PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA449083 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6955780_1.fastq.gz | Fastqsanger.gz | |||
| SRR6955780_2.fastq.gz | Fastqsanger.gz | |||
| SRR6955781_1.fastq.gz | Fastqsanger.gz | |||
| SRR6955781_2.fastq.gz | Fastqsanger.gz | |||
| SRR6955782_1.fastq.gz | Fastqsanger.gz |
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Project description:Overcoming cellular growth restriction, including the evasion of cellular senescence, is a hallmark of cancer. We report that PAK4 is overexpressed in all human breast cancer subtypes and associated with poor patient outcome. In mice, MMTV-PAK4 overexpression promotes spontaneous mammary cancer, while PAK4 gene depletion delays MMTV-PyMT driven tumors. Importantly, PAK4 prevents senescence-like growth arrest in breast cancer cells in vitro, in vivo and ex vivo, but is not needed in non-immortalized cells, while PAK4 overexpression in untransformed human mammary epithelial cells abrogates H-Ras-V12-induced senescence. Mechanistically, a PAK4 – RELB - C/EBPa axis controls the senescence-like growth arrest and a PAK4 phosphorylation residue (RELB-Se151) is critical for RELB-DNA interaction, transcriptional activity and expression of the senescence regulator C/EBPa. These findings establish PAK4 as a promoter of breast cancer that can overcome oncogene-induced senescence and reveal a selective vulnerability of cancer to PAK4 inhibition.
2019-07-09 | GSE112817 | GEO
Project description:Overcoming cellular growth restriction, including the evasion of cellular senescence, is a hallmark of cancer. We report that PAK4 is overexpressed in all human breast cancer subtypes and associated with poor patient outcome. In mice, MMTV-PAK4 overexpression promotes spontaneous mammary cancer, while PAK4 gene depletion delays MMTV-PyMT driven tumors. Importantly, PAK4 prevents senescence-like growth arrest in breast cancer cells in vitro, in vivo and ex vivo, but is not needed in non-immortalized cells, while PAK4 overexpression in untransformed human mammary epithelial cells abrogates H-RAS-V12-induced senescence. Mechanistically, a PAK4 - RELB - C/EBPβ axis controls the senescence-like growth arrest and a PAK4 phosphorylation residue (RELB-Ser151) is critical for RELB-DNA interaction, transcriptional activity and expression of the senescence regulator C/EBPβ. These findings establish PAK4 as a promoter of breast cancer that can overcome oncogene-induced senescence and reveal a selective vulnerability of cancer to PAK4 inhibition.
| S-EPMC6689091 | biostudies-literature
Project description:Thymic medullary epithelial cell (mTEC) expression of the autoimmune regulator AIRE, and of tissue-specific antigens, is controlled by members of the non-canonical NF-kB signalling pathway, including RelB and NF-kB2. Of the genes in this pathway, RelB-/- mice develop a particularly severe multi-organ autoimmune syndrome, resembling Foxp3-deficiency. RelB-/- mice have medullary atrophy and few mTECs but the mechanism is unknown. We show that RelB is required for expression of medullary chemokines and mTEC AIRE, selection of a diverse peripheral T cell repertoire, and for peripheral Foxp3+ Treg function. Vβ families of T cells infiltrating diseased peripheral organs and thymic Treg were similarly skewed. Surprisingly, medullary atrophy results from intra-thymic granulocyte infiltration, consequent upon the Th2-mediated autoimmune disease. Dominant tolerance corrects thymic inflammatory disease and loss of thymic function. We demonstrate a reversible RelB-dependent inflammatory mechanism for loss of central tolerance associated with medullary atrophy. Thymi from 4 RelB+/- mice and 3 RelB-/- mice were profiled by microarays
2012-12-27 | E-GEOD-43154 | biostudies-arrayexpress
Project description:Thymic medullary epithelial cell (mTEC) expression of the autoimmune regulator AIRE, and of tissue-specific antigens, is controlled by members of the non-canonical NF-kB signalling pathway, including RelB and NF-kB2. Of the genes in this pathway, RelB-/- mice develop a particularly severe multi-organ autoimmune syndrome, resembling Foxp3-deficiency. RelB-/- mice have medullary atrophy and few mTECs but the mechanism is unknown. We show that RelB is required for expression of medullary chemokines and mTEC AIRE, selection of a diverse peripheral T cell repertoire, and for peripheral Foxp3+ Treg function. Vβ families of T cells infiltrating diseased peripheral organs and thymic Treg were similarly skewed. Surprisingly, medullary atrophy results from intra-thymic granulocyte infiltration, consequent upon the Th2-mediated autoimmune disease. Dominant tolerance corrects thymic inflammatory disease and loss of thymic function. We demonstrate a reversible RelB-dependent inflammatory mechanism for loss of central tolerance associated with medullary atrophy.
2012-12-27 | GSE43154 | GEO
Project description:PAK4 has emerged as a promising target for anti-cancer drug development. However, its role in oxidative stress conditions remains elusive. We investigated the effects of PAK4 signaling on hepatic ischemia/reperfusion (I/R) injury. To elucidate molecular mechanisms, we performed RNA-sequencing analysis using littermate WT and hepatocyte-specific Pak4 KO mice in I/R condition. Transcriptomic analysis enabled us to find the main signaling nodes altered by Pak4 deficiency in close association with antioxidant response.
2022-04-20 | GSE200913 | GEO
Project description:Using multi-omic analyses, we identified PAK4 (P21 (RAC1) Activated Kinase 4) amplification and overexpression of Kinase PAK4 in a subset of bladder cancers. We confirmed the role of PAK4 in bladder cancer cell proliferation and invasion by in vitro experiments. Furthermore, our studies showed that PAK4 inhibitor is effective in curtailing bladder cancer cell growth. In order to understand the effect of PAK4 inhibition and knockdown on bladder cancer transcriptome, we performed RNA-sequencing of PAK4 siRNA transfected and PAK4 inhibitor (PF-3758309) treated bladder cancer cells (VM-CUB1). Analyses led to identification of direct targets of PAK4 in bladder cancer and associated pathways.
2020-04-20 | GSE130455 | GEO
Project description:PAK4 was knocked down in human glioblastoma (GBM)-associated endothelial cells (ECs) using CRISPR-Cas9/gRNA. RNA was isolated and analyzed by RNAseq. The effects of PAK4 knockout on gene expression were determined.
2020-09-13 | GSE154133 | GEO
Project description:p21-activated kinase 4 (PAK4) is a serine/threonine kinase critical during development and with a proposed role in cancer and related cellular processes, including cell proliferation, survival and migration. However, while a limited number of PAK4-interacting proteins have been identified, the PAK4 interactome has not been systematically characterized. Here, we employed iTRAQ-based quantitative mass spectrometry of PAK4-immunioprecipitations from three distinct isolated cellular fractions to comprehensively profile the PAK4 interactome in human. These data will provide a valuable resource for further investigations on the role of PAK4 in physiology and disease.
2018-10-27 | PXD004086 | Pride
Project description:Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of p21-activated kinase 4 (PAK4), and its potential as a new target in MM for clinical applications. PAK4 promoted MM cell growth and survival via activation of MM survival signaling pathways, including the MEK-ERK pathway. Furthermore, treatment with orally bioavailable PAK4 allosteric modulator (KPT-9274) significantly impacted MM cell growth and survival in a large panel of MM cell lines and primary MM cells alone and in the presence of bone marrow microenvironment. Intriguingly, we have identified FGFR3 as a novel binding partner of PAK4 and observed significant activity of KPT-9274 against t(4;14)-positive MM cells. These data support PAK4 as an oncogene in myeloma, and provide the rationale for the clinical evaluation of PAK4 modulator in myeloma.
2017-01-19 | GSE93745 | GEO