Browse
Submit Data
Databases
API
Help

Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

0 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-?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

ORGANISM(S): Homo sapiens

SUBMITTER: Noa Bossel Ben-Moshe

PROVIDER: E-GEOD-74493 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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-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.

2018-10-25 | PXD003120 | Pride

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

LATS1 and LATS2 suppress breast cancer progression by maintaining cell identity and metabolic state [mouse]

Project description:Deregulated activity of the LATS tumor suppressors has broad implications on cellular and tissue homeostasis. We examined the consequences of downregulation of either LATS1 or LATS2 in breast cancer. Consistent with their proposed tumor suppressive roles, expression of both paralogs is significantly downregulated in human breast cancer, and loss of either paralog accelerated mammary tumorigenesis in mice. However, each paralog had a distinct impact on breast cancer. Thus, LATS2 depletion in luminal B tumors resulted in metabolic rewiring, with increased glycolysis and reduced PPARg signaling. Furthermore, pharmacological activation of PPARg elicited LATS2-dependent death in luminal B-derived cells. In contrast, LATS1 depletion augmented cancer cell plasticity, skewing luminal B tumors towards increased expression of basal-like features, in association with increased resistance to hormone therapy. Hence, these two closely related paralogs play distinct roles in protection against breast cancer; tumors with reduced expression of either LATS1 or LATS2 may rewire signaling networks differently and thus respond differently to anti-cancer treatments.

2018-10-28 | GSE116817 | GEO

LATS1 and LATS2 suppress breast cancer progression by maintaining cell identity and metabolic state [human]

2018-10-28 | GSE116816 | 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

The Hippo pathway kinase LATS1 scaffolds Beclin1 in autophagy regulation in hepatocellular carcinoma

Project description:Autophagy perturbation represents an emerging therapeutic strategy in cancer. The mammalian Hippo pathway is an evolutionary conserved tumor suppressive network, where the kinases LATS1/2 phosphorylate and inactivate oncogenic YAP/TAZ. Here, we demonstrated a pro-survival role of LATS1, but not LATS2, in hepatocellular carcinoma cells in response to sorafenib, a standard care of advanced HCC. Transcriptomic analysis revealed a restrictive role of LATS1 in autophagy regulation in HCC cells. Further, we found that the autophagy regulation by LATS1 was independent of its kinase activity. Instead, LATS1 stabilized autophagy core-machinery component Beclin 1 via promoting a non-canonical form of K27-linked ubiquitination, and consequently, inactive Beclin 1 self-dimer, in a E3 ligase NEDD4 dependent manner. Our study highlights a functional diversity between LATS1 and LATS2 and uncovers a scaffolding role of LATS1 in mediating a cross-talk between Hippo signalling and autophagy in HCC and therapy response.

2019-11-13 | GSE117116 | GEO

Expression profiling in primary embryonic fibroblasts deficient for the N-terminal truncation of Lats1

Project description:Lats1 and Lats2 are the mediators of the Hippo pathway that regulates tissue growth and proliferation. Lats1 and Lats2 kinases share 85% sequence identity in the kinase domain. However, their non-kinase regions at the N-terminus are distinct except for Lats conserved domain 1 (LCD1) and LCD2, suggesting that their N-terminal regions are important for Lats1/2-specific functions. In this study, we generated Lats1 knockout mice disrupting the N-terminal region containing LCD1 (Lats1ΔN/ΔN). We show that some Lats1ΔN/ΔN mice were born safely and grew normally. However, mouse embryonic fibroblasts (MEFs) from Lats1ΔN/ΔN mice displayed drastic defects in mitosis, showing enhanced centrosome overduplication, chromosomal misalignment, multipolar spindle formation, chromosome bridging, and cytokinesis failure. Moreover, they displayed accelerated cell cycle and cell growth bypassing a cell-cell contact inhibition like tumor cells, and exhibited anchorage independent growth. Indeed, Lats1ΔN/ΔN MEFs produced tumors in nude mice after subcutaneous injection, although the tumor growth rate was much slower than ordinary cancer cells. Furthermore, Yap, the key transcriptional co-activator in the Hippo pathway, was overexpressed and retained stable in Lats1ΔN/ΔN MEFs under high cell density, and expression of Lats2 mRNA were down-regulated.

2012-12-17 | GSE37871 | GEO

Expression profiling in primary embryonic fibroblasts deficient for the N-terminal truncation of Lats1

Project description:Lats1 and Lats2 are the mediators of the Hippo pathway that regulates tissue growth and proliferation. Lats1 and Lats2 kinases share 85% sequence identity in the kinase domain. However, their non-kinase regions at the N-terminus are distinct except for Lats conserved domain 1 (LCD1) and LCD2, suggesting that their N-terminal regions are important for Lats1/2-specific functions. In this study, we generated Lats1 knockout mice disrupting the N-terminal region containing LCD1 (Lats1M-NM-^TN/M-NM-^TN). We show that some Lats1M-NM-^TN/M-NM-^TN mice were born safely and grew normally. However, mouse embryonic fibroblasts (MEFs) from Lats1M-NM-^TN/M-NM-^TN mice displayed drastic defects in mitosis, showing enhanced centrosome overduplication, chromosomal misalignment, multipolar spindle formation, chromosome bridging, and cytokinesis failure. Moreover, they displayed accelerated cell cycle and cell growth bypassing a cell-cell contact inhibition like tumor cells, and exhibited anchorage independent growth. Indeed, Lats1M-NM-^TN/M-NM-^TN MEFs produced tumors in nude mice after subcutaneous injection, although the tumor growth rate was much slower than ordinary cancer cells. Furthermore, Yap, the key transcriptional co-activator in the Hippo pathway, was overexpressed and retained stable in Lats1M-NM-^TN/M-NM-^TN MEFs under high cell density, and expression of Lats2 mRNA were down-regulated. Total RNAs were extracted from MEFs under high or low cell density using miRNeasy extraction kit (Qiagen). A Dye-swapped experiment was performed by hybridizing complimentary RNA (cRNA) labeled with either Cyanine (Cy) -3 or Cy-5 (Perkin-Elmer) onto Whole Mouse Genome Oligo Microarray (G4122F; Agilent Technologies). Co-hybridizations were performed and data from Cy3 or Cy5 channels were analyzed as normalized signal intensities rather than as log ratios corresponding to each array.

2012-12-17 | E-GEOD-37871 | biostudies-arrayexpress

Deletion of Lats1/2 in adult kidney epithelia leads to renal cell carcinoma

Project description:We characterized the transcriptomes of both primary tumors and lung metastases tha developed in mice following deletion of Lats1 and Lats2 from Slc34a1-expressing cells as well as tumors arising from kidney allografts of and immortalized Lats1-/-;Lats2-/- cell line derived from the renal papilla.

2021-01-15 | GSE164879 | GEO

Transcription profiling by array of human MCF10A cells expressing YAP to identify the targets of the YAP oncogene

Project description:YAP is an oncogene and an inducer of Epithelial-to-Mesenchymal Transition (EMT). We used microarrays to detail the global program of gene expression to identify YAP target genes. PUBLICATION ABSTRACT:; The Hippo pathway defines a novel signaling cascade regulating cell proliferation and survival in Drosophila, which involves the negative regulation of the transcriptional coactivator Yorkie by the kinases Hippo and Warts. We have recently shown that the human ortholog of Yorkie, YAP, maps to a minimal amplification locus in mouse and human cancers, and that it mediates dramatic transforming activity in MCF10A primary mammary epithelial cells. Here we show that LATS proteins (mammalian orthologs of Warts) interact directly with YAP in mammalian cells and that ectopic expression of LATS1, but not LATS2, effectively suppresses the YAP phenotypes. Furthermore, shRNA-mediated knockdown of LATS1 phenocopies YAP overexpression. Since this effect can be suppressed by simultaneous YAP knockdown, it suggests that YAP is the primary target of LATS1 in mammalian cells. Expression profiling of genes induced by ectopic expression of YAP or by knockdown of LATS1 reveals a subset of potential Hippo pathway targets implicated in epithelial-to-mesenchymal transition (EMT), suggesting that this is a key feature of YAP signaling in mammalian cells. Experiment Overall Design: MCF10A cells were infected with retrovirus constructs (vector or YAP) and puromycin was used to select for transduced cells. Cells were split and grown to ~60-75%% confluency at which point they were harvested for RNA. Vector vs. YAP comparison was done in duplicate.

2008-06-11 | E-GEOD-10196 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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