tumor suppressor adenomatous polyposis coli (APC) and the ADP-ribose polymerase Tankyrase (Tnks) have evolutionarily conserved roles in maintaining basal Axin levels below this in vivo threshold, and we define separable domains in Axin that are important for APC- or Tnks-dependent destabilization. Together, these findings reveal that both APC and Tnks maintain basal Axin levels below a critical in vivo threshold to promote robust pathway activation following Wnt stimulation.
Copyright © 2016 by the Genetics Society of America.
0 Communities
1 Members
0 Resources
12 MeSH Terms