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ROCK-nmMyoII, Notch and gene-dosage link epithelial morphogenesis with cell fate in the pancreatic endocrine-progenitor niche.
Bankaitis ED, Bechard ME, Gu G, Magnuson MA, Wright CVE
(2018) Development 145:
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Movement, Endocrine Cells, Gene Dosage, Mice, Mice, Transgenic, Nerve Tissue Proteins, Organogenesis, Pancreas, Receptors, Notch, Stem Cells, Transcriptional Activation, rho-Associated Kinases
Show Abstract · Added August 24, 2018
During mouse pancreas organogenesis, endocrine cells are born from progenitors residing in an epithelial plexus niche. After a period in a lineage-primed state, progenitors become endocrine committed via upregulation of We find that the to transition is associated with distinct stages of an epithelial egression process: narrowing the apical surface of the cell, basalward cell movement and eventual cell-rear detachment from the apical lumen surface to allow clustering as nascent islets under the basement membrane. Apical narrowing, basalward movement and transcriptional upregulation still occur without Neurog3 protein, suggesting that morphogenetic cues deployed within the plexus initiate endocrine commitment upstream or independently of Neurog3. Neurog3 is required for cell-rear detachment and complete endocrine-cell birth. The ROCK-nmMyoII pathway coordinates epithelial-cell morphogenesis and the progression through -expressing states. NmMyoII is necessary for apical narrowing, basalward cell displacement and upregulation, but all three are limited by ROCK activity. We propose that ROCK-nmMyoII activity, gene-dose and Notch signaling integrate endocrine fate allocation with epithelial plexus growth and morphogenesis, representing a feedback control circuit that coordinates morphogenesis with lineage diversification in the endocrine-birth niche.
© 2018. Published by The Company of Biologists Ltd.
2 Communities
2 Members
0 Resources
15 MeSH Terms
Structural and biochemical differences between the Notch and the amyloid precursor protein transmembrane domains.
Deatherage CL, Lu Z, Kroncke BM, Ma S, Smith JA, Voehler MW, McFeeters RL, Sanders CR
(2017) Sci Adv 3: e1602794
MeSH Terms: Amyloid beta-Protein Precursor, Humans, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Protein Domains, Receptors, Notch
Show Abstract · Added May 3, 2017
γ-Secretase cleavage of the Notch receptor transmembrane domain is a critical signaling event for various cellular processes. Efforts to develop inhibitors of γ-secretase cleavage of the amyloid-β precursor C99 protein as potential Alzheimer's disease therapeutics have been confounded by toxicity resulting from the inhibition of normal cleavage of Notch. We present biochemical and structural data for the combined transmembrane and juxtamembrane Notch domains (Notch-TMD) that illuminate Notch signaling and that can be compared and contrasted with the corresponding traits of C99. The Notch-TMD and C99 have very different conformations, adapt differently to changes in model membrane hydrophobic span, and exhibit different cholesterol-binding properties. These differences may be exploited in the design of agents that inhibit cleavage of C99 while allowing Notch cleavage.
0 Communities
3 Members
0 Resources
6 MeSH Terms
The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis.
Astudillo L, Da Silva TG, Wang Z, Han X, Jin K, VanWye J, Zhu X, Weaver K, Oashi T, Lopes PE, Orton D, Neitzel LR, Lee E, Landgraf R, Robbins DJ, MacKerell AD, Capobianco AJ
(2016) Cancer Res 76: 3593-603
MeSH Terms: Animals, Cell Line, Tumor, DNA-Binding Proteins, Humans, Mice, Neoplasms, Receptors, Notch, Somites, Thiazolidines, Transcription Factors, Transcriptional Activation, Zebrafish
Show Abstract · Added February 13, 2017
In many cancers, aberrant Notch activity has been demonstrated to play a role in the initiation and maintenance of the neoplastic phenotype and in cancer stem cells, which may allude to its additional involvement in metastasis and resistance to therapy. Therefore, Notch is an exceedingly attractive therapeutic target in cancer, but the full range of potential targets within the pathway has been underexplored. To date, there are no small-molecule inhibitors that directly target the intracellular Notch pathway or the assembly of the transcriptional activation complex. Here, we describe an in vitro assay that quantitatively measures the assembly of the Notch transcriptional complex on DNA. Integrating this approach with computer-aided drug design, we explored potential ligand-binding sites and screened for compounds that could disrupt the assembly of the Notch transcriptional activation complex. We identified a small-molecule inhibitor, termed Inhibitor of Mastermind Recruitment-1 (IMR-1), that disrupted the recruitment of Mastermind-like 1 to the Notch transcriptional activation complex on chromatin, thereby attenuating Notch target gene transcription. Furthermore, IMR-1 inhibited the growth of Notch-dependent cell lines and significantly abrogated the growth of patient-derived tumor xenografts. Taken together, our findings suggest that a novel class of Notch inhibitors targeting the transcriptional activation complex may represent a new paradigm for Notch-based anticancer therapeutics, warranting further preclinical characterization. Cancer Res; 76(12); 3593-603. ©2016 AACR.
©2016 American Association for Cancer Research.
0 Communities
1 Members
0 Resources
12 MeSH Terms
AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival.
Kishton RJ, Barnes CE, Nichols AG, Cohen S, Gerriets VA, Siska PJ, Macintyre AN, Goraksha-Hicks P, de Cubas AA, Liu T, Warmoes MO, Abel ED, Yeoh AE, Gershon TR, Rathmell WK, Richards KL, Locasale JW, Rathmell JC
(2016) Cell Metab 23: 649-62
MeSH Terms: AMP-Activated Protein Kinases, Animals, Cell Line, Tumor, Cell Survival, Glycolysis, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Inbred C57BL, Mitochondria, Multiprotein Complexes, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Receptors, Notch, Signal Transduction, Stress, Physiological, T-Lymphocytes, TOR Serine-Threonine Kinases
Show Abstract · Added August 8, 2016
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy associated with Notch pathway mutations. While both normal activated and leukemic T cells can utilize aerobic glycolysis to support proliferation, it is unclear to what extent these cell populations are metabolically similar and if differences reveal T-ALL vulnerabilities. Here we show that aerobic glycolysis is surprisingly less active in T-ALL cells than proliferating normal T cells and that T-ALL cells are metabolically distinct. Oncogenic Notch promoted glycolysis but also induced metabolic stress that activated 5' AMP-activated kinase (AMPK). Unlike stimulated T cells, AMPK actively restrained aerobic glycolysis in T-ALL cells through inhibition of mTORC1 while promoting oxidative metabolism and mitochondrial Complex I activity. Importantly, AMPK deficiency or inhibition of Complex I led to T-ALL cell death and reduced disease burden. Thus, AMPK simultaneously inhibits anabolic growth signaling and is essential to promote mitochondrial pathways that mitigate metabolic stress and apoptosis in T-ALL.
Copyright © 2016 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Deleting the TGF-β receptor in proximal tubules impairs HGF signaling.
Nlandu Khodo S, Neelisetty S, Woodbury L, Green E, Harris RC, Zent R, Gewin L
(2016) Am J Physiol Renal Physiol 310: F499-510
MeSH Terms: Amyloid Precursor Protein Secretases, Animals, Cells, Cultured, Hepatocyte Growth Factor, Kidney Tubules, Proximal, Mice, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-met, Receptor, Transforming Growth Factor-beta Type II, Receptors, Notch, Receptors, Transforming Growth Factor beta, Signal Transduction, Transforming Growth Factor beta
Show Abstract · Added January 29, 2016
Transforming growth factor-β (TGF-β) and hepatocyte growth factor (HGF) play key roles in regulating the response to renal injury but are thought to mediate divergent effects on cell behavior. However, how TGF-β signaling alters the response to HGF in epithelia, the key site of HGF signaling in the injured kidney, is not well studied. Contrary to our expectation, we showed that deletion of the TGF-β type II receptor in conditionally immortalized proximal tubule (PT) cells impaired HGF-dependent signaling. This reduced signaling was due to decreased transcription of c-Met, the HGF receptor, and the TGF-β-dependent c-Met transcription and increased response to HGF in PT cells were mediated by the Notch pathway. The interactions of TGF-β, HGF, and Notch pathways had biologically significant effects on branching morphogenesis, cell morphology, migration, and proliferation. In conclusion, epithelial TGF-β signaling promotes HGF signaling in a Notch-dependent pathway. These findings suggest that TGF-β modulates PT responses not only by direct effects, but also by affecting other growth factor signaling pathways.
1 Communities
3 Members
0 Resources
13 MeSH Terms
Feedback control of growth, differentiation, and morphogenesis of pancreatic endocrine progenitors in an epithelial plexus niche.
Bankaitis ED, Bechard ME, Wright CV
(2015) Genes Dev 29: 2203-16
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Cycle, Cell Differentiation, Endocrine Cells, Epithelial Cells, Feedback, Physiological, Mice, Nerve Tissue Proteins, Organogenesis, Pancreas, Receptors, Notch, SOX9 Transcription Factor, Stem Cells
Show Abstract · Added November 3, 2015
In the mammalian pancreas, endocrine cells undergo lineage allocation upon emergence from a bipotent duct/endocrine progenitor pool, which resides in the "trunk epithelium." Major questions remain regarding how niche environments are organized within this epithelium to coordinate endocrine differentiation with programs of epithelial growth, maturation, and morphogenesis. We used EdU pulse-chase and tissue-reconstruction approaches to analyze how endocrine progenitors and their differentiating progeny are assembled within the trunk as it undergoes remodeling from an irregular plexus of tubules to form the eventual mature, branched ductal arbor. The bulk of endocrine progenitors is maintained in an epithelial "plexus state," which is a transient intermediate during epithelial maturation within which endocrine cell differentiation is continually robust and surprisingly long-lived. Within the plexus, local feedback effects derived from the differentiating and delaminating endocrine cells nonautonomously regulate the flux of endocrine cell birth as well as proliferative growth of the bipotent cell population using Notch-dependent and Notch-independent influences, respectively. These feedback effects in turn maintain the plexus state to ensure prolonged allocation of endocrine cells late into gestation. These findings begin to define a niche-like environment guiding the genesis of the endocrine pancreas and advance current models for how differentiation is coordinated with the growth and morphogenesis of the developing pancreatic epithelium.
© 2015 Bankaitis et al.; Published by Cold Spring Harbor Laboratory Press.
1 Communities
2 Members
0 Resources
14 MeSH Terms
Comprehensive genomic profiles of small cell lung cancer.
George J, Lim JS, Jang SJ, Cun Y, Ozretić L, Kong G, Leenders F, Lu X, Fernández-Cuesta L, Bosco G, Müller C, Dahmen I, Jahchan NS, Park KS, Yang D, Karnezis AN, Vaka D, Torres A, Wang MS, Korbel JO, Menon R, Chun SM, Kim D, Wilkerson M, Hayes N, Engelmann D, Pützer B, Bos M, Michels S, Vlasic I, Seidel D, Pinther B, Schaub P, Becker C, Altmüller J, Yokota J, Kohno T, Iwakawa R, Tsuta K, Noguchi M, Muley T, Hoffmann H, Schnabel PA, Petersen I, Chen Y, Soltermann A, Tischler V, Choi CM, Kim YH, Massion PP, Zou Y, Jovanovic D, Kontic M, Wright GM, Russell PA, Solomon B, Koch I, Lindner M, Muscarella LA, la Torre A, Field JK, Jakopovic M, Knezevic J, Castaños-Vélez E, Roz L, Pastorino U, Brustugun OT, Lund-Iversen M, Thunnissen E, Köhler J, Schuler M, Botling J, Sandelin M, Sanchez-Cespedes M, Salvesen HB, Achter V, Lang U, Bogus M, Schneider PM, Zander T, Ansén S, Hallek M, Wolf J, Vingron M, Yatabe Y, Travis WD, Nürnberg P, Reinhardt C, Perner S, Heukamp L, Büttner R, Haas SA, Brambilla E, Peifer M, Sage J, Thomas RK
(2015) Nature 524: 47-53
MeSH Terms: Alleles, Animals, Cell Line, Tumor, Chromosome Breakpoints, Cyclin D1, DNA-Binding Proteins, Disease Models, Animal, Female, Gene Expression Profiling, Genome, Human, Genomics, Humans, Lung Neoplasms, Male, Mice, Mutation, Neurosecretory Systems, Nuclear Proteins, Receptors, Notch, Retinoblastoma Protein, Signal Transduction, Small Cell Lung Carcinoma, Tumor Protein p73, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
Show Abstract · Added February 16, 2016
We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
0 Communities
1 Members
0 Resources
25 MeSH Terms
Integrated compensatory network is activated in the absence of NCC phosphorylation.
Grimm PR, Lazo-Fernandez Y, Delpire E, Wall SM, Dorsey SG, Weinman EJ, Coleman R, Wade JB, Welling PA
(2015) J Clin Invest 125: 2136-50
MeSH Terms: Amiloride, Ammonia, Animals, Biological Transport, Blood Pressure, Carbonic Anhydrases, Chlorides, Disease Models, Animal, Enzyme Activation, Epithelial Sodium Channels, Gene Expression Profiling, Gene Regulatory Networks, Gitelman Syndrome, Ketoglutaric Acids, Kidney Glomerulus, Male, Mice, Mice, Knockout, Natriuresis, Nephrons, Paracrine Communication, Phosphorylation, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, Receptors, Notch, Receptors, Purinergic P2, Renal Reabsorption, Signal Transduction, Sodium Chloride, Sodium-Potassium-Chloride Symporters, Solute Carrier Family 12, Member 3
Show Abstract · Added May 3, 2017
Thiazide diuretics are used to treat hypertension; however, compensatory processes in the kidney can limit antihypertensive responses to this class of drugs. Here, we evaluated compensatory pathways in SPAK kinase-deficient mice, which are unable to activate the thiazide-sensitive sodium chloride cotransporter NCC (encoded by Slc12a3). Global transcriptional profiling, combined with biochemical, cell biological, and physiological phenotyping, identified the gene expression signature of the response and revealed how it establishes an adaptive physiology. Salt reabsorption pathways were created by the coordinate induction of a multigene transport system, involving solute carriers (encoded by Slc26a4, Slc4a8, and Slc4a9), carbonic anhydrase isoforms, and V-type H⁺-ATPase subunits in pendrin-positive intercalated cells (PP-ICs) and ENaC subunits in principal cells (PCs). A distal nephron remodeling process and induction of jagged 1/NOTCH signaling, which expands the cortical connecting tubule with PCs and replaces acid-secreting α-ICs with PP-ICs, were partly responsible for the compensation. Salt reabsorption was also activated by induction of an α-ketoglutarate (α-KG) paracrine signaling system. Coordinate regulation of a multigene α-KG synthesis and transport pathway resulted in α-KG secretion into pro-urine, as the α-KG-activated GPCR (Oxgr1) increased on the PP-IC apical surface, allowing paracrine delivery of α-KG to stimulate salt transport. Identification of the integrated compensatory NaCl reabsorption mechanisms provides insight into thiazide diuretic efficacy.
0 Communities
1 Members
0 Resources
31 MeSH Terms
miR-216a regulates snx5, a novel notch signaling pathway component, during zebrafish retinal development.
Olena AF, Rao MB, Thatcher EJ, Wu SY, Patton JG
(2015) Dev Biol 400: 72-81
MeSH Terms: Analysis of Variance, Animals, Cloning, Molecular, DNA Primers, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Image Processing, Computer-Assisted, Immunoblotting, In Situ Hybridization, Intracellular Signaling Peptides and Proteins, Membrane Proteins, MicroRNAs, Microarray Analysis, Models, Biological, Receptors, Notch, Retina, Signal Transduction, Sorting Nexins, Ubiquitin-Protein Ligases, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 4, 2016
Precise regulation of Notch signaling is essential for normal vertebrate development. Mind bomb (Mib) is a ubiquitin ligase that is required for activation of Notch by Notch׳s ligand, Delta. Sorting Nexin 5 (SNX5) co-localizes with Mib and Delta complexes and has been shown to directly bind to Mib. We show that microRNA-216a (miR-216a) is expressed in the retina during early development and regulates snx5 to precisely regulate Notch signaling. miR-216a and snx5 have complementary expression patterns. Knocking down miR-216a and/or overexpression of snx5 resulted in increased Notch activation. Conversely, knocking down snx5 and/or miR-216a overexpression caused a decrease in Notch activation. We propose a model in which SNX5, precisely controlled by miR-216a, is a vital partner of Mib in promoting endocytosis of Delta and subsequent activation of Notch signaling.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
22 MeSH Terms
The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation.
Parang B, Rosenblatt D, Williams AD, Washington MK, Revetta F, Short SP, Reddy VK, Hunt A, Shroyer NF, Engel ME, Hiebert SW, Williams CS
(2015) FASEB J 29: 786-95
MeSH Terms: Amyloid Precursor Protein Secretases, Animals, Apoptosis, Blotting, Western, Cell Differentiation, Cell Lineage, Cell Proliferation, Cells, Cultured, Epithelial Cells, Flow Cytometry, Immunoenzyme Techniques, Immunoprecipitation, Intestinal Mucosa, Intestines, Mice, Mice, Knockout, Paneth Cells, Protease Inhibitors, RNA, Messenger, Real-Time Polymerase Chain Reaction, Receptors, Notch, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added December 8, 2014
Notch signaling largely determines intestinal epithelial cell fate. High Notch activity drives progenitors toward absorptive enterocytes by repressing secretory differentiation programs, whereas low Notch permits secretory cell assignment. Myeloid translocation gene-related 1 (MTGR1) is a transcriptional corepressor in the myeloid translocation gene/Eight-Twenty-One family. Given that Mtgr1(-/-) mice have a dramatic reduction of intestinal epithelial secretory cells, we hypothesized that MTGR1 is a key repressor of Notch signaling. In support of this, transcriptome analysis of laser capture microdissected Mtgr1(-/-) intestinal crypts revealed Notch activation, and secretory markers Mucin2, Chromogranin A, and Growth factor-independent 1 (Gfi1) were down-regulated in Mtgr1(-/-) whole intestines and Mtgr1(-/-) enteroids. We demonstrate that MTGR1 is in a complex with Suppressor of Hairless Homolog, a key Notch effector, and represses Notch-induced Hairy/Enhancer of Split 1 activity. Moreover, pharmacologic Notch inhibition using a γ-secretase inhibitor (GSI) rescued the hyperproliferative baseline phenotype in the Mtgr1(-/-) intestine and increased production of goblet and enteroendocrine lineages in Mtgr1(-/-) mice. GSI increased Paneth cell production in wild-type mice but failed to do so in Mtgr1(-/-) mice. We determined that MTGR1 can interact with GFI1, a transcriptional corepressor required for Paneth cell differentiation, and repress GFI1 targets. Overall, the data suggest that MTGR1, a transcriptional corepressor well characterized in hematopoiesis, plays a critical role in intestinal lineage allocation.
© FASEB.
1 Communities
4 Members
0 Resources
23 MeSH Terms