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HEK293T MS - Representing dynamic biological networks with multi-scale probabilistic models

ABSTRACT: As an example of a comprehensive model of signal transduction, we provide a Wnt network that shows remarkable robustness under a range of phenotypical and pathological conditions. Its simulation allows the clarification of controversially discussed molecular mechanisms of Wnt signalling by predicting wet-lab measurements. A loss of Rac1 (Ras-related C3 botulinum toxin substrate 1) or JNK2 affected the TCF/LEF reporter whereas a loss of JNK1 had only mild effects, likely due to low abundance of JNK1.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Kidney

SUBMITTER: Johann Kraus

LAB HEAD: Hans A. Kestler

PROVIDER: PXD011835 | Pride | 2019-11-12

REPOSITORIES: Pride

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	CUPro18461.raw	Raw
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Representing dynamic biological networks with multi-scale probabilistic models.

Groß Alexander A Kracher Barbara B Kraus Johann M JM Kühlwein Silke D SD Pfister Astrid S AS Wiese Sebastian S Luckert Katrin K Pötz Oliver O Joos Thomas T Van Daele Dries D De Raedt Luc L Kühl Michael M Kestler Hans A HA

Communications biology 20190117

Dynamic models analyzing gene regulation and metabolism face challenges when adapted to modeling signal transduction networks. During signal transduction, molecular reactions and mechanisms occur in different spatial and temporal frames and involve feedbacks. This impedes the straight-forward use of methods based on Boolean networks, Bayesian approaches, and differential equations. We propose a new approach, ProbRules, that combines probabilities and logical rules to represent the dynamics of a ...[more]

PMID: 30675519

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Project description:During canonical Wnt signalling the activity of nuclear beta-catenin is largely mediated by the TCF/LEF family of transcription factors. To challenge this view we used the CRISPR/Cas9 genome editing approach to generate HEK 293T cell clones simultaneously carrying loss-of-function alleles of all four TCF/LEF genes. Exploiting unbiased whole transcriptome sequencing studies, we found that a subset of beta-catenin transcriptional targets did not require TCF/LEF factors for their regulation. Consistent with this finding, we observed in a genome-wide analysis that beta-catenin occupied specific genomic regions in the absence of TCF/LEF. Finally, we revealed the existence of a transcriptional activity of beta-catenin that specifically appears when TCF/LEF factors are absent, and refer to this as beta-catenin-GHOST response. Collectively, this study uncovers a previously neglected modus operandi of beta-catenin that bypasses the TCF/LEF transcription factors.

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TCF/LEF dependent and independent regulation of Wnt/beta-catenin transcription

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Gene Expression Analysis of WT and dnTCF4-expressing Short-Term Hematopoietic Stem Cells (ST-HSC)

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Project description:The forkhead box transcription factor FOXQ1 is aberrantly induced in various cancers, and contributes to tumour growth and metastasis. It has been suggested that the oncogenic potential of FOXQ1 may be explained by its activation of the Wnt/β-catenin signalling pathway.However, the mode of action of FOXQ1 in the Wnt pathway remains to be resolved. Here we report that FOXQ1 is bimodal transcriptional activator of Wnt target gene expression in normal and cancer cells. Using co-immunoprecipitation, proximity proteomics, and reporter assays, we show that FOXQ1 engages the Wnt transcriptional complex to promote gene expressionvia TCF/LEF transcription factors.

2022-10-05 | PXD030464 | Pride

The oncogenic transcription factor FOXQ1 is a bimodal regulator of Wnt target genes

Project description:The forkhead box transcription factor FOXQ1 is aberrantly induced in various cancers, and contributes to tumour growth and metastasis. It has been suggested that the oncogenic potential of FOXQ1 may be explained by its activation of the Wnt/β-catenin signalling pathway. However, the mode of action of FOXQ1 in the Wnt pathway remains to be resolved. Here we report that FOXQ1 is bimodal transcriptional regulator of Wnt target gene expression in normal and cancer cells. Using co-immunoprecipitation, proximity proteomics, and reporter assays, we show that FOXQ1 partly engages the Wnt transcriptional complex to promote gene expression via TCF/LEF transcription factors.

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Non-coding RNAs Activated in Hepatoblastoma

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The fusion protein SS18-SSX1 employs core Wnt pathway transcription factors to induce a partial Wnt signature in synovial sarcoma

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The fusion protein SS18-SSX1 employs core Wnt pathway transcription factors to induce a partial Wnt signature in synovial sarcoma

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