Gene expression data from colorectal cancers
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE106535 | GEO | 2018/02/14
REPOSITORIES: GEO
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Project description:Natural killer (NK) cells have evolved to detect and kill aberrant cells with this activity being governed by the cytokine interleukin (IL)-15 and foreign and self-ligands. We have identified CIS (Cytokine-inducible SH2-containing protein; Cish gene) as the critical negative regulator of IL-15 signalling in NK cells. Cish was rapidly induced in response to IL-15 and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by superior proliferation, survival, IFN-γ production and cytotoxicity towards tumours. This was associated with enhanced JAK/STAT signalling in Cish-deleted NK cells. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish-/- mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. This study has uncovered a potent checkpoint in NK cell-mediated tumour immunity and holds promise for novel immunotherapies directed at blocking CIS function.
2016-05-20 | GSE79409 | GEO
Project description:Media conditioned by undifferentiated human embryonic stem cells enhanced karyokinesis, cytokinesis and cell proliferation in cultures of differentiated, beating primary rat cardiomyocytes without altering their final contractile phenotype. Transcriptome analysis of proliferating cardiomyocytes revealed comprehensive activation of the ROCK 1 and 2 G-protein coupled receptor (GPCR) pathway associated with cytokinesis, and the RAS/RAF/MEK/ERK receptor tyrosine kinase pathways (RTK) and JAK/STAT-cytokine pathway involved in cell cycle progression. Correlative multi-analyte profiling (85 proteins) of conditioned media identified 33 proteins at significantly elevated levels compared to unconditioned media including ligands specific to the GPCR signal transduction pathways (serum amyloid A, monocyte chemoattractant protein-1, macrophage inhibitory protein, IL-8, macrophage inflammatory protein 1-alpha, eotaxin), RTK activation (IGFbp-1, IGFbp-2, HGF) and JAK-STAT stimulation pathways (IL-6, IFNa) activated in the treated cardiomyocytes. These data indicated that ES cells secreted a unique admixture of factors associated with induction of mitotic replication, cytokinesis and proliferation in cardiomyocytes.
2010-06-01 | GSE13708 | GEO
Project description:The consitutive activation of the JAK/STAT signalling cascade is reponsible for the majority of meyoproliferative disorders in humans, a disease that is also conserved in Drosophila. A gain-of-function mutation in the Drosophila JAK kinase leads to blood cell (haemocyte) overproliferation which eventually is manifested as black melanotic tumors. Haemocyte-like Drosophila Kc167 cells were used to identify downstream target genes of the JAK/STAT pathway which may be responsible for tumour generation and progression.
2009-08-31 | GSE15584 | GEO
Project description:The consitutive activation of the JAK/STAT signalling cascade is reponsible for the majority of meyoproliferative disorders in humans, a disease that is also conserved in Drosophila. A gain-of-function mutation in the Drosophila JAK kinase leads to blood cell (haemocyte) overproliferation which eventually is manifested as black melanotic tumors. Haemocyte-like Drosophila Kc167 cells were used to identify downstream target genes of the JAK/STAT pathway which may be responsible for tumour generation and progression. Experiment Overall Design: Kc167 cells were activated with the principal JAK/STAT pathway ligand Unpaired (UPD) in a time course manner. To this end, for each transcript profiling condition and time point, biological duplicates were activated with UPD or Mock conditioned media for 30 min, and total RNA was extracted 2, 4 or 10h after initial addition of conditioned media. 12 samples were used for hybridization to the arrays.
2009-09-12 | E-GEOD-15584 | biostudies-arrayexpress
Project description:In Interleukin (IL)-6 signalling, IL-6 site I binds to the IL-6 receptor (IL-6R) first, following by IL-6 site II interaction to domain 2/3 of gp130 to form premature trimeric IL-6:IL‑6R:gp130 receptor complexes. Formation of the mature hexameric receptor complex is then facilitated by the inter-trimeric interaction of IL-6 site III with domain 1 of the opposing gp130. The two gp130-associated Janus kinases (JAKs) trans-phosphorylate when their spatiotemporal pairing is correct, which causes the activation of STAT, ERK, and AKT pathways in a balanced manner. Since the intracellular domain (ICD) of IL-6R is not needed for STAT/ERK/AKT phosphorylation, we investigated the conditions under which a chimeric IL-6RECD-gp130TMD/ICD receptor protein confers biological activity. For IL‑6RECD‑gp130TMD/ICD, the extracellular domain (ECD) of IL-6R was fused to the transmembrane domain (TMD) and ICD of gp130. Co-expression of IL‑6RECD‑gp130TMD/ICD with signalling-deficient gp130 variants did not induce IL-6 signalling, suggesting that the assembly of hexameric complexes failed to dimerize the IL-6R-associated JAKs correctly. By mimicking the premature trimeric receptor complex, IL-6-mediated dimerization of IL-6RECD-gp130TMD/ICD with the single-cytokine-binding variant gp130DD1 induced signalling. Of note, IL-6 signalling via these synthetic gp130DD1:IL-6RECD-gp130TMD/ICD complexes resulted predominantly in STAT3 phosphorylation. A STAT3-dominated profile was also observed after IL-6-induced signalling mediated by a JAK-deficient IL‑6RECD‑gp130TMD/ICDDJAK variant in complex with the JAK-proficient but STAT/ERK/AKT-deficient gp130JAKDICD variant. Our data showed that effective ERK/AKT signalling could not be executed after intracellular domain swapping from gp130 to the IL-6R. Taken together, the chimeric IL-6R/gp130 receptor may be helpful in the creation of customized synthetic IL-6 signalling.
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Project description:Qi2013 - IL-6 and IFN crosstalk model
This model
[BIOMD0000000544]
describes the crosstalk between IFN-gamma and IL-6 induced
signalling; it aims to outline mechanisms and factors that may
control the interaction between both signalling pathways,
discussing a role of heterodimer formation in signalling
dysfunction.
To account for the possibility of different IFNR and gp130
binding sites for STAT1 and STAT3, model 1
[BIOMD0000000543]
assumes that there is no competition between STAT1 and STAT3 for
the receptor complexes (includes two extra reactions).
The reverse of this is true in model 2
[BIOMD0000000544]
where it generally is assumed that there is competition between
STAT1 and STAT3 for the receptor complexes.
This model is described in the article:
Elucidating the crosstalk
mechanism between IFN-gamma and IL-6 via mathematical
modelling.
Qi YF, Huang YX, Wang HY, Zhang Y,
Bao YL, Sun LG, Wu Y, Yu CL, Song ZB, Zheng LH, Sun Y, Wang GN,
Li YX.
BMC Bioinformatics 2013; 14: 41
Abstract:
BACKGROUND: Interferon-gamma (IFN-gamma) and interleukin-6
(IL-6) are multifunctional cytokines that regulate immune
responses, cell proliferation, and tumour development and
progression, which frequently have functionally opposing roles.
The cellular responses to both cytokines are activated via the
Janus kinase/signal transducer and activator of transcription
(JAK/STAT) pathway. During the past 10 years, the crosstalk
mechanism between the IFN-gamma and IL-6 pathways has been
studied widely and several biological hypotheses have been
proposed, but the kinetics and detailed crosstalk mechanism
remain unclear. RESULTS: Using established mathematical models
and new experimental observations of the crosstalk between the
IFN-gamma and IL-6 pathways, we constructed a new crosstalk
model that considers three possible crosstalk levels: (1) the
competition between STAT1 and STAT3 for common receptor docking
sites; (2) the mutual negative regulation between SOCS1 and
SOCS3; and (3) the negative regulatory effects of the formation
of STAT1/3 heterodimers. A number of simulations were tested to
explore the consequences of cross-regulation between the two
pathways. The simulation results agreed well with the
experimental data, thereby demonstrating the effectiveness and
correctness of the model. CONCLUSION: In this study, we
developed a crosstalk model of the IFN-gamma and IL-6 pathways
to theoretically investigate their cross-regulation mechanism.
The simulation experiments showed the importance of the three
crosstalk levels between the two pathways. In particular, the
unbalanced competition between STAT1 and STAT3 for IFNR and
gp130 led to preferential activation of IFN-gamma and IL-6,
while at the same time the formation of STAT1/3 heterodimers
enhanced preferential signal transduction by sequestering a
fraction of the activated STATs. The model provided a good
explanation of the experimental observations and provided
insights that may inform further research to facilitate a
better understanding of the cross-regulation mechanism between
the two pathways.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000544.
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 | BIOMD0000000544 | BioModels
Project description:Qi2013 - IL-6 and IFN crosstalk model
(non-competitive)
This model
[BIOMD0000000543]
describes the crosstalk between IFN-gamma and IL-6 induced
signalling; it aims to outline mechanisms and factors that may
control the interaction between both signalling pathways,
discussing a role of heterodimer formation in signalling
dysfunction.
To account for the possibility of different IFNR and gp130
binding sites for STAT1 and STAT3, model 1
[BIOMD0000000543]
assumes that there is no competition between STAT1 and STAT3 for
the receptor complexes (includes two extra reactions).
The reverse of this is true in model 2
[BIOMD0000000544]
where it generally is assumed that there is competition between
STAT1 and STAT3 for the receptor complexes.
This model is described in the article:
Elucidating the crosstalk
mechanism between IFN-gamma and IL-6 via mathematical
modelling.
Qi YF, Huang YX, Wang HY, Zhang Y,
Bao YL, Sun LG, Wu Y, Yu CL, Song ZB, Zheng LH, Sun Y, Wang GN,
Li YX.
BMC Bioinformatics 2013; 14: 41
Abstract:
BACKGROUND: Interferon-gamma (IFN-gamma) and interleukin-6
(IL-6) are multifunctional cytokines that regulate immune
responses, cell proliferation, and tumour development and
progression, which frequently have functionally opposing roles.
The cellular responses to both cytokines are activated via the
Janus kinase/signal transducer and activator of transcription
(JAK/STAT) pathway. During the past 10 years, the crosstalk
mechanism between the IFN-gamma and IL-6 pathways has been
studied widely and several biological hypotheses have been
proposed, but the kinetics and detailed crosstalk mechanism
remain unclear. RESULTS: Using established mathematical models
and new experimental observations of the crosstalk between the
IFN-gamma and IL-6 pathways, we constructed a new crosstalk
model that considers three possible crosstalk levels: (1) the
competition between STAT1 and STAT3 for common receptor docking
sites; (2) the mutual negative regulation between SOCS1 and
SOCS3; and (3) the negative regulatory effects of the formation
of STAT1/3 heterodimers. A number of simulations were tested to
explore the consequences of cross-regulation between the two
pathways. The simulation results agreed well with the
experimental data, thereby demonstrating the effectiveness and
correctness of the model. CONCLUSION: In this study, we
developed a crosstalk model of the IFN-gamma and IL-6 pathways
to theoretically investigate their cross-regulation mechanism.
The simulation experiments showed the importance of the three
crosstalk levels between the two pathways. In particular, the
unbalanced competition between STAT1 and STAT3 for IFNR and
gp130 led to preferential activation of IFN-gamma and IL-6,
while at the same time the formation of STAT1/3 heterodimers
enhanced preferential signal transduction by sequestering a
fraction of the activated STATs. The model provided a good
explanation of the experimental observations and provided
insights that may inform further research to facilitate a
better understanding of the cross-regulation mechanism between
the two pathways.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000543.
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 | BIOMD0000000543 | BioModels