Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

FTO Regulates Activation of Rho GTPases Signaling as N6-methyladenosine RNA Demethylase and an Rhotekin Partner Protein

ABSTRACT: Reversible RNA modification of N6-methyladenosine (m6A) plays a critical role in post-transcriptional gene regulation1-13. Although the fat mass and obesity-associated protein (FTO) has been previously shown to function as an m6A demethylase in nuclear RNA1,14, its exact function in disease pathogenesis remains a mystery. Here, we demonstrate that FTO suppresses the activation of Rho GTPase signaling via both its demethylation activity and specific interaction with Rho effector, Rhotekin (RTKN)15. The knockdown of FTO activates RhoA and RhoC, induces stress fibres, and accelerates cell migration. Endogenous RTKN is highly expressed in certain cancer and cancer-derived cell lines16,17 with overexpression of RTKN leading to moderate activation of Rho18. We further found that overexpression of RTKN blocks nuclear import of FTO and traps FTO in the cytoplasm to mediate m6A demethylation of cytosolic mRNA, thereby changing gene expression by preventing m6A-dependent mRNA decay and translation. Our results illustrate how FTO represses Rho activation through m6A demethylation and direct interaction with RTKN, and shed new light on FTO-dependent post-transcriptional gene regulation in RTKN overexpressed cancers, which may provide a new direction for developing anti-cancer therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83540 | GEO | 2018/12/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Quantitative Proteomics of Mouse Liver (FTO-KO,WT) in response to DEN injection

Project description:Single nucleotide polymorphisms in the FTO gene encoding a m6A demthylase are associated with obesity and cancer development. However, the functional role of FTO in the developemnt of progression of hepatocellular carcinoma (HCC) as a proteotypic obesity-associated cancer remains unclear. Here, we have generated mice with hepatic FTO deficiency (FTOL-KO) and subjected them to DEN induced HCC-development. FTOL-KO mice exhibit increased HCC burden. While control mice exhibit a dynamic regulation of FTO upon induction of liver damage, this response is abrogated in mice lacking FTO. Proteomic analyses revealed that liver damage-induced increases in FTO expression promotes m6A-demethylation of CUL4A reducing its protein expression. Functionally, knockdown of CUL4A restores the increased hepatocyte proliferation observed upon loss of FTO. Collectively, our study reveals a protective role for FTO-dependent dynamic m6A mRNA demethylation of CUL4A in the initiation of HCC development.

2020-11-03 | PXD018223 | Pride

The Obesity-associated Fto gene regulates activity of the dopaminergic midbrain circuitry [FTO KO]

Project description:Here we use MeRIP-Seq to analyze global adenosine methylation (m6A) in mRNAs in the midbrain and striatum of Fto-deficient mice. We find that Fto deficiency leads to increased methylation within a subset of mRNAs important for neuronal signaling, including many within the dopaminergic signaling pathway. Collectively, our results show that Fto regulates demethylation of specific mRNAs in vivo, and this activity relates to control of dopaminergic transmission. Profiling of m6A in midbrain and striatum from FTO knockout mice

2013-06-15 | E-GEOD-47216 | biostudies-arrayexpress

Elevated expression of wildtype RhoC promotes ErbB2- and Pik3ca-induced mammary tumor formation

Project description:Copy number gains in genes coding for Rho activating exchange factors as well as losses affecting genes coding for RhoGAP proteins are common in breast cancer, suggesting that elevated Rho signaling may play an important role. Extra copies and overexpression of RhoC also occur, although a role for RhoC overexpression in driving tumor formation has not been assessed in vivo. To this end, we report on the development of a Rosa26 (R26)-targeted Cre-conditional RhoC overexpression mouse (R26-RhoC). This mouse was crossed to two models for ERBB2/NEU+ breast cancer: one based on expression of an oncogenic ErbB2/Neu cDNA downstream of the endogenous ErbB2 promoter (FloxNeoNeuNT), the other, a metastatic model that is based on high-level expression from MMTV regulatory elements (NIC). RhoC overexpression dramatically enhanced mammary tumor formation in FloxNeoNeuNT mice but showed a more subtle effect in the NIC line, which forms multiple mammary tumors after a very short latency. Many mammary tumors that form in FloxNeoNeuNT mice show selection for increased NeuNT expression linked to high-level amplification of the ErbB2/NeuNT locus. In contrast, NeuNT overexpression did not require high-level amplification of ErbB2/NeuNT in RhoC-FloxNeoNeuNT lesions. RhoC overexpression also enhanced mammary tumor formation in a model for breast cancer induced by Pik3ca(H1047R). The transforming effect of RhoC was associated with epithelial/mesenchymal transition (EMT) in ErbB2/NeuNT and Pik3ca-H1047R systems. Thus, RhoC copy number gains with resultant overexpression contribute to breast tumor formation and/or progression.

2024-04-11 | GSE249601 | GEO

The Obesity-associated Fto gene regulates activity of the dopaminergic midbrain circuitry [WT]

2013-06-15 | E-GEOD-47215 | biostudies-arrayexpress

FTO demethyltion of N6-methyladenosine depends on the RRACH motif [m6A-seq]

Project description:The fat mass and obesity-associated (FTO) protein is a well-characterized demethylase that removes N6-methyladenosine (m6A) from animal mRNAs. However, it is unclear yet how the demethylation operates in living cells. In this study, we applied genome-wide approaches to study how FTO finds its demethylation targets in human cells. We overexpressed FTO in human HeLa cells, demonstrating that FTO effectively removes m6A from the RRACH motif enriched in the 3’UTR regions and leaves m6A at other motifs unaffected. RRACH elements are clearly enriched at FTO binding sites; however, m6A has a lower tendency to be removed from the FTO-bound RRACH. Taken together with the experimental validaton results, we propose a model in which FTO effectivly recognizes m6A-containing RRACH motifs in RNAs, leading to a faster demethylation and dissociation kinetic than the association, and consequently undectable FTO-mRNA association. However, when FTO binds to the non-m6A RRACH motif, the binding has a lower dissociation kinetics, yielding the detectable FTO binding signals which would enable FTO to have roles in regulating other mRNA processing events.

2020-03-22 | GSE101954 | GEO

FTO demethyltion of N6-methyladenosine depends on the RRACH motif [CLIP-seq]

2020-03-22 | GSE101953 | GEO

N6-methyladenosine modification is essential for prostate cancer cells

Project description:N6-methyladenosine (m6A) modification of messenger RNAs (mRNAs) is a pivotal mechanism controlling mRNA fate in cells. RNA m6A modification is regulated by the functional balance between methyltransferases and demethylases. Here we demonstrated that FTO-IT1 enhancer RNA (eRNA), a long non-coding RNA (lncRNA) transcribed from the last intron of FTO gene is significantly upregulated in CRPC and aggressive tumors compared to primary tumors. FTO-IT1 knockout by CRISPR/Cas9 almost completely blocks growth and G1-S cell cycle transition of both androgen-sensitive and castration-resistant prostate cancer cells. Meanwhile, the mRNA m6A was dramatically increased in FTO-IT knockout PCa cells and we identified FTO-IT1 as a binding partner of FTO. From m6A-seq, we unexpectedly found hypermethylated m6A associated with upregulated levels of the mRNAs for p53 signaling pathway genes in 22Rv1 prostate cancer cells. Mechanistic study showed that FTO-IT1 recruits FTO to the P53 target mRNA to promote their m6A demethylation, which leads to their degradation.

2023-07-09 | GSE189465 | GEO

Pilot Study 13C flux effects when RhoC or RhoA perturbed (13C BCs)

Project description:Rho-GTPases are small GTP-binding proteins that contribute to the epithelial-to-mesenchymal transition by regulating several cellular processes including organization of the actin cytoskeleton, cell motility, transcription, and cell proliferation. Overexpression of RhoC-GTPases (RhoC) in breast cancer has been implicated in poor disease prognosis due to increased cancer cells invasion, migration, and motility, which warranted its consideration as a therapeutic target for inhibiting breast cancer metastasis. Using silencing RNA (siRNA) molecules to knockdown RhoC expression is a promising approach to inhibit breast cancer metastases.

2015-02-11 | ST000282 | MetabolomicsWorkbench

FTO mediates LINE1 m6A demethylation and chromatin regulation in mESCs and mouse development

Project description:N6-methyladenosine (m6A) is the most abundant internal modification on mammalian messenger RNA (mRNA). It is installed by a writer complex and can be reversed by erasers such as the fat mass and obesity-associated protein (FTO). Despite extensive research, the primary physiological substrates of FTO in mammalian tissues and development remain elusive. Here, we show that FTO mediates m6A demethylation of long-interspersed element-1 (LINE1) RNA in mouse embryonic stem cells (mESCs), regulating LINE1 RNA abundance and the local chromatin state, which in turn modulates transcription of LINE1-containing genes. FTO-mediated LINE1 RNA m6A demethylation also plays regulatory roles in shaping chromatin state and gene expression during mouse oocyte and embryonic development. Our results suggest broad effects of LINE1 RNA m6A demethylation by FTO in mammals.

2022-05-05 | GSE151780 | GEO

N6-methyladenosine demethylation by the fat mass and obesity-associated gene (FTO) defines tyrosine kinase inhibitor resistance in leukemia

Project description:The discovery of activating mutations in receptor tyrosine kinases (RTKs) leads to clinical testing of RTK inhibitors (TKIs). However, the rapid acquisition of resistance limits TKI effectiveness. Here we establish TKI-resistant cells that propagate in the absence of RTK signaling. Relative to sensitive cells, TKI-resistant cells display decreased N6-methyladenosine (m6A), a ubiquitous and reversible modification on RNA, but upregulated fat mass and obesity-associated gene (FTO), an m6A demethylase. Notably, the naïve leukemia cell populations are heterogeneous with respect to FTO levels. Cells with higher intrinsic and transient FTO expression demonstrate reduction of m6A methylation and TKI sensitivity with higher tumorigenic. Genetic or pharmacological dysfunction of FTO increases m6A abundance sensitizing resistant cells to TKIs. Mechanistically, FTO-mediated m6A demethylation promotes mRNA stability and protein translation rate, upregulating oncogenes that are indispensable for survival and proliferation. Our findings therefore establish a role of FTO-dependent m6A demethylation for TKI-resistance, offering a therapeutic window for incorporating m6A modulators in counteracting acquired TKI resistance.

2018-11-14 | GSE80481 | GEO

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