Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

JNK promotes epithelial cells anoikis by transcriptional and post-translational regulation of BH3-only proteins

ABSTRACT: Developmental morphogenesis, tissue injury, and oncogenic transformation can cause the detachment of epithelial cells. These cells are eliminated by a specialized form of apoptosis (anoikis). While the processes that contribute to this form of cell death have been studied, the underlying mechanisms remain unclear. Here we tested the role of the cJUN NH2-terminal kinase (JNK) signaling pathway using murine models with compound JNK-deficiency in mammary and kidney epithelial cells. These studies demonstrated that JNK is required for efficient anoikis in vitro and in vivo. Moreover, JNK-promoted anoikis required pro-apoptotic members of the BCL2 family of proteins. We show that JNK acts through a BAK/BAX-dependent apoptotic pathway by increasing BIM expression and phosphorylating BMF leading to death of detached epithelial cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE88856 | GEO | 2017/11/14

SECONDARY ACCESSION(S): PRJNA348813

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Gene expression of attached and suspended Bim-/- Bmf-/- murine kidney epithelial cells

Project description:Suspension-induced cell death, or anoikis, is implicated in different stages of breast development as well as tumor progression and metastasis. The pro-apoptotic BH3-only proteins BIM and BMF are known positive regulators of anoikis. We examined the gene expression changes that occur in BIM-/- BMF-/- cells during attachment and suspension. This study is supplemental to our work establishing a role for JNK in anoikis (Girnius N, Davis RJ. 2017. JNK promotes epithelial cell anoikis by transcriptional and post-translational regulation of BH3-only proteins. (2017) Cell Reports 21: 1910-1921; doi: 10.1016/j.celrep.2017.10.067)

2018-02-28 | GSE111221 | GEO

Mitochondrial E3 ubiquitin ligase MARCHF5 controls BAK function independently of BH3-only proteins

Project description:Intrinsic apoptosis is principally regulated by the BCL-2 family of proteins, but some non-BCL-2 proteins also serve as important regulators. To identify novel apoptosis regulators, we performed a genome-wide CRISPR-Cas9 library screen, and it identified the mitochondrial E3 ubiquitin ligase MARCHF5/MITOL/RNF153 as an important regulator of BAK apoptotic function. Deleting MARCHF5 in multiple BAX-deficient cell lines conferred profound resistance to BH3-mimetic drugs. The loss of MARCHF5 or its E3 ubiquitin ligase activity surprisingly drove BAK to adopt an active conformation, with resistance to BH3-mimetics afforded by the formation of inhibitory complexes with pro-survival proteins MCL-1 and BCL-XL. Importantly, these changes to BAK conformation and pro-survival association occurred independently of BH3-only proteins. This study identifies a mechanism by which MARCHF5 regulates apoptotic cell death and provides new insight into how cancer cells respond to BH3-mimetic drugs. These data also highlight the emerging role of ubiquitin signalling in apoptosis that may be exploited therapeutically.

2022-09-25 | PXD030246 | Pride

BMF repression keeps mitosis away from anoikis

Project description:FOXM1 repression increases mitotic death upon antimitotic chemotherapy through BMF upregulation

| PRJEB44770 | ENA

BRN2 expression increases anoikis resistance in melanoma.

Project description:Melanoma tumors are highly heterogeneous, comprising of many cell populations that vary in their potential for growth and invasion. Differential transcription factor expression contributes to these phenotypic traits. BRN2, a member of the POU domain family of transcription factors is thought to play important roles in melanoma invasion and metastasis. However, how BRN2 functions during the metastatic process of melanoma remains largely unknown. We therefore investigated the effects of BRN2 expression in melanoma cells with no or low constitutive expression using a doxycycline-inducible system. Induction of BRN2 expression led to reduced proliferation and partial resistance to an inhibitor of mutated BRAF. Whole genome profiling analysis revealed novel targets and signaling pathway changes related to prevention of cell death induced by detachment from the extracellular matrix, known as anoikis resistance. Further investigation confirmed increased survival of BRN2 expressing cell lines in non-adherent conditions. Functionally, expression of BRN2 promoted induction of c-MET levels as well as increased phosphorylation of STAT3. Treatment with crizotinib, a c-MET inhibitor, decreased cellular viability of BRN2 expressing cells under non-adherent conditions to death by anoikis. These results highlight the importance of a largely overlooked transcription factor in the progression and metastasis of melanoma, and may suggest a strategy to target BRN2 expressing cells resistant to therapy and cell death by anoikis.

2020-02-25 | GSE145806 | GEO

SPIB promotes anoikis resistance via elevated autolysosomal process in lung cancer cells [ChIP-seq]

Project description:Anoikis (detachment-induced cell death) is a specific type of programmed cell death which occurs in response to the loss of the correct extracellular matrix connections. Anoikis resistance is an important mechanism in cancer invasiveness and metastatic behavior. Autophagy, on the other hand, involves the degradation of damaged organelles and the recycling of misfolded proteins and intracellular components. However, the intersection of these two cellular responses in lung cancer cells has not been extensively studied. Here, we identified that upon matrix deprivation, the lymphocyte lineage-specific Ets transcription factor SPIB was activated and directly enhanced SNAP47 transcription in certain lung cancer cells. Loss of attachment-induced autophagy significantly increased anoikis resistance by SPIB activation. Consistent with this function, SPIB depletion by short hairpin RNA abrogated SNAP47 transcriptional activation upon matrix deprivation. Therefore, these data delineate an important role of SPIB in autophagy-mediated anoikis resistance in lung cancer cells. Accordingly, these findings suggest that manipulating SPIB-regulated pathways in vivo and evaluating the impact of anoikis resistance warrant further investigation.

2019-03-11 | GSE125561 | GEO

SPIB promotes anoikis resistance via elevated autolysosomal process in lung cancer cells [RNA-seq]

2019-03-11 | GSE106592 | GEO

Efficient Mammary Gland Involution Requires c-Jun N-terminal kinase

Project description:Involution returns the lactating mammary gland to a quiescent state after weaning. The mechanism of involution involves collapse of the mammary epithelial cell compartment. To test whether the cJUN NH2-terminal kinase (JNK) signal transduction pathway contributes to involution, we established mice with JNK deficiency in the mammary epithelium. We found that JNK is required for efficient involution. JNK deficiency did not alter the STAT3/5 or SMAD2/3 signaling pathways that have been previously implicated in this process. Nevertheless, JNK promotes the expression of genes that drive involution, including matrix metalloproteases, cathepsins, and BH3-only proteins. These data demonstrate that JNK has a key role in mammary gland involution post lactation.

2018-03-09 | GSE89495 | GEO

Gene expression signatures in anoikis-resistance of human prostate PC-3 cells

Project description:To investigate potential molecular targets that regulate metastasis and metabolism in anoikis-resistance of prostate cancer cells, we have establised anoikis-resistant prostate PC-3 cells with ultra-low attachment 6-well plates (Corning) and employed whole genome microarray expression profiling as a discovery platform to identify differentially expressed genes between anoikis-resistant PC-3 cells and corresponding parental cells.

2020-06-26 | GSE100629 | GEO

The transcription factor IRF4 represses pro-apoptotic BMF and BIM to licence Multiple Myeloma survival

Project description:The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for the survival of the plasma cell malignancy multiple myeloma (MM), although the mechanism by which this is achieved remains unknown. Here we have explored the genetic basis for IRF4 addiction through CRISPR-Cas9 genetic ablation of IRF4 across several MM cells lines. We report that IRF4 loss uniformly resulted in the upregulation of two related pro-apoptotic proteins belonging to the BH3-only subgroup of the BCL2 family: BCL2 modifying factor (BMF) and BCL2 interacting mediator of cell death (BIM). Direct IRF4 binding was identified in the proximal promoter region of both genes. Remarkably, genetic ablation of BMF alone or in combination with BIM largely prevented the cell death that follows IRF4 inactivation, establishing that IRF4 maintains MM survival through the direct transcriptional repression of BMF and BIM.

2022-12-22 | GSE148984 | GEO

Differential microRNA expression in adherent versus suspended MCF10A mammary epithelial cells

Project description:The ability to survive following loss of adhesion underpins cancer metastasis and significantly contributes triple negative breast cancer (TNBC) morbidity. Epithelial cells that form solid tumors must evade anoikis, a special type of cell death that occurs upon detachment from the extracellular matrix in order to colonize in distal sites. While there have been several advances in the understanding of the mechanisms by which cells undergo anoikis, the role for noncoding RNAs (ncRNAs) in this process is less well understood. An important role for microRNAs (miRNAs) in regulating anoikis is beginning to emerge, however in general the mechanisms by which miRNAs regulate anoikis are largely unknown. Thus we utilized the anoikis-sensitive immortalized mammary epithelial cell line, MCF10A to unbiasedly determine the microRNAs differentially regulated upon detachment.

2023-10-30 | GSE244857 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data