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Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors.
Emerling BM, Hurov JB, Poulogiannis G, Tsukazawa KS, Choo-Wing R, Wulf GM, Bell EL, Shim HS, Lamia KA, Rameh LE, Bellinger G, Sasaki AT, Asara JM, Yuan X, Bullock A, Denicola GM, Song J, Brown V, Signoretti S, Cantley LC
(2013) Cell 155: 844-57
MeSH Terms: Animals, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Cell Respiration, Cellular Senescence, Embryo, Mammalian, Gene Knockdown Techniques, Genes, Lethal, Heterografts, Humans, Mice, Neoplasm Transplantation, Phosphotransferases (Alcohol Group Acceptor), Reactive Oxygen Species, Signal Transduction, Tumor Suppressor Protein p53
Show Abstract · Added November 26, 2018
Here, we show that a subset of breast cancers express high levels of the type 2 phosphatidylinositol-5-phosphate 4-kinases α and/or β (PI5P4Kα and β) and provide evidence that these kinases are essential for growth in the absence of p53. Knocking down PI5P4Kα and β in a breast cancer cell line bearing an amplification of the gene encoding PI5P4K β and deficient for p53 impaired growth on plastic and in xenografts. This growth phenotype was accompanied by enhanced levels of reactive oxygen species (ROS) leading to senescence. Mice with homozygous deletion of both TP53 and PIP4K2B were not viable, indicating a synthetic lethality for loss of these two genes. Importantly however, PIP4K2A(-/-), PIP4K2B(+/-), and TP53(-/-) mice were viable and had a dramatic reduction in tumor formation compared to TP53(-/-) littermates. These results indicate that inhibitors of PI5P4Ks could be effective in preventing or treating cancers with mutations in TP53.
Copyright © 2013 Elsevier Inc. All rights reserved.
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MeSH Terms
Mutations in the paxillin-binding site of integrin-linked kinase (ILK) destabilize the pseudokinase domain and cause embryonic lethality in mice.
Moik D, Böttcher A, Makhina T, Grashoff C, Bulus N, Zent R, Fässler R
(2013) J Biol Chem 288: 18863-71
MeSH Terms: Amino Acid Motifs, Animals, Binding Sites, Cell Adhesion, Cell Movement, Embryo, Mammalian, Flow Cytometry, Focal Adhesions, Gene Expression Regulation, Developmental, Genes, Lethal, Mice, Microfilament Proteins, Mutation, Paxillin, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Time Factors
Show Abstract · Added December 10, 2013
Integrin-linked kinase (ILK) localizes to focal adhesions (FAs) where it regulates cell spreading, migration, and growth factor receptor signaling. Previous reports showed that overexpressed ILK in which Val(386) and Thr(387) were substituted with glycine residues (ILK-VT/GG) could neither interact with paxillin nor localize to FA in cells expressing endogenous wild-type ILK, implying that paxillin binding to ILK is required for its localization to FAs. Here, we show that introducing this mutation into the germ line of mice (ILK-VT/GG) caused vasculogenesis defects, resulting in a general developmental delay and death at around embryonic day 12.5. Fibroblasts isolated from ILK-VT/GG mice contained mutant ILK in FAs, showed normal adhesion to and spreading on extracellular matrix substrates but displayed impaired migration. Biochemical analysis revealed that VT/GG substitutions decreased ILK protein stability leading to decreased ILK levels and reduced binding to paxillin and α-parvin. Because paxillin depletion did not affect ILK localization to FAs, the embryonic lethality and the in vitro migration defects are likely due to the reduced levels of ILK-VT/GG and diminished binding to parvins.
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19 MeSH Terms
Autophagy induction is a Tor- and Tp53-independent cell survival response in a zebrafish model of disrupted ribosome biogenesis.
Boglev Y, Badrock AP, Trotter AJ, Du Q, Richardson EJ, Parslow AC, Markmiller SJ, Hall NE, de Jong-Curtain TA, Ng AY, Verkade H, Ober EA, Field HA, Shin D, Shin CH, Hannan KM, Hannan RD, Pearson RB, Kim SH, Ess KC, Lieschke GJ, Stainier DY, Heath JK
(2013) PLoS Genet 9: e1003279
MeSH Terms: Animals, Autophagy, Cell Cycle Proteins, Cell Survival, Genes, Lethal, Mutation, Protein Biosynthesis, RNA, Ribosomal, 18S, Ribosomes, TOR Serine-Threonine Kinases, Tumor Suppressor Protein p53, Zebrafish, Zebrafish Proteins
Show Abstract · Added September 24, 2013
Ribosome biogenesis underpins cell growth and division. Disruptions in ribosome biogenesis and translation initiation are deleterious to development and underlie a spectrum of diseases known collectively as ribosomopathies. Here, we describe a novel zebrafish mutant, titania (tti(s450)), which harbours a recessive lethal mutation in pwp2h, a gene encoding a protein component of the small subunit processome. The biochemical impacts of this lesion are decreased production of mature 18S rRNA molecules, activation of Tp53, and impaired ribosome biogenesis. In tti(s450), the growth of the endodermal organs, eyes, brain, and craniofacial structures is severely arrested and autophagy is up-regulated, allowing intestinal epithelial cells to evade cell death. Inhibiting autophagy in tti(s450) larvae markedly reduces their lifespan. Somewhat surprisingly, autophagy induction in tti(s450) larvae is independent of the state of the Tor pathway and proceeds unabated in Tp53-mutant larvae. These data demonstrate that autophagy is a survival mechanism invoked in response to ribosomal stress. This response may be of relevance to therapeutic strategies aimed at killing cancer cells by targeting ribosome biogenesis. In certain contexts, these treatments may promote autophagy and contribute to cancer cells evading cell death.
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13 MeSH Terms
Drosophila rolling blackout displays lipase domain-dependent and -independent endocytic functions downstream of dynamin.
Vijayakrishnan N, Phillips SE, Broadie K
(2010) Traffic 11: 1567-78
MeSH Terms: Animals, Carboxylic Ester Hydrolases, Catalytic Domain, Drosophila Proteins, Drosophila melanogaster, Dynamins, Endocytosis, Female, Genes, Lethal, Lipase, Male, Protein Structure, Tertiary, Synapses
Show Abstract · Added March 29, 2017
Drosophila temperature-sensitive rolling blackout (rbo(ts) ) mutants display a total block of endocytosis in non-neuronal cells and a weaker, partial defect at neuronal synapses. RBO is an integral plasma membrane protein and is predicted to be a serine esterase. To determine if lipase activity is required for RBO function, we mutated the catalytic serine 358 to alanine in the G-X-S-X-G active site, and assayed genomic rescue of rbo mutant non-neuronal and neuronal phenotypes. The rbo(S358A) mutant is unable to rescue rbo null 100% embryonic lethality, indicating that the lipase domain is critical for RBO essential function. Likewise, the rbo(S358A) mutant cannot provide any rescue of endocytic blockade in rbo(ts) Garland cells, showing that the lipase domain is indispensable for non-neuronal endocytosis. In contrast, rbo(ts) conditional paralysis, synaptic transmission block and synapse endocytic defects are all fully rescued by the rbo(S358A) mutant, showing that the RBO lipase domain is dispensable in neuronal contexts. We identified a synthetic lethal interaction between rbo(ts) and the well-characterized dynamin GTPase conditional shibire (shi(ts1)) mutant. In both non-neuronal cells and neuronal synapses, shi(ts1); rbo(ts) phenocopies shi(ts1) endocytic defects, indicating that dynamin and RBO act in the same pathway, with dynamin functioning upstream of RBO. We conclude that RBO possesses both lipase domain-dependent and scaffolding functions with differential requirements in non-neuronal versus neuronal endocytosis mechanisms downstream of dynamin GTPase activity.
© 2010 John Wiley & Sons A/S.
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13 MeSH Terms
SSBP2 is an in vivo tumor suppressor and regulator of LDB1 stability.
Wang Y, Klumpp S, Amin HM, Liang H, Li J, Estrov Z, Zweidler-McKay P, Brandt SJ, Agulnick A, Nagarajan L
(2010) Oncogene 29: 3044-53
MeSH Terms: Animals, Cell Differentiation, Cricetinae, DNA-Binding Proteins, Genes, Lethal, Genes, Tumor Suppressor, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Thymus Gland, Transcription, Genetic, Tumor Suppressor Protein p53
Show Abstract · Added March 19, 2014
SSBP proteins bind and stabilize transcriptional cofactor LIM domain-binding protein1 (LDB1) from proteosomal degradation to promote tissue-specific transcription through an evolutionarily conserved pathway. The human SSBP2 gene was isolated as a candidate tumor suppressor from a critical region of loss in chromosome 5q14.1. By gene targeting, we show increased predisposition to B-cell lymphomas and carcinomas in Ssbp2(-/-) mice. Remarkably, loss of Ssbp2 causes increased LDB1 turnover in the thymus, a pathway exploited in Trp53(-/-)Ssbp2(-/-) mice to develop highly aggressive, immature thymic lymphomas. Using T-cell differentiation as a model, we report a stage-specific upregulation of Ssbp2 expression, which in turn regulates LDB1 turnover under physiological conditions. Furthermore, transcript levels of pTalpha, a target of LDB1-containing complex, and a critical regulator T-cell differentiation are reduced in Ssbp2(-/-) immature thymocytes. Our findings suggest that disruption of the SSBP2-regulated pathways may be an infrequent but critical step in malignant transformation of multiple tissues.
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14 MeSH Terms
IL-24 transgenic mice: in vivo evidence of overlapping functions for IL-20, IL-22, and IL-24 in the epidermis.
He M, Liang P
(2010) J Immunol 184: 1793-8
MeSH Terms: Animals, COS Cells, Cell Differentiation, Cell Line, Cell Proliferation, Cercopithecus aethiops, Cricetinae, Epidermis, Female, Genes, Lethal, Genes, Overlapping, Humans, Hyperplasia, Immunophenotyping, Interleukins, Keratinocytes, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Protein Binding, Recombinant Fusion Proteins
Show Abstract · Added August 13, 2010
IL-20 and IL-24 share two different heterodimeric receptors consisting of either IL-20R1 or IL-22R1 and a common IL-20R2 subunit, whereas IL-22 signals through IL-22R1/IL-10R2. However, until now, only IL-20 and IL-22 have been proven to play important roles in vivo in the epidermis where all four receptor subunits are expressed. In this study, we show that IL-24 transgenic mice manifest many similar phenotypes to that of IL-20 and IL-22, including neonatal lethality, epidermal hyperplasia, and abnormality in keratinocyte differentiation. These results support a largely redundant role in epidermal functions for IL-20, IL-22, and IL-24, which seem to be IL-22R1 dependent. Moreover, we show that IL-24 transgenic mice exhibit infiltrating macrophages in the dermis with concomitant increases in MCP-1 production from both keratinocytes in the epidermis and immune infiltrates in the adjacent dermal layer below. Furthermore, we demonstrate that the homodimeric IL-20R2 soluble receptor is a potent blocker for IL-24 and can be used to further dissect the crosstalk among the IL-20 family of cytokines in normal development as well as in autoimmune diseases.
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22 MeSH Terms
Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons.
Chao JR, Parganas E, Boyd K, Hong CY, Opferman JT, Ihle JN
(2008) Nature 452: 98-102
MeSH Terms: Animals, Apoptosis, Cell Survival, Genes, Lethal, High-Temperature Requirement A Serine Peptidase 2, Lymphocytes, Metalloproteases, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondrial Proteins, Neurons, Protein Binding, Protein Processing, Post-Translational, Proteins, Serine Endopeptidases, bcl-2-Associated X Protein
Show Abstract · Added March 5, 2014
Cytokines affect a variety of cellular functions, including regulation of cell numbers by suppression of programmed cell death. Suppression of apoptosis requires receptor signalling through the activation of Janus kinases and the subsequent regulation of members of the B-cell lymphoma 2 (Bcl-2) family. Here we demonstrate that a Bcl-2-family-related protein, Hax1, is required to suppress apoptosis in lymphocytes and neurons. Suppression requires the interaction of Hax1 with the mitochondrial proteases Parl (presenilin-associated, rhomboid-like) and HtrA2 (high-temperature-regulated A2, also known as Omi). These interactions allow Hax1 to present HtrA2 to Parl, and thereby facilitates the processing of HtrA2 to the active protease localized in the mitochondrial intermembrane space. In mouse lymphocytes, the presence of processed HtrA2 prevents the accumulation of mitochondrial-outer-membrane-associated activated Bax, an event that initiates apoptosis. Together, the results identify a previously unknown sequence of interactions involving a Bcl-2-family-related protein and mitochondrial proteases in the ability to resist the induction of apoptosis when cytokines are limiting.
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17 MeSH Terms
A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X.
Tai SJ, Herzog RW, Margaritis P, Arruda VR, Chu K, Golden JA, Labosky PA, High KA
(2008) J Thromb Haemost 6: 339-45
MeSH Terms: Amino Acid Substitution, Animals, Cardiomyopathies, Exons, Factor X, Factor X Deficiency, Female, Fetal Death, Fibrosis, Gene Targeting, Genes, Lethal, Genetic Complementation Test, Genomic Imprinting, Genotype, Hemosiderosis, Humans, Male, Mice, Mice, Knockout, Mice, Transgenic, Models, Animal, Myocardium
Show Abstract · Added July 20, 2010
BACKGROUND - Activated factor X (FXa) is a vitamin K-dependent serine protease that plays a pivotal role in blood coagulation by converting prothrombin to thrombin. There are no reports of humans with complete deficiency of FX, and knockout of murine F10 is embryonic or perinatal lethal.
OBJECTIVE - We sought to generate a viable mouse model of FX deficiency.
METHODS - We used a socket-targeting construct to generate F10-knockout mice by eliminating F10 exon 8 (knockout allele termed F10(tm1Ccmt), abbreviated as '-'; wild-type '+'), and a plug-targeting construct to generate mice expressing a FX variant with normal antigen levels but low levels of FX activity [4-9% normal in humans carrying the defect, Pro343-->Ser, termed FX Friuli (mutant allele termed F10(tm2Ccmt), abbreviated as F)].
RESULTS - F10 knockout mice exhibited embryonic or perinatal lethality. In contrast, homozygous Friuli mice [F10 (F/F)] had FX activity levels of approximately 5.5% (sufficient to rescue both embryonic and perinatal lethality), but developed age-dependent iron deposition and cardiac fibrosis. Interestingly, F10 (-/F) mice with FX activity levels of 1-3% also showed complete rescue of lethality. Further study of this model provides evidence supporting a role of maternal FX transfer in the embryonic survival.
CONCLUSIONS - We demonstrate that, while complete absence of FX is incompatible with murine survival, minimal FX activity as low as 1-3% is sufficient to rescue the lethal phenotype. This viable low-FX mouse model will facilitate the development of FX-directed therapies as well as investigation of the FX role in embryonic development.
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22 MeSH Terms
Essential functions of Alk3 during AV cushion morphogenesis in mouse embryonic hearts.
Song L, Fässler R, Mishina Y, Jiao K, Baldwin HS
(2007) Dev Biol 301: 276-86
MeSH Terms: Animals, Atrioventricular Node, Bone Morphogenetic Protein Receptors, Type I, Cell Proliferation, Cell Survival, Female, Fluorescent Antibody Technique, Genes, Lethal, Heart, Male, Mice, Morphogenesis
Show Abstract · Added June 11, 2010
Accumulated evidence has suggested that BMP pathways play critical roles during mammalian cardiogenesis and impairment of BMP signaling may contribute to human congenital heart diseases (CHDs), which are the leading cause of infant morbidity and mortality. Alk3 encodes a BMP specific type I receptor expressed in mouse embryonic hearts. To reveal functions of Alk3 during atrioventricular (AV) cushion morphogenesis and to overcome the early lethality of Alk3(-/-) embryos, we applied a Cre/loxp approach to specifically inactivate Alk3 in the endothelium/endocardium. Our studies showed that endocardial depletion of Alk3 severely impairs epithelium-mesenchymal-transformation (EMT) in the atrioventricular canal (AVC) region; the number of mesenchymal cells formed in Tie1-Cre;Alk3(loxp/loxp) embryos was reduced to only approximately 20% of the normal level from both in vivo section studies and in vitro explant assays. We showed, for the first time, that in addition to its functions on mesenchyme formation, Alk3 is also required for the normal growth/survival of AV cushion mesenchymal cells. Functions of Alk3 are accomplished through regulating expression/activation/subcellular localization of multiple downstream genes including Smads and cell-cycle regulators. Taken together, our study supports the notion that Alk3-mediated BMP signaling in AV endocardial/mesenchymal cells plays a central role during cushion morphogenesis.
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12 MeSH Terms
Transgenic mice expressing tamoxifen-inducible Cre for somatic gene modification in renal epithelial cells.
Lantinga-van Leeuwen IS, Leonhard WN, van de Wal A, Breuning MH, Verbeek S, de Heer E, Peters DJ
(2006) Genesis 44: 225-32
MeSH Terms: Animals, Cadherins, Epithelial Cells, Gene Expression, Gene Targeting, Genes, Lethal, Integrases, Kidney, Mice, Mice, Inbred C57BL, Mice, Transgenic, Promoter Regions, Genetic, TRPP Cation Channels, Tamoxifen
Show Abstract · Added September 9, 2013
Gene inactivation often leads to an embryonic-lethal phenotype. In focal diseases like renal cell carcinomas and polycystic kidney disease, somatic gene inactivation in subsets of cells is likely to occur at later stages. We generated a transgenic mouse line with an inducible form of Cre recombinase for conditional gene modifications in kidney epithelial cells. To this end a 1.4-kb promoter fragment of the kidney-specific cadherin gene (KspCad) was cloned upstream of a tamoxifen-inducible Cre recombinase (CreER(T2)) encoding sequence. Expression and activity of Cre was evaluated using reverse transcriptase polymerase chain reaction (RT-PCR) analysis and by crossbreeding to Z/EG reporter mice. One KspCad-CreER(T2) line showed kidney-specific Cre expression and mediated recombination upon tamoxifen treatment in Z/EG reporter mice. No reporter gene expression was detected in untreated animals or in extrarenal tissues upon treatment. Within the kidneys, enhanced green fluorescent protein (EGFP) fluorescence was observed in epithelial cells in several nephronic segments. In addition, the system successfully recombined a floxed Pkd1 gene.
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14 MeSH Terms