Inhibition of Cxcr4 chemokine receptor signaling improves habituation learning in a zebrafish model of Neurofibromatosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE317922 | GEO | 2026/01/28
REPOSITORIES: GEO
Similar Datasets
Project description:Neurofibromin (NF1) is a fundamental inhibitor of cell growth that is conserved from yeast to humans. NF1 negatively regulates oncogenic RAS proteins by accelerating the hydrolysis of RAS-bound GTP. This activity blocks growth factor signalling upstream of both mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. However, the structure and regulatory mechanisms of NF1 have remained elusive. Here we report crosslinking mass spectrometry analysis of the 320 kDa NF1 protein.
2022-08-12 | PXD023593 | Pride
Project description:Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcoma that occurs in carriers of mutations in the neurofibromatosis type I gene (Nf1) as well as sporadically. Plexiform neurofibromas in NF1 patients have a significant risk of developing into MPNSTs leading to increased morbidity and mortality from this syndrome. Surgery is the primary intervention but it is not always effective due to the tendency of MPNSTs to infiltrate the surrounding tissue or grow in an inoperable location. Neurofibromin, the protein coded by the Nf1 gene, functions as a GTPase activating protein (GAP) whose mutation leads to constitutive activation of RAS and mitogen-activated protein kinase (MAPK) signaling in NF1 patients’ tumors. However, therapeutic targeting of RAS and MAPK have had limited success (Kalamarides, et al., 2012). In this study, we modulated NRAS, MEK1/2 and neurofibromin levels in MPNST cell lines and determined the global gene expression changes that were associated with each experimental condition. Furthermore, gene expression changes due to neurofibromin deficiency but independent of NRAS and MEK1/2 regulation were characterized for the first time in MPNST cell lines.
2013-03-15 | GSE39764 | GEO
Project description:Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcoma that occurs in carriers of mutations in the neurofibromatosis type I gene (Nf1) as well as sporadically. Plexiform neurofibromas in NF1 patients have a significant risk of developing into MPNSTs leading to increased morbidity and mortality from this syndrome. Surgery is the primary intervention but it is not always effective due to the tendency of MPNSTs to infiltrate the surrounding tissue or grow in an inoperable location. Neurofibromin, the protein coded by the Nf1 gene, functions as a GTPase activating protein (GAP) whose mutation leads to constitutive activation of RAS and mitogen-activated protein kinase (MAPK) signaling in NF1 patients’ tumors. However, therapeutic targeting of RAS and MAPK have had limited success (Kalamarides, et al., 2012). In this study, we modulated NRAS, MEK1/2 and neurofibromin levels in MPNST cell lines and determined the global gene expression changes that were associated with each experimental condition. Furthermore, gene expression changes due to neurofibromin deficiency but independent of NRAS and MEK1/2 regulation were characterized for the first time in MPNST cell lines. There are total 4 comparison scenarios. Each scenario has two different samples to compare and each sample has three replicates. Comparison 1: ST88-14 cell line versus normal human schwann cell; comparison 2: U0126 treated ST88-14 versus DMSO treat ST88-14 as control; comparison 3: siNRAS treated ST88-14 versus scrambled control treated ST88-14 cell line; comparison 4: siNf1 treated STS26T cell line versus scrambled control RNA treated STS26T cell line.
2013-03-15 | E-GEOD-39764 | biostudies-arrayexpress
Project description:Neurofibromatosis type 1 (NF1) is a multi-system disease caused by mutations in the NF1 gene encoding a Ras-GAP protein, neurofibromin, which negatively regulates Ras signalling. Besides neuroectodermal malformations and tumours, the skeletal system is often affected (e.g. scoliosis and long bone dysplasia), demonstrating the importance of neurofibromin for development and maintenance of the musculoskeletal system. Here we focus on the role of neurofibromin in skeletal muscle development. Nf1 gene inactivation in the early limb bud mesenchyme using Prx1-cre (Nf1Prx1) resulted in muscle dystrophy characterised by fibrosis, reduced number of muscle fibres, and reduced muscle force. To gain insight into the molecular changes of the observed muscle dystrophy and fibrosis and to compare these with other known muscle dystrophies, we performed transcriptional profiling of the entire triceps muscles of threemonth-old wild type (wt) and mutant animals using Affymetrix high-density microrrays. We analyzed triceps muscles from 4 three-month-old wt controls and 4 three-month-old Nf1Prx1 mice using the Affymetrix Mouse Gene 1.0 ST platform. Array data was processed by the Affymetrix Exon Array Computational Tool. RNA isolated from each animal was hybridized to a separate microarray.
2011-05-18 | E-GEOD-29343 | biostudies-arrayexpress
Project description:Neurofibromatosis type 1 (NF1) is a multi-system disease caused by mutations in the NF1 gene encoding a Ras-GAP protein, neurofibromin, which negatively regulates Ras signalling. Besides neuroectodermal malformations and tumours, the skeletal system is often affected (e.g. scoliosis and long bone dysplasia), demonstrating the importance of neurofibromin for development and maintenance of the musculoskeletal system. Here we focus on the role of neurofibromin in skeletal muscle development. Nf1 gene inactivation in the early limb bud mesenchyme using Prx1-cre (Nf1Prx1) resulted in muscle dystrophy characterised by fibrosis, reduced number of muscle fibres, and reduced muscle force. To gain insight into the molecular changes of the observed muscle dystrophy and fibrosis and to compare these with other known muscle dystrophies, we performed transcriptional profiling of the entire triceps muscles of threemonth-old wild type (wt) and mutant animals using Affymetrix high-density microrrays.
2011-05-18 | GSE29343 | GEO
Project description:Neurofibromatosis 1 (NF1) is a genetic, neurocutaneous syndrome caused by a mutation in the gene encoding neurofibromin. Individuals with NF1 develop growths that define the NF1 phenotype, including Lisch nodules, cafe-au-lait spots, and neurofibromas. However, more than 50% of individuals with NF1 have cognitive deficits, such as learning disorders and attention deficit/hyperactive disorder that are neuroanatomically unrelated to the neurofibromas. The purpose of this study is to determine the molecular basis of the neurodevelopmental changes that result from the primary gene mutation using a mouse model of NF. These mice are heterozygous for the Nf1 gene (NF+/-), and develop learning and memory difficulties that mimic humans, but do not develop tumors. By applying the technique of gene expression profiling to both NF+/- and control mice, we expect get a genetic fingerprint of 12,000 RNA molecules expressed in different parts of the brain during development. Comparison of the genetic fingerprints in these mice during development may help us identify key molecular changes that eventually result in cognitive deficits. Such an understanding of the molecular changes triggered by the primary gene mutation may eventually lead to treatments that prevent the cognitive deficits in NF1.
2007-10-10 | E-GEOD-1482 | biostudies-arrayexpress
Project description:Mutation or deletion of Neurofibromin (NF1), an inhibitor of RAS signaling, frequently occurs in epithelial ovarian cancer (EOC), supporting therapies that target downstream RAS effectors, such as the RAF-MEK-ERK pathway. However, no comprehensive studies have been carried out testing the efficacy of MEK inhibition in NF1-deficient EOC. Here, we performed a detailed characterization of MEK inhibition in NF1-deficient EOC cell lines using kinome profiling and RNA sequencing. Our studies showed MEK inhibitors were ineffective at providing durable growth inhibition in NF1-deficient cells due to kinome reprogramming. MEKi-mediated destabilization of FOSL1 resulted in induced expression of RTKs and their downstream RAF and PI3K signaling overcoming MEKi therapy. MEKi synthetic enhancement screens identified BRD2 and BRD4 as integral mediators of the MEKi-induced RTK signatures. Inhibition of BET proteins using BET bromodomain inhibitors (BETi) blocked MEKi-induced RTK reprogramming, indicating BRD2 and BRD4 represent promising therapeutic targets in combination with MEKi to block resistance due to kinome reprogramming in NF1-deficient EOC.
2019-05-17 | GSE127886 | GEO
Project description:Cancer treatment decisions are increasingly guided by which specific genes are mutated within each patient’s tumor. For example, agents inhibiting the epidermal growth factor receptor (EGFR) benefit many colorectal cancer (CRC) patients, with the general exception of those whose tumor includes a KRAS mutation. However, among the various KRAS mutations, the G13D mutation behaves differently; for unknown reasons, CRC patients with the KRAS G13D mutation (also written KRASG13D) appear to benefit from the EGFR-blocking antibody cetuximab. Controversy surrounds this observation, because it appears to contradict the well-established mechanisms of EGFR signaling and of RAS mutations. Here, we identified a systems-level, mechanistic basis that explains why KRASG13D cancers respond to EGFR inhibition. We first investigated the problem with a computational model of RAS signaling, which unexpectedly revealed that the known biophysical differences between the three most common KRAS mutant proteins are sufficient to generate different sensitivities to inhibition. Computation and experimentation together revealed a non-intuitive, mutant-specific dependency of wild-type RAS activation by EGFR that is determined by the interaction strength between KRAS and the tumor suppressor neurofibromin (NF1). KRAS mutants that strongly interact with NF1 drive wild-type RAS activation in an EGFR independent manner through competitive inhibition of NF1, whereas KRAS G13D cells remain dependent upon EGFR for wild-type Ras activation because they cannot competitively inhibit NF1 due to a weak interaction between these two proteins. Overall, our work demonstrates how systems approaches enable mechanism-based inference in genomic medicine and can help identify patients for selective therapeutic strategies.
2020-05-27 | PXD014755 | Pride
Project description:Phillips2003 - The Mechanism of Ras GTPase
Activation by Neurofibromin
A mathematical model for Ras-GTP
activation by neurofibromin and the kinetic rates of the relevant
reactions.
This model is described in the article:
The mechanism of Ras GTPase
activation by neurofibromin.
Phillips RA, Hunter JL, Eccleston
JF, Webb MR.
Biochemistry 2003 Apr; 42(13):
3956-3965
Abstract:
Individual rate constants have been determined for each step
of the Ras.GTP hydrolysis mechanism, activated by
neurofibromin. Fluorescence intensity and anisotropy
stopped-flow measurements used the fluorescent GTP analogue,
mantGTP (2'(3')-O-(N-methylanthraniloyl)GTP), to determine rate
constants for binding and release of neurofibromin. Quenched
flow measurements provided the kinetics of the hydrolytic
cleavage step. The fluorescent phosphate sensor, MDCC-PBP was
used to measure phosphate release kinetics. Phosphate-water
oxygen exchange, using (18)O-substituted GTP and inorganic
phosphate (P(i)), was used to determine the extent of reversal
of the hydrolysis step and of P(i) binding. The data show that
neurofibromin and P(i) dissociate from the NF1.Ras.GDP.P(i)
complex with identical kinetics, which are 3-fold slower than
the preceding cleavage step. A model is presented in which the
P(i) release is associated with the change of Ras from "GTP" to
"GDP" conformation. In this model, the conformation change on
P(i) release causes the large change in affinity of
neurofibromin, which then dissociates rapidly.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000692.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000692 | BioModels
Project description:Besozzi2012 - Oscillatory regimes in the Ras/cAMP/PKA pathway in S.cerevisiae
Mechanistic model of the Ras/cAMP/PKA in yeast S.cerevisiae. The Ras/cAMP/PKA pathway plays a major role in the regulation of metabolism, stress resistance and cell cycle progress and is tightly regulated by multiple feedback loops, exerted by the protein kinase A (PKA). This model investigates the dynamics of the second messenger cAMP on Ras/cAMP/PKA pathway, to determine the effects of the feedback mechanisms on establising stable oscillatory regimes.
The model has been defined according to the stochastic formulation of chemical kinetics [Gillespie DT, 1977]
, which requires to specify the set of molecular species occurring in the pathway and their respective interactions, formally described as a set of biochemical reactions.
The volume considered for this system is 30fL; this value can be used to convert the model into the deterministic formulation.
This model is described in the article:
The role of feedback control mechanisms on the establishment of oscillatory regimes in the Ras/cAMP/PKA pathway in S. cerevisiae.
Besozzi D, Cazzaniga P, Pescini D, Mauri G, Colombo S, Martegani E.
EURASIP J Bioinform Syst Biol. 2012 Jul 20;2012(1):10.
Abstract:
In the yeast Saccharomyces cerevisiae, the Ras/cAMP/PKA pathway is involved in the regulation of cell growth and proliferation in response to nutritional sensing and stress conditions. The pathway is tightly regulated by multiple feedback loops, exerted by the protein kinase A (PKA) on a few pivotal components of the pathway. In this article, we investigate the dynamics of the second messenger cAMP by performing stochastic simulations and parameter sweep analysis of a mechanistic model of the Ras/cAMP/PKA pathway, to determine the effects that the modulation of these feedback mechanisms has on the establishment of stable oscillatory regimes. In particular, we start by studying the role of phosphodiesterases, the enzymes that catalyze the degradation of cAMP, which represent the major negative feedback in this pathway. Then, we show the results on cAMP oscillations when perturbing the amount of protein Cdc25 coupled with the alteration of the intracellular ratio of the guanine nucleotides (GTP/GDP), which are known to regulate the switch of the GTPase Ras protein. This multi-level regulation of the amplitude and frequency of oscillations in the Ras/cAMP/PKA pathway might act as a fine tuning mechanism for the downstream targets of PKA, as also recently evidenced by some experimental investigations on the nucleocytoplasmic shuttling of the transcription factor Msn2 in yeast cells.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000478
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2024-09-02 | BIOMD0000000478 | BioModels