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Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance.
McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA
(2007) Biochim Biophys Acta 1773: 1263-84
MeSH Terms: Animals, Apoptosis, Cell Cycle, Cell Proliferation, Cell Transformation, Neoplastic, Drug Resistance, Neoplasm, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Female, Humans, MAP Kinase Signaling System, Male, Mitogen-Activated Protein Kinase Kinases, Models, Biological, Neoplasms, Oxidative Stress, raf Kinases
Show Abstract · Added January 20, 2015
Growth factors and mitogens use the Ras/Raf/MEK/ERK signaling cascade to transmit signals from their receptors to regulate gene expression and prevent apoptosis. Some components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf). Mutations also occur at genes encoding upstream receptors (e.g., EGFR and Flt-3) and chimeric chromosomal translocations (e.g., BCR-ABL) which transmit their signals through these cascades. Even in the absence of obvious genetic mutations, this pathway has been reported to be activated in over 50% of acute myelogenous leukemia and acute lymphocytic leukemia and is also frequently activated in other cancer types (e.g., breast and prostate cancers). Importantly, this increased expression is associated with a poor prognosis. The Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways interact with each other to regulate growth and in some cases tumorigenesis. For example, in some cells, PTEN mutation may contribute to suppression of the Raf/MEK/ERK cascade due to the ability of activated Akt to phosphorylate and inactivate different Rafs. Although both of these pathways are commonly thought to have anti-apoptotic and drug resistance effects on cells, they display different cell lineage specific effects. For example, Raf/MEK/ERK is usually associated with proliferation and drug resistance of hematopoietic cells, while activation of the Raf/MEK/ERK cascade is suppressed in some prostate cancer cell lines which have mutations at PTEN and express high levels of activated Akt. Furthermore the Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways also interact with the p53 pathway. Some of these interactions can result in controlling the activity and subcellular localization of Bim, Bak, Bax, Puma and Noxa. Raf/MEK/ERK may promote cell cycle arrest in prostate cells and this may be regulated by p53 as restoration of wild-type p53 in p53 deficient prostate cancer cells results in their enhanced sensitivity to chemotherapeutic drugs and increased expression of Raf/MEK/ERK pathway. Thus in advanced prostate cancer, it may be advantageous to induce Raf/MEK/ERK expression to promote cell cycle arrest, while in hematopoietic cancers it may be beneficial to inhibit Raf/MEK/ERK induced proliferation and drug resistance. Thus the Raf/MEK/ERK pathway has different effects on growth, prevention of apoptosis, cell cycle arrest and induction of drug resistance in cells of various lineages which may be due to the presence of functional p53 and PTEN and the expression of lineage specific factors.
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17 MeSH Terms
Artery/vein specification is governed by opposing phosphatidylinositol-3 kinase and MAP kinase/ERK signaling.
Hong CC, Peterson QP, Hong JY, Peterson RT
(2006) Curr Biol 16: 1366-72
MeSH Terms: Animals, Arteries, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Embryo, Nonmammalian, Endothelial Cells, Endothelium, Vascular, Extracellular Signal-Regulated MAP Kinases, MAP Kinase Signaling System, Mutation, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor A, Veins, Zebrafish, Zebrafish Proteins
Show Abstract · Added August 19, 2012
Angioblasts are multipotent progenitor cells that give rise to arteries or veins . Genetic disruption of the gridlock gene perturbs the artery/vein balance, resulting in generation of insufficient numbers of arterial cells . However, within angioblasts the precise biochemical signals that determine the artery/vein cell-fate decision are poorly understood. We have identified by chemical screening two classes of compounds that compensate for a mutation in the gridlock gene . Both target the VEGF signaling pathway and reveal two downstream branches emanating from the VEGF receptor with opposing effects on arterial specification. We show that activation of ERK (p42/44 MAP kinase) is a specific marker of early arterial progenitors and is among the earliest known determinants of arterial specification. In embryos, cells fated to contribute to arteries express high levels of activated ERK, whereas cells fated to contribute to veins do not. Inhibiting the phosphatidylinositol-3 kinase (PI3K) branch with GS4898 or known PI3K inhibitors, or by expression of a dominant-negative form of AKT promotes arterial specification. Conversely, inhibition of the ERK branch blocks arterial specification, and expression of constitutively active AKT promotes venous specification. In summary, chemical genetic analysis has uncovered unanticipated opposing roles of PI3K and ERK in artery/vein specification.
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17 MeSH Terms
The impact of altered annexin I protein levels on apoptosis and signal transduction pathways in prostate cancer cells.
Hsiang CH, Tunoda T, Whang YE, Tyson DR, Ornstein DK
(2006) Prostate 66: 1413-24
MeSH Terms: Annexin A1, Apoptosis, Cell Line, Cell Line, Tumor, Cell Proliferation, Cell Survival, Disease Progression, Epidermal Growth Factor, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Kinase 4, Male, Prostatic Neoplasms, Signal Transduction, Tetradecanoylphorbol Acetate, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added February 27, 2013
BACKGROUND - Although reduced expression levels of annexin I (ANX I) protein is a common finding in all stages of prostate cancer a causative relationship between ANX I dysregulation and prostate cancer development has yet to be established.
METHODS - Annexin I expression was restored in LNCaP and MDA PCa 2b that normally express low or undetectable levels of ANX I protein. The impact of restoring ANX I expression on cell viability, colony formation in soft agar, apoptosis, and extracellular signal-regulated kinases (ERK), p38, c-Jun N-terminal kinases (JNK) activation was examined.
RESULTS - Restoring ANX I expression reduced cell viability, colony formation, in addition to inducing apoptosis. The proliferative response of epidermal growth factor was blocked by restoring ANX I expression. Furthermore, increasing basal and induced levels of phosphorylated p38 and JNK were observed in prostate cancer cells following restoration of ANX I expression.
CONCLUSIONS - Annexin I may have tumor suppressor functions in prostate cancer. The pro-apoptotic effect of ANX I involves the activation of p38 and JNK, which appears to shift the balance of signal transduction away from proliferation and toward apoptosis.
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17 MeSH Terms
Fgf8 is required for anterior heart field development.
Ilagan R, Abu-Issa R, Brown D, Yang YP, Jiao K, Schwartz RJ, Klingensmith J, Meyers EN
(2006) Development 133: 2435-45
MeSH Terms: Animals, Bone Morphogenetic Protein 4, Bone Morphogenetic Proteins, Branchial Region, Cardiovascular Abnormalities, Craniofacial Abnormalities, Embryo, Mammalian, Endoderm, Extracellular Signal-Regulated MAP Kinases, Fibroblast Growth Factor 8, Gene Expression Regulation, Developmental, Genes, Reporter, Heart, Homeodomain Proteins, In Situ Hybridization, Mesoderm, Mice, Mice, Knockout, Neural Crest, Signal Transduction, Transcription Factors
Show Abstract · Added August 28, 2017
In the mouse embryo, the splanchnic mesodermal cells of the anterior heart field (AHF) migrate from the pharynx to contribute to the early myocardium of the outflow tract (OT) and right ventricle (RV). Recent studies have attempted to distinguish the AHF from other precardiac populations, and to determine the genetic and molecular mechanisms that regulate its development. Here, we have used an Fgf8lacZ allele to demonstrate that Fgf8 is expressed within the developing AHF. In addition, we use both a hypomorphic Fgf8 allele (Fgf8neo) and Cre-mediated gene ablation to show that Fgf8 is essential for the survival and proliferation of the AHF. Nkx2.5Cre is expressed in the AHF, primary heart tube and pharyngeal endoderm, while TnT-Cre is expressed only within the specified heart tube myocardium. Deletion of Fgf8 by Nkx2.5Cre results in a significant loss of the Nkx2.5Cre lineage and severe OT and RV truncations by E9.5, while the remaining heart chambers (left ventricle and atria) are grossly normal. These defects result from significant decreases in cell proliferation and aberrant cell death in both the pharyngeal endoderm and splanchnic mesoderm. By contrast, ablation of Fgf8 in the TnT-Cre domain does not result in OT or RV defects, providing strong evidence that Fgf8 expression is crucial in the pharyngeal endoderm and/or overlying splanchnic mesoderm of the AHF at a stage prior to heart tube elongation. Analysis of downstream signaling components, such as phosphorylated-Erk and Pea3, identifies the AHF splanchnic mesoderm itself as a target for Fgf8 signaling.
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21 MeSH Terms
H-Ras, R-Ras, and TC21 differentially regulate ureteric bud cell branching morphogenesis.
Pozzi A, Coffa S, Bulus N, Zhu W, Chen D, Chen X, Mernaugh G, Su Y, Cai S, Singh A, Brissova M, Zent R
(2006) Mol Biol Cell 17: 2046-56
MeSH Terms: Animals, Cell Movement, Cell Proliferation, Cells, Cultured, Enzyme Activation, Epithelium, Extracellular Signal-Regulated MAP Kinases, Kidney Tubules, Collecting, Membrane Proteins, Mesoderm, Mice, Monomeric GTP-Binding Proteins, Morphogenesis, Signal Transduction, Ureter, p38 Mitogen-Activated Protein Kinases, ras Proteins
Show Abstract · Added February 24, 2014
The collecting system of the kidney, derived from the ureteric bud (UB), undergoes repetitive bifid branching events during early development followed by a phase of tubular growth and elongation. Although members of the Ras GTPase family control cell growth, differentiation, proliferation, and migration, their role in development of the collecting system of the kidney is unexplored. In this study, we demonstrate that members of the R-Ras family of proteins, R-Ras and TC21, are expressed in the murine collecting system at E13.5, whereas H-Ras is only detected at day E17.5. Using murine UB cells expressing activated H-Ras, R-Ras, and TC21, we demonstrate that R-Ras-expressing cells show increased branching morphogenesis and cell growth, TC21-expressing cells branch excessively but lose their ability to migrate, whereas H-Ras-expressing cells migrated the most and formed long unbranched tubules. These differences in branching morphogenesis are mediated by differential regulation/activation of the Rho family of GTPases and mitogen-activated protein kinases. Because most branching of the UB occurs early in development, it is conceivable that R-Ras and TC-21 play a role in facilitating branching and growth in early UB development, whereas H-Ras might favor cell migration and elongation of tubules, events that occur later in development.
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17 MeSH Terms
Phosphorylation of serine 526 is required for MEKK3 activity, and association with 14-3-3 blocks dephosphorylation.
Fritz A, Brayer KJ, McCormick N, Adams DG, Wadzinski BE, Vaillancourt RR
(2006) J Biol Chem 281: 6236-45
MeSH Terms: 14-3-3 Proteins, Alanine, Amino Acid Sequence, Catalysis, Cell Line, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Humans, Isoenzymes, MAP Kinase Kinase 6, MAP Kinase Kinase Kinase 3, Molecular Sequence Data, Mutagenesis, Site-Directed, NF-kappa B, Osmotic Pressure, Phosphoprotein Phosphatases, Phosphorylation, Protein Phosphatase 2, Serine, Signal Transduction, Threonine
Show Abstract · Added December 10, 2013
MAPK/ERK kinase kinase 3 (MEKK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that functions upstream of the MAP kinases and IkappaB kinase. Phosphorylation is believed to be a critical component for MEKK3-dependent signal transduction, but little is known about the phosphorylation sites of this MAP3K. To address this question, point mutations were introduced in the activation loop (T-loop), substituting alanine for serine or threonine, and the mutants were transfected into HEK293 Epstein-Barr virus nuclear antigen cells. MEKK3-dependent activation of an NF-kappaB reporter gene as well as ERK, JNK, and p38 MAP kinases correlated with a requirement for serine at position 526. Constitutively active mutants of MEKK3, consisting of S526D and S526E, were capable of activating a NF-kappaB luciferase reporter gene as well as ERK and MEK, suggesting that a negative charge at Ser526 was necessary for MEKK3 activity and implicating Ser526 as a phosphorylation site. An antibody was developed that specifically recognized phospho-Ser526 of MEKK3 but did not recognize the S526A point mutant. The catalytically inactive (K391M) mutant of MEKK3 was not phosphorylated at Ser526, indicating that phosphorylation of Ser526 occurs via autophosphorylation. Endogenous MEKK3 was phosphorylated on Ser526 in response to osmotic stress. In addition, phosphorylation of Ser526 was required for MKK6 phosphorylation in vitro, whereas dephosphorylation of Ser526 was mediated by protein phosphatase 2A and sensitive to okadaic acid and sodium fluoride. Finally, the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526. In summary, Ser526 of MEKK3 is an autophosphorylation site within the T-loop that is regulated by PP2A and 14-3-3 proteins.
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21 MeSH Terms
Distinct protein phosphatase 2A heterotrimers modulate growth factor signaling to extracellular signal-regulated kinases and Akt.
Van Kanegan MJ, Adams DG, Wadzinski BE, Strack S
(2005) J Biol Chem 280: 36029-36
MeSH Terms: Animals, Cells, Cultured, Dimerization, Dose-Response Relationship, Drug, Down-Regulation, Epidermal Growth Factor, Extracellular Signal-Regulated MAP Kinases, Fibroblast Growth Factor 2, Gene Silencing, Genes, Reporter, Growth Substances, Immunoblotting, MAP Kinase Signaling System, Mutation, Nerve Growth Factor, Okadaic Acid, PC12 Cells, Phosphoprotein Phosphatases, Phosphorylation, Protein Phosphatase 2, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-akt, RNA Interference, Rats, Signal Transduction
Show Abstract · Added December 10, 2013
A key regulator of many kinase cascades, heterotrimeric protein serine/threonine phosphatase 2A (PP2A), is composed of catalytic (C), scaffold (A), and variable regulatory subunits (B, B', B'' gene families). In neuronal PC12 cells, PP2A acts predominantly as a gatekeeper of extracellular signal-regulated kinase (ERK) activity, as shown by inducible RNA interference of the Aalpha scaffolding subunit and PP2A inhibition by okadaic acid. Although okadaic acid potentiates Akt/protein kinase B and ERK phosphorylation in response to epidermal, basic fibroblast, or nerve growth factor, silencing of Aalpha paradoxically has the opposite effect. Epidermal growth factor receptor Tyr phosphorylation was unchanged following Aalpha knockdown, suggesting that chronic Akt and ERK hyperphosphorylation leads to compensatory down-regulation of signaling molecules upstream of Ras and blunted growth factor responses. Inducible exchange of wild-type Aalpha with a mutant with selective B' subunit binding deficiency implicated PP2A/B' heterotrimers as Akt modulators. Conversely, silencing of the B-family regulatory subunits Balpha and Bdelta led to hyperactivation of ERK stimulated by constitutively active MEK1. In vitro dephosphorylation assays further support a role for Balpha and Bdelta in targeting the PP2A heterotrimer to dephosphorylate and inactivate ERKs. Thus, receptor tyrosine kinase signaling cascades leading to Akt and ERK activation are modulated by PP2A holoenzymes with distinct regulatory properties.
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25 MeSH Terms
Inhibition of Pkhd1 impairs tubulomorphogenesis of cultured IMCD cells.
Mai W, Chen D, Ding T, Kim I, Park S, Cho SY, Chu JS, Liang D, Wang N, Wu D, Li S, Zhao P, Zent R, Wu G
(2005) Mol Biol Cell 16: 4398-409
MeSH Terms: Animals, Apoptosis, Cell Adhesion, Cell Communication, Cell Differentiation, Cell Line, Cell Movement, Cilia, Dogs, Extracellular Signal-Regulated MAP Kinases, Focal Adhesion Kinase 2, Integrins, Kidney Tubules, Collecting, Mice, Polycystic Kidney, Autosomal Recessive, RNA Interference, Receptors, Cell Surface, Signal Transduction
Show Abstract · Added December 10, 2013
Fibrocystin/polyductin (FPC), the gene product of PKHD1, is responsible for autosomal recessive polycystic kidney disease (ARPKD). This disease is characterized by symmetrically large kidneys with ectasia of collecting ducts. In the kidney, FPC predominantly localizes to the apical domain of tubule cells, where it associates with the basal bodies/primary cilia; however, the functional role of this protein is still unknown. In this study, we established stable IMCD (mouse inner medullary collecting duct) cell lines, in which FPC was silenced by short hairpin RNA inhibition (shRNA). We showed that inhibition of FPC disrupted tubulomorphogenesis of IMCD cells grown in three-dimensional cultures. Pkhd1-silenced cells developed abnormalities in cell-cell contact, actin cytoskeleton organization, cell-ECM interactions, cell proliferation, and apoptosis, which may be mediated by dysregulation of extracellular-regulated kinase (ERK) and focal adhesion kinase (FAK) signaling. These alterations in cell function in vitro may explain the characteristics of ARPKD phenotypes in vivo.
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18 MeSH Terms
L-DOPA reverses the MPTP-induced elevation of the arrestin2 and GRK6 expression and enhanced ERK activation in monkey brain.
Bezard E, Gross CE, Qin L, Gurevich VV, Benovic JL, Gurevich EV
(2005) Neurobiol Dis 18: 323-35
MeSH Terms: Animals, Antiparkinson Agents, Arrestins, Basal Ganglia, Brain, Cyclic AMP-Dependent Protein Kinases, Disease Models, Animal, Extracellular Signal-Regulated MAP Kinases, Female, G-Protein-Coupled Receptor Kinases, Levodopa, Macaca fascicularis, Parkinsonian Disorders, Phosphoproteins, Phosphorylation, Protein-Serine-Threonine Kinases, Receptors, G-Protein-Coupled, Up-Regulation, beta-Adrenergic Receptor Kinases
Show Abstract · Added December 10, 2013
Dysregulation of dopamine receptors (DARs) is believed to contribute to Parkinson disease (PD) pathology. G protein-coupled receptors (GPCR) undergo desensitization via activation-dependent phosphorylation by G protein-coupled receptor kinases (GRKs) followed by arrestin binding. Using quantitative Western blotting, we detected profound differences in the expression of arrestin2 and GRKs among four experimental groups of nonhuman primates: (1) normal, (2) parkinsonian, (3) parkinsonian treated with levodopa without or (4) with dyskinesia. Arrestin2 and GRK6 expression was significantly elevated in the MPTP-lesioned group in most brain regions; GRK2 was increased in caudal caudate and internal globus pallidus. Neither levodopa-treated group differed significantly from control. The only dyskinesia-specific change was an elevation of GRK3 in the ventral striatum of the dyskinetic group. Changes in arrestin and GRK expression in the MPTP group were accompanied by enhanced ERK activation and elevated total ERK expression, which were also reversed by L-DOPA. The data suggest the involvement of arrestins and GRKs in Parkinson disease pathology and the effects of levodopa treatment.
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19 MeSH Terms
Extracellular signal-regulated kinase 7, a regulator of hormone-dependent estrogen receptor destruction.
Henrich LM, Smith JA, Kitt D, Errington TM, Nguyen B, Traish AM, Lannigan DA
(2003) Mol Cell Biol 23: 5979-88
MeSH Terms: Animals, Binding Sites, Breast, Breast Neoplasms, Cells, Cultured, Cricetinae, Cysteine Proteinase Inhibitors, Estrogen Receptor alpha, Extracellular Signal-Regulated MAP Kinases, Female, Hormones, Humans, Kidney, Leupeptins, Mitogen-Activated Protein Kinases, Mutation, Peptide Hydrolases, Phosphorylation, Proteasome Endopeptidase Complex, Receptors, Estrogen, Reference Values, Signal Transduction, Ubiquitin
Show Abstract · Added January 20, 2015
Estrogen receptor alpha (ER alpha) degradation is regulated by ubiquitination, but the signaling pathways that modulate ER alpha turnover are unknown. We found that extracellular signal-regulated kinase 7 (ERK7) preferentially enhances the destruction of ER alpha but not the related androgen receptor. Loss of ERK7 was correlated with breast cancer progression, and all ER alpha-positive breast tumors had decreased ERK7 expression compared to that found in normal breast tissue. In human breast cells, a dominant-negative ERK7 mutant decreased the rate of endogenous ER alpha degradation >4-fold in the presence of hormone and potentiated estrogen responsiveness. ERK7 targets the ER alpha ligand-binding domain for destruction by enhancing its ubiquitination. Thus, ERK7 is a novel regulator of estrogen responsiveness through its control of ER alpha turnover.
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23 MeSH Terms