HOXB8 counteracts MAPK/ERK oncogenic signaling in a chicken embryo model of neoplasia
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ABSTRACT:
PROVIDER: PRJNA754408 | ENA |
REPOSITORIES: ENA
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Project description:HOX transcription factors are members of an evolutionarily conserved family of proteins required for the establishment of the anteroposterior body axis during bilaterian development. Although they are often deregulated in cancers, the molecular mechanisms by which they act as oncogenes or tumor suppressor genes are only partially understood. Since the MAPK/ERK signaling pathway is deregulated in most cancers, we aimed at apprehending if and how Hox proteins interact with ERK oncogenicity. Using an in vivo neoplasia model in the chicken embryo that we have developed, consisting in the overactivation of the ERK1/2 kinases in the trunk neural tube, we analyzed the consequences of HOXB8 gain of function at morphological and transcriptional level in this model. We found that HOXB8 acts as a tumor suppressor, counteracting ERK-induced neoplasia. HOXB8 tumor suppressor function in this model relies on a large reversion of the oncogenic transcriptome induced by ERK. In addition to showing that HOXB8 protein controls the transcriptional responsiveness to ERK oncogenic signaling, our study identified new downstream targets of ERK oncogenic activation in an in vivo context that could provide clues for therapeutic strategies.
2021-08-17 | GSE182076 | GEO
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Project description:We have established functions of the stimulus dependent MAPKs, ERK1/2 and ERK5 in DRG, motor neuron, and Schwann cell development. Surprisingly, many aspects of early DRG and motor neuron development were found to be ERK1/2 independent and Erk5 deletion had no obvious effect on embryonic PNS. In contrast, Erk1/2 deletion in developing neural crest resulted in peripheral nerves that were devoid of Schwann cell progenitors, and deletion of Erk1/2 in Schwann cell precursors caused disrupted differentiation and marked hypomyelination of axons. The Schwann cell phenotypes are similar to those reported in neuregulin-1 and ErbB mutant mice and neuregulin effects could not be elicited in glial precursors lacking Erk1/2. ERK/MAPK regulation of myelination was specific to Schwann cells, as deletion in oligodendrocyte precursors did not impair myelin formation, but reduced precursor proliferation. Our data suggest a tight linkage between developmental functions of ERK/MAPK signaling and biological actions of specific RTK-activating factors. Microarray analysis on RNA extracts derived from E12.5 Erk1/2CKO(Wnt1) and wildtype DRGs
2010-10-16 | E-GEOD-24730 | biostudies-arrayexpress
Project description:The mammalian genome contains two ERK/MAP kinase kinase genes, Mek1 and Mek2, which encode dual-specificity kinases responsible for ERK/MAP kinase activation. To define the function of ERK/MAPK signaling pathway in lung development, we performed tissue-specific deletions of Mek1 function in a Mek2 null background. Inactivation of both Mek genes in mesenchyme resulted in several phenotypes including giant omphalocele, skeletal defects, pulmonary hypoplasia, abnormal trachea patterning, and death at birth. Microarray analysis with RNA extracted from lungs of E15.5 Dermo1+/Cre, Mek1+/flox;Mek2-/-;Dermo1+/Cre and Mek1flox/flox;Mek2-/-;Dermo1+/Cre embryos was performed to evaluate the molecular impact of the loss of all Mek alleles in mesenchyme on lung development. . Total RNA was isolated from lungs of E15.5 Dermo1+/Cre embryos (control), from E15.5 Mek1+/flox;Mek2- /-;Dermo1+/Cre embryos (experimental) and from E15.5 Mek1flox/flox;Mek2-/-;Dermo1+/Cre embryos (experimental). Four specimens were analyzed per genotype.
2014-09-02 | E-GEOD-51643 | biostudies-arrayexpress
Project description:The mammalian genome contains two ERK/MAP kinase kinase genes, Mek1 and Mek2, which encode dual-specificity kinases responsible for ERK/MAP kinase activation. To define the function of ERK/MAPK signaling pathway in lung development, we performed tissue-specific deletions of Mek1 function in a Mek2 null background. Inactivation of both Mek genes in mesenchyme resulted in several phenotypes including giant omphalocele, skeletal defects, pulmonary hypoplasia, abnormal trachea patterning, and death at birth. Microarray analysis with RNA extracted from lungs of E15.5 Dermo1+/Cre, Mek1+/flox;Mek2-/-;Dermo1+/Cre and Mek1flox/flox;Mek2-/-;Dermo1+/Cre embryos was performed to evaluate the molecular impact of the loss of all Mek alleles in mesenchyme on lung development. .
2014-09-02 | GSE51643 | GEO
Project description:We have established functions of the stimulus dependent MAPKs, ERK1/2 and ERK5 in DRG, motor neuron, and Schwann cell development. Surprisingly, many aspects of early DRG and motor neuron development were found to be ERK1/2 independent and Erk5 deletion had no obvious effect on embryonic PNS. In contrast, Erk1/2 deletion in developing neural crest resulted in peripheral nerves that were devoid of Schwann cell progenitors, and deletion of Erk1/2 in Schwann cell precursors caused disrupted differentiation and marked hypomyelination of axons. The Schwann cell phenotypes are similar to those reported in neuregulin-1 and ErbB mutant mice and neuregulin effects could not be elicited in glial precursors lacking Erk1/2. ERK/MAPK regulation of myelination was specific to Schwann cells, as deletion in oligodendrocyte precursors did not impair myelin formation, but reduced precursor proliferation. Our data suggest a tight linkage between developmental functions of ERK/MAPK signaling and biological actions of specific RTK-activating factors.
2010-10-16 | GSE24730 | GEO
Project description:SOX7 regulates MAPK/ERK-BIM mediated apoptosis in cancer cells
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Project description:Current therapeutic management of advanced melanoma patients largely depends on their BRAF mutation status. However, the vast heterogeneity of the tumors hampers the success of therapies targeting the MAPK/ERK pathway alone. Dissecting this heterogeneity will contribute to identifying key players in the oncogenic progression to tailor more effective therapies. We performed a comprehensive molecular and phenotypic characterization of a panel of patient-derived BRAFV600E-positive melanoma cell lines. Transcriptional profiling was used to identify groups of coregulated genes whose expression relates to an increased migratory potential and a higher resistance. A decrease in sensitivity to MAPK/ERK pathway inhibition with vemurafenib or trametinib corresponded with an increasing quiescence and migratory properties of the cells. This was accompanied by the loss of transcriptional signatures of melanocytic differentiation, and the gain of stem cell features that conferred highly-resistant/mesenchymal-like cells with increased xenobiotic efflux capacity. Nevertheless, targeting of the implicated ABC transporters did not improve the response to vemurafenib, indicating that incomplete BRAF inhibition due to reduced drug uptake is not a main driver of resistance. Rather, indifference to MAPK/ERK pathway inhibition arose from the activation of compensatory signaling cascades. The PI3K/AKT pathway in particular showed a higher activity in mesenchymal-like cells, conferring a lower dependency on MAPK/ERK signaling and supporting stem-like properties that could be reverted by dual PI3K/mTOR inhibition with dactolisib. In case of MAPK/ERK independency, therapeutic focus may be shifted to the PI3K/AKT pathway to overcome late-stage resistance in melanoma tumors that have acquired a mesenchymal phenotype.
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Project description:Deregulated cell migration and invasion, which are hallmarks of metastatic cancer cells, are correlated to structural and functional alterations of the actin cytoskeleton associated to a large panel of actin-binding proteins. Among these, the actin-bundling protein L-plastin, initially detected in leukocytes, is ectopically expressed in several solid tumours and is often considered as a metastatic marker. Phosphorylation of L-plastin on residue serine 5 (Ser5) has been shown to activate L-plastin and to be crucial for invasion and metastasis formation. Here, we investigate the signalling pathway leading to L-plastin Ser5 phosphorylation in four breast cancer cell lines. Whole genome microarray analysis comparing cell lines with different invasive capacities and corresponding L-plastin Ser5 phosphorylation levels revealed that genes of the MAPK/ERK pathway are differentially expressed. In line, in vitro kinase assays showed that MAPK/ERK pathway downstream kinases RSK1 and RSK2 are able to directly phosphorylate L-plastin on Ser5. In parallel to a knockdown approach, activation and inhibition studies of signalling molecules of the MAPK/ERK pathway, followed by computational modelling analysis, confirmed that RSK is an important activator of L-plastin in all four studied cell lines. Finally and rounding up our study, RSK knockdown significantly impaired migratory and invasive capacities of a selected invasive cell line, thus consolidating RSK as a promising therapeutic target in certain invasive carcinomas. Altogether, our data provide substantial evidence that the MAPK/ERK pathway is involved in L-plastin Ser5 phosphorylation in breast cancer cells with its downstream kinases RSK1 and RSK2 being able to directly phosphorylate L-plastin on Ser5.
2016-03-26 | E-MTAB-3487 | biostudies-arrayexpress
Project description:Inactivation of ERK/MAPK signaling in developing postmitotic cortical excitatory neurons results in a significent loss of Ctip2 positive layer 5 neurons and axon projections. Microarray dada revealed the reduced levels of a vast majority of layer V specific transcripts.
2016-02-02 | GSE75129 | GEO