Browse
Submit Data
Databases
API
Help

Dataset Information

322 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Downregulation of LATS kinases alters p53 to promote cell migration

ABSTRACT: p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in non-transformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-κB subunit. Moreover, it partly shifts p53’s conformation and transcriptional output towards a state resembling cancer-associated p53 mutants, and endow p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are frequently downregulated in breast cancer; we propose that such downregulation might benefit cancer by converting p53 from a tumor suppressor into a tumor facilitator.

OTHER RELATED OMICS DATASETS IN: PRJNA300555

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Yair Pozniak

LAB HEAD: Tamar Geiger

PROVIDER: PXD003120 | Pride | 2018-10-25

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Publications

Down-regulation of LATS kinases alters p53 to promote cell migration.

Furth Noa N Bossel Ben-Moshe Noa N Pozniak Yair Y Porat Ziv Z Geiger Tamar T Domany Eytan E Aylon Yael Y Oren Moshe M

Genes & development 20151101 22

p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in nontransformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-κB subunit. Moreover, it partly shifts p53's conformation and transcriptional output toward a state resembling cancer-associated p53 mutants and endows p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are ...[more]

PMID: 26588988

Similar Datasets

Downregulation of LATS kinases alters p53 to promote cell migration

Project description:p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in non-transformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-?B subunit. Moreover, it partly shifts p53âs conformation and transcriptional output towards a state resembling cancer-associated p53 mutants, and endow p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are frequently downregulated in breast cancer; we propose that such downregulation might benefit cancer by converting p53 from a tumor suppressor into a tumor facilitator. MCF10A cells transfected with siRNA against LATS1/2 alone, p53 alone or LATS1/2 and p53 together. Two independent MCF10A batches provided biological replicates

2015-12-11 | E-GEOD-74493 | biostudies-arrayexpress

Downregulation of LATS kinases alters p53 to promote cell migration

Project description:p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in non-transformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-?B subunit. Moreover, it partly shifts p53’s conformation and transcriptional output towards a state resembling cancer-associated p53 mutants, and endow p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are frequently downregulated in breast cancer; we propose that such downregulation might benefit cancer by converting p53 from a tumor suppressor into a tumor facilitator.

2015-12-11 | GSE74493 | GEO

Mutant p53 promotes tumor progression by the endoplasmic reticulum UDPase ENTPD5

Project description:Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and often associated with progression from benign to invasive, metastatic stages. Mutations inactivate tumor suppression by p53 and endow the protein with novel gain-of-function (GOF) activities that actively promote tumor progression, metastasis and therapy resistance. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 (mutp53) target gene. A comprehensive pan-cancer analysis revealed a highly significant correlation between GOF p53 mutations and elevated expression of ENTPD5. Mechanistically, regulation of ENTPD5 by mutp53 is mediated by the histone H3 lysine 4 (H3K4) methyltransferase COMPASS complex. ENTPD5 has been shown to function in the endoplasmic reticulum as a UDPase to promote the N-glycosylation and folding of membrane proteins such as growth factor receptors and integrins. We show ENTPD5 to be a mediator of mutp53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals N-glycosylation in the endoplasmic reticulum as a novel mechanism underlying the progression of tumors with mutp53 that could provide new possibilities for treating cancers driven by GOF p53 mutations.

2016-11-29 | E-MTAB-4672 | biostudies-arrayexpress

Mutant p53 attenuates the anti-tumorigenic activity of fibroblasts secreted interferon (IFN) beta

2013-10-10 | GSE41477 | GEO

Mutant p53 attenuates the anti-tumorigenic activity of fibroblasts secreted interferon (IFN) beta

Project description:Mutations in the p53 tumor suppressor protein are highly frequent in tumors and often endow cells with tumorigenic capacities. We sought to examine a possible role for mutant p53 in the cross-talk between cancer cells and their surrounding stroma, which is a crucial factor affecting tumor outcome. Here we present a novel model which enables to individually monitor the response of cancer cells and stromal cells (fibroblasts) to co-culturing. We found that fibroblasts elicit the interferon beta (IFNβ) pathway when in contact with cancer cells, thereby inhibiting their migration. Mutant p53 in the tumor was able to alleviate this response via SOCS1 mediated inhibition of STAT1 phosphorylation. IFNβ on the other hand, reduced mutant p53 RNA levels by restricting its RNA stabilizer, WIG1. These data underscore mutant p53 oncogenic properties in the context of the tumor microenvironment and suggest that mutant p53 positive cancer patients might benefit from IFNβ treatment. As we planned to investigate the effect of mutant p53 we chose to work with lung cancer cells (H1299) which are null for p53 expression and introduce them with two p53 ‘hotsopt’ mutations residing within the DNA binding domain namely R175H and R248Q (H1299175 and H1299248 respectively, Figure 1A and B). The cells were then labeled with a red fluorescent protein (dsRed), while lung CAFs (HK3-T) were labeled with a green fluorescent protein (GFP). The labeled populations were co-cultivated for 24 hours and separated by Fluorescence Associated Cell Sorting (FACS) based on their specific fluorescent marker. RNA was extracted and samples were loaded on chips. Samples were loaded against a common reference sample which contained equal amount of RNA from all samples.

2013-10-10 | E-GEOD-41477 | biostudies-arrayexpress

Breast cancer plasticity is restrictedby a LATS1-NCOR1 repressive axis [MARS-seq]

Project description:The tumor suppressor LATS1, whose expression is often downregulated in human breast cancer, helps maintain luminal breast cancer cell identity by keeping basal-specific genes in a closed chromatin state, preventing their spurious activation. This is achieved via interaction of LATS1 with the NCOR1 nuclear corepressor and recruitment of HDAC1,driving histone H3K27 deacetylation near NCOR1-repressed “basal” genes. Consequently, decreased expression of LATS1 elevates the expression of such “basal” genes and promotes luminal-to-basal slippage.

2022-10-19 | GSE195715 | GEO

Breast cancer plasticity is restrictedby a LATS1-NCOR1 repressive axis [ATAC-seq]

2022-10-19 | GSE195714 | GEO

Identification of LATS transcriptional targets in HeLa cells using whole human genome oligonucleotide micorarray

Project description:Human LATS1 and LATS2 (LATS1/2) are tumor suppressors that have been shown to be mutated or downregulated in several human cancers including leukemia, lung, prostate and breast cancers. However, the precise mechanisms and the proteins modulated by LATS1/2 that are responsible for these events remain largely unknown. To elucidate potential signaling pathways, the current study investigated the expression profile in HeLa cells with reduced expression of LATS1/2. Using RNA-mediated intereference, both LATS1 and LATS2 were substantially knocked-down, and accordingly, this lead to an increase in multiple phenotypes associated with tumor progression, including enhanced cell proliferation, resistance to drug-induced cell death, and increase cell migration. Using whole human genome oligo (60-mer) arrays (Agilent), gene modulated by loss of LATS1/2 were identified and functionally grouped into categories including cell proliferation, cell death, cell adhesion and motility, as well as cell communication. Selected genes, including known tumor suppressor genes and oncogenes such as CDKN1A, WISP2, SLIT2, TP53INP1, BIRC4BP, SPRY2, SPRY4, SPRED1, FAT4,and CYR61 were confirmed by qRT-PCR to be significantly differentially expressed. Importantly, the collection of genes identified suggests that LATS1/2 functions through diverse mechanisms and multiple signaling pathways including the Hippo signaling pathway, as well as the p53, Ras-ERK, or WNT networks, in inhibit tumor progression.

2009-09-17 | GSE18138 | GEO

Mus musculus

Project description:A p53 super-tumor suppressor reveals a tumor suppressive p53-Ptpn14-Yap axis in pancreatic cancer

| PRJNA371474 | ENA

Stage-specific sensitivity to p53 restoration in lung cancer: cell line data

Project description:Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumor-suppressor pathways. The quest to personalize cancer medicine based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumor suppressors and activation of oncogenes are required for tumor maintenance. Mutations in the p53 tumor-suppressor pathway are a hallmark of cancer and significant efforts toward pharmaceutical reactivation of mutant p53 pathways are underway1-3. Here we show that restoration of p53 in established murine lung tumors leads to significant but incomplete tumor cell loss specifically in malignant adenocarcinomas but not in adenomas. Also, we define amplification of MAPK signaling as a critical determinant of malignant progression. The differential response to p53 restoration depends on activation of the Arf tumor suppressor downstream of hyperactive MAPK signaling. We propose that p53 naturally limits malignant progression by responding to increased oncogenic signaling, but is unresponsive to low levels of oncogene activity that are sufficient for early stages of lung tumor development. These data suggest that restoration of pathways important in tumor progression, as opposed to initiation, may lead to incomplete tumor regression due to the stage-heterogeneity of tumor cell populations. 3 cell lines each treated with Tamoxifen or EtOH vehicle. Tamoxifen treatment results in reactivation of p53 expression

2010-11-24 | E-GEOD-23873 | biostudies-arrayexpress

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