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Group I Paks are essential for epithelial-mesenchymal transition in an Apc-driven mouse model of colorectal cancer

ABSTRACT: Group I Paks are essential for epithelial-mesenchymal transition in an Apc-driven mouse model of colorectal cancer

PROVIDER: PRJNA480307 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7501481_1.fastq.gz	Fastqsanger.gz
	SRR7501481_2.fastq.gz	Fastqsanger.gz
	SRR7501482_1.fastq.gz	Fastqsanger.gz
	SRR7501482_2.fastq.gz	Fastqsanger.gz
	SRR7501483_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Group I Paks are essential for epithelial-mesenchymal transition in an Apc-driven mouse model of colorectal cancer

Project description:p21-activated kinases (Paks) play an important role in oncogenic signaling pathways, and have therefore been considered as potential therapeutic targets in various cancers. Most studies of Pak function employ loss of function methods such as gene knock-out or knock-down, but these approaches result in loss of both the enzymatic and scaffolding properties of these proteins, and thus may not reflect the effects of small molecule inhibitors that block catalytic function. In this study we use a new transgenic mouse model in which a specific peptide inhibitor of Group I Paks (Pak1, -2, and -3) is conditionally expressed in response to Cre recombinase. Using this model, we show that inhibition of endogenous Pak function impedes the transition of adenoma to carcinoma in an Apc-driven mouse model of colorectal cancer. These effects are mediated by inhibition of Wnt signaling through reduced β-catenin activity as well as suppression of an epithelial-mesenchymal transition program mediated by miR-200 and Snai1. These results highlight the potential therapeutic role of Pak1 inhibitors in colorectal cancer and suggest new therapeutic strategies in this disease.

2018-08-02 | GSE116832 | GEO

Group I Paks are essential for epithelial- mesenchymal transition in an Apc-driven model of colorectal cancer.

Project description:p21-activated kinases (Paks) play an important role in oncogenic signaling pathways and have been considered as potential therapeutic targets in various cancers. Most studies of Pak function employ gene knock-out or knock-down methods, but these approaches result in loss of both enzymatic and scaffolding properties of these proteins, and thus may not reflect the effects of small molecule inhibitors. Here we use a transgenic mouse model in which a specific peptide inhibitor of Group I Paks is conditionally expressed in response to Cre recombinase. Using this model, we show that inhibition of endogenous Paks impedes the transition of adenoma to carcinoma in an Apc-driven mouse model of colorectal cancer. These effects are mediated by inhibition of Wnt signaling through reduced ?-catenin activity as well as suppression of an epithelial-mesenchymal transition program mediated by miR-200 and Snai1. These results highlight the potential therapeutic role of Pak1 inhibitors in colorectal cancer.

| S-EPMC6110733 | biostudies-literature

SUMO targets the APC/C in a phosphorylation-dependent manner to regulate transition from metaphase to anaphase

Project description:Signal transduction by Small Ubiquitin-like Modifier (SUMO) regulates a myriad of nuclear processes. Here, we report on the role of SUMO in mitosis in human cell lines. Knocking down the SUMO conjugation machinery resulted in a delay in mitosis and defects in mitotic chromosome separation. Searching for relevant SUMOylated proteins in mitosis, we identified the APC/C complex, a master regulator of metaphase to anaphase transition, as a SUMO target. The APC4 subunit is the major SUMO target in the complex, containing SUMO acceptor lysines at positions 772 and 798. SUMOylation increased APC/C ubiquitylation activity towards a subset of its targets, including the newly identified target KIF18B. Intriguingly, SUMOylation of APC/C was regulated by casein kinase driven phosphorylation of serines at positions 777 and 779. Combined, our findings demonstrate the importance of SUMO signal transduction for genome integrity during mitotic progression and reveal a triad of PTMs, cooperating to drive mitosis.

2018-09-19 | PXD006335 | Pride

Transcriptional profiling of murine intestine during APC-driven tumourigenesis

Project description:Transcriptional profiling of murine intestine during APC-driven tumourigenesis

| PRJNA513010 | ENA

Polyclonal interactions overcome fitness barriers in Apc-driven intestinal tumorigenesis

Project description:Polyclonal interactions overcome fitness barriers in Apc-driven intestinal tumorigenesis

| PRJNA1139121 | ENA

Polyclonal interactions overcome fitness barriers in Apc-driven intestinal tumorigenesis

Project description:Loss-of-function mutations in the tumour suppressor APC are an initial step in intestinal tumorigenesis. APC-mutant intestinal stem cells (ISCs) outcompete their wild type neighbours through the secretion of Wnt antagonists, accelerating the fixation and subsequent rapid clonal expansion of mutants. Reports of polyclonal intestinal tumours in patients and mouse models appear at odds with this process. Here we combine multicolour lineage tracing with chemical mutagenesis in mice to show that a large proportion of intestinal tumours have a multiancestral origin. Polyclonal tumours retain a structure comprising subclones with distinct Apc mutations and transcriptional states, driven predominantly by differences in KRAS and MYC signalling. These pathway level changes are accompanied by profound cancer stem cell phenotypic differences. Importantly, these findings are confirmed by introducing an oncogenic Kras mutation that results in predominantly monoclonal tumour formation. Further, polyclonal tumours have accelerated growth dynamics suggesting a link between polyclonality and tumour progression. Together, these findings demonstrate the role of interclonal interactions in promoting tumorigenesis through non-cell autonomous pathways dependent on the differential activation of oncogenic pathways between clones.

2024-08-30 | GSE272850 | GEO

The APC/CFZY-1/Cdc20 complex coordinates with OMA-1 to regulate the oocyte-to-embryo transition in C. elegans

Project description:During oocyte maturation and the oocyte-to-embryo transition, key developmental regulators such as RNA-binding proteins coordinate translation of particular mRNAs and related developmental processes by binding to their cognate maternal mRNAs. In the nematode C. elegans, these processes are regulated by a set of CCCH zinc finger proteins. OMA-1 and OMA-2 are two functionally redundant CCCH zinc finger proteins that turnover rapidly during the first embryonic cell division. These turnovers are required for proper transition from oogenesis to embryogenesis. A gain-of-function mutant of OMA-1, oma-1(zu405), stabilizes and delays degradation of OMA-1, resulting in delayed turnover and mis-segregation of other cell fate determinants, which eventually causes embryonic lethality. We performed a large-scale forward genetic screen to identify suppressors of the oma-1(zu405) mutant. We show here that multiple alleles affecting functions of various APC/C subunits, including MAT-1, MAT-2, MAT-3, EMB-30, and FZY-1, suppress the gain-of-function mutant of OMA-1. Mutations in APC/C genes prevent OMA-1 enrichment in P granules and correct delayed degradation of downstream cell fate determinants including PIE-1, POS-1, MEX-3, and MEG-1. Transcriptome analysis also suggested that overall transcription in early embryos occurred after introducing mutations in APC/C genes into the oma-1(zu405) mutant. We demonstrated that only the activator FZY-1, but not FZR-1, is incorporated in the APC/C complex to regulate the oocyte-to-embryo transition. Our findings suggested a genetic relationship linking the APC/C complex and OMA-1, and support a model in which the APC/C complex promotes P granule accumulation and modifies RNA binding of OMA-1 to regulate the oocyte-to-embryo transition process.

2021-10-02 | GSE181115 | GEO

C-FOS-driven basal to squamous cell transition

Project description:C-FOS-driven basal to squamous cell transition

| PRJNA707051 | ENA

Differential RNA-seq analysis comparing APC-defective and APC-restored SW480 colorectal cancer cells

Project description:Identify genes that are differentially regulated as a consequence of restoration of full-length functional APC in a colorectal cancer cell lines.

2016-02-01 | GSE76307 | GEO

Synthetic Essentiality of Tryptophan 2,3-dioxygenase 2 in APC-Mutated Colorectal Cancer I

Project description:We examined the pathways that are regulated by TDO2 in APC-deficient cancer cells by analyzing gene expression profiles of APC-WT and APC-KO MC38 cells that are transduced with inducible shTDO2 constructs. This study establishs that the TDO2-Kyn-AhR axis serves a critical role in promoting APC-deficient tumor growth via cancer cell autonomous (metabolism and proliferation) and non-autonomous mechanisms (tumor immunity).

2022-07-13 | GSE200908 | GEO

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