INPP4B protects from metabolic disease and obesity associated prostate neoplasia.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE134466 | GEO | 2021/02/04
REPOSITORIES: GEO
Similar Datasets
Project description:Activation and transcriptional reprograming of AR in advanced prostate cancer frequently overlaps with the loss of two tumor suppressors, INPP4B and PTEN, which are highly expressed in human and mouse prostate epithelium. While regulation of AR signaling by PTEN has been described by multiple groups, it is not known whether the loss of INPP4B affects AR activity. Using prostate cancer cell lines we showed that INPP4B regulates AR transcriptional activity and oncogenic signaling pathways Akt and PKC. Analysis of gene expression in prostate cancer patient cohorts showed a positive correlation between INPP4B expression and both AR mRNA levels and AR transcriptional output. Using an Inpp4b-/- mouse model, we demonstrated that INPP4B suppresses Akt and PKC signaling pathways and modulates AR transcriptional activity in normal mouse prostate. It has been previously shown that the high fat diet activates Akt pathway in mouse prostate. We showed that the loss of INPP4B further increases Akt phosphorylation in dorsolateral and ventral lobes of mice fed with the high fat diet. Remarkably, PTEN protein levels and phosphorylation of S380 were the same in Inpp4b-/- and WT males, suggesting that observed changes were due exclusively to the loss of INPP4B. Our data show that INPP4B modulates AR activity in normal prostate and its loss contributes to the AR-dependent transcriptional profile in prostate cancer.
2021-03-12 | GSE111725 | GEO
Project description:Phosphatase activities on PI(3,4,5)P3 and
PI(3,4)P2
This model describes the action of various phosphatases on
PI(3,4,5)P3 and PI(3,4)P2, in response to a stimulation by EGF. It
contains boolean switches to simulate knock-down and knock-out of
phosphatases as well as inhibition of PI3 kinase.
This model is described in the article:
PTEN Regulates PI(3,4)P2
Signaling Downstream of Class I PI3K
Mouhannad Malek, Anna Kielkowska,
Tamara Chessa, Karen E. Anderson, David Barneda, P?nar Pir,
Hiroki Nakanishi, Satoshi Eguchi, Atsushi Koizumi, Junko Sasaki,
Véronique Juvin, Vladimir Y. Kiselev, Izabella Niewczas,
Alexander Gray, Alexandre Valayer, Dominik Spensberger, Marine
Imbert, Sergio Felisbino, Tomonori Habuchi, Soren Beinke, Sabina
Cosulich, Nicolas Le Novère, Takehiko Sasaki, Jonathan
Clark, Phillip T. Hawkins and Len R. Stephens
Molecular Cell
Abstract:
The PI3K signaling pathway regulates cell growth and
movement and is heavily mutated in cancer. Class I PI3Ks
synthesize the lipid messenger PI(3,4,5)P3. PI(3,4,5)P3 can be
dephosphorylated by 3- or 5-phosphatases, the latter producing
PI(3,4)P2. The PTEN tumor suppressor is thought to function
primarily as a PI(3,4,5)P3 3-phosphatase, limiting activation
of this pathway. Here we show that PTEN also functions as a
PI(3,4)P2 3-phosphatase, both in vitro and in vivo. PTEN is a
major PI(3,4)P2 phosphatase in Mcf10a cytosol, and loss of PTEN
and INPP4B, a known PI(3,4)P2 4-phosphatase, leads to
synergistic accumulation of PI(3,4)P2, which correlated with
increased invadopodia in epidermal growth factor
(EGF)-stimulated cells. PTEN deletion increased PI(3,4)P2
levels in a mouse model of prostate cancer, and it inversely
correlated with PI(3,4)P2 levels across several EGF-stimulated
prostate and breast cancer lines. These results point to a role
for PI(3,4)P2 in the phenotype caused by loss-of-function
mutations or deletions in PTEN.
This model is hosted on
BioModels Database
and identified by:
MODEL1704190000.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
| MODEL1704190000 | BioModels
Project description:Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and higher rates of mortality. Anti-aging targeted small molecule screens have been carried outperformed many times, however, few have focused on endogenous metabolic intermediates—metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an conserved metabolite through eEukaryotes-conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggestsed that MI alleviates aging through its derivative PI(4,5)P2. MI and PI(4,5)P2 are precursors of PI(3,4,5)P3, which is negatively related to longevity. However, the mechanism study shows itslongevity effects could be fully blocked by a null-allele mutation of the tumor suppressor gene, daf-18 (homologous to mouse Pten), areand was independent of its classical pathway downstream elements, akt or daf-16., but Instead, we found MI effects on aging were dependent on its downstream mitophagy regulator pink-1. MI’s anti-aging effect is was also conserved in mouse model, implicatingindicating a conserved mechanism in mammals that may extend to human.
2020-08-03 | GSE154417 | GEO
Project description:Adipose tissue plays an important role in storing excess nutrients and preventing ectopic lipid accumulation in other organs. Obesity leads to excess lipid storage in adipocytes, resulting in the generation of stress signals and the derangement of metabolic functions. SIRT1 is an important regulatory sensor of nutrient availability in many metabolic tissues. Here we report that SIRT1 functions in adipose tissue to protect from the development of inflammation and obesity under normal feeding conditions, and the progression to metabolic dysfunction under dietary stress. Genetic ablation of SIRT1 from adipose tissue leads to gene expression changes that highly overlap with changes induced by high fat diet in wild type mice, suggesting that dietary stress signals inhibit the activity of SIRT1. Indeed, we show that high fat diet induces the cleavage of SIRT1 in adipose tissue by the inflammation-activated caspase-1, providing a link between dietary stress and predisposition to metabolic dysfunction. Four replicates from four different biological conditions: 1) SIRT1 wild-type fed low fat diet, 2) SIRT1 wild-type fed high fat diet, 3) SIRT1 knock-out fed low fat diet, 4) SIRT1 knock-out fed high fat diet
2012-12-21 | E-GEOD-30247 | biostudies-arrayexpress
Project description:We previously demonstrated that antisense oligonucleotide (ASO)-mediated knockdown of Mboat7, the gene encoding Membrane Bound O-Acyltransferase 7, in the liver and adipose tissue of mice promoted high fat diet-induced hepatic steatosis, hyperinsulinemia, and systemic insulin resistance. Thereafter, other groups showed that hepatocyte-specific genetic deletion of Mboat7 promoted striking fatty liver and NAFLD progression in mice but does not alter insulin sensitivity, suggesting the potential for cell autonomous roles. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. We generated floxed Mboat7 mice and created hepatocyte- and adipocyte-specific knockout mice using Cre-recombinase mice under the control of the albumin and adiponectin promoter, respectively. After chow and high fat diet feeding (60% kCal fat), mice were subjected to metabolic phenotyping and tissues to molecular workup and analysis. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. The expression of Mboat7 in white adipose tissue closely correlates with diet-induced obesity across a panel of ~100 inbred strains of mice fed a high fat/high sucrose diet. Moreover, we found that adipocyte-specific genetic deletion of Mboat7 is sufficient to promote hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, where Mboat7 plays a relatively minor role in maintaining arachidonic acid (AA)-containing PI pools, Mboat7 is the major source of AA-containing PI pools in adipose tissue. Our data demonstrate that MBOAT7 is a critical regulator of adipose tissue PI homeostasis, and adipocyte MBOAT7-driven PI biosynthesis is closely linked to hyperinsulinemia and insulin resistance in mice.
2023-05-10 | PXD039894 | Pride
Project description:The PIP3/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP3/PI(3,4)P2-phosphatase, PTEN. Despite huge investment, the drivers of the PI3K network in normal tissues and how they adapt to overactivation are unclear. We find that in healthy mouse prostate PI3K activity is driven by RTK/IRS signalling and constrained by pathway-feedback. In the absence of PTEN, the network is dramatically remodelled. A poorly understood, YXXM- and PIP3/PI(3,4)P2-binding PH domain-containing, adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP3, AKT-phosphorylation and growth in PTEN-null prostate. This was because PLEKHS1 evaded pathway-feedback and experienced enhanced PI3K- and SRC-family kinase-dependent phosphorylation of Y258XXM, eliciting PI3K-activation. hPLEKHS1-mRNA and activating-Y419-phosphorylation of hSRC correlated with PI3K-pathway activity in human prostate cancers. We propose that in PTEN-null cells, receptor-independent, SRC-dependent tyrosine-phosphorylation of PLEKHS1 creates positive-feedback that escapes homeostasis, drives PIP3-signalling and supports tumour progression.
2023-08-23 | PXD043239 | Pride
Project description:Metabolic dysfunction-associated fatty liver disease is the most prevalent liver disease and affects a quarter of the global population. Estrogens are associated to safeguard the liver from metabolic diseases. We fed male and female mice a control or high-fat diet for 13 weeks. Only male mice developed fatty livers. We injected a subset of male mice fed a high-fat diet with four different estrogen receptor (ER) agonists for the last three weeks of the high-fat diet, activating the nuclear ERalpha and ERbeta. Livers were collected and flash-frozen before RNA isolation, DNAse treatment, library preparation and sequencing on an Illumina NextSeq 500 instrument.
2024-02-22 | E-MTAB-11833 | biostudies-arrayexpress
Project description:Adipose tissue is a crucial metabolic organ maintaining energy homeostasis via catabolic and anabolic metabolism. As high-fat diet feeding leads to metabolic dysfunction, here, we aimed to study the effect of 8 weeks of high-fat diet feeding on WT mice and compare genes differentially regulated depending on the type of diets intaking.
2021-08-30 | GSE182930 | GEO
Project description:We found that hyperglycemia and elevated fatty acids in diabetes could activate protein kinase C-β isoforms and selectively induce insulin resistance via inhibiting vascular insulin signaling. To further investigate the effect of high fat diet and specific PKC β inactivation on STZ-induced atherosclerosis using the PKC β inhibitor, ruboxistaurin (RBX, or LY333531), ApoE-/- mice were used and fed with high fat diet (42% of fat Kcal) with or without RBX after onset of diabetes. Isolated total RNA from whole aortas of each group was used and analyzed for gene expression. The gene expression profiles were processed by using the Microarray Suite version 5.0 (MAS 5.0) with Affymetrix default analysis settings. ApoE-/- mice were used as a rodent atherosclerosis model. Isolated total RNA from aortas of each ApoE-/- mouse fed with high fat diet for 10 weeks after STZ-induced diabetes or control groups were used for preparation and hybridization on Affymetrix microarrays. There were total 4 different mice groups, which were fed with high fat diet with or without RBX. Each group had four individual mouse (N=4).
2016-03-26 | E-GEOD-79623 | biostudies-arrayexpress
Project description:While thousands of previously unannotated small and alternative open reading frames (alt-ORFs) have recently been revealed in the human genome, the functions of only a handful are currently known, leaving open the question of their biological significance as a class. Using a proteomic strategy for discovery of unannotated short open reading frames in human cells, we report the detection of alt-RPL36, a 148-amino acid protein co-encoded with and overlapping human RPL36. Alt-RPL36 interacts with TMEM24, which transports the phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] precursor phosphatidylinositol from the endoplasmic reticulum to the plasma membrane. Knock-out of alt-RPL36 in HEK 293T cells increased PI(4,5)P2 levels in the plasma membrane and upregulated the PI3K-AKT-mTOR signaling pathway. Remarkably, we find that four serine residues of alt-RPL36 are phosphorylated, and mutation of these four serines to alanine abolished the interaction with TMEM24 and regulation of PI3K signaling. These results implicate alt-RPL36 as a novel regulator of PI(4,5)P2 synthesis upstream of the PI3K-AKT-mTOR signaling pathway, and the first example of a phosphorylated alt-ORF product. More broadly, both alt-RPL36 and RPL36 regulate protein synthesis and cell growth via different molecular mechanisms – AKT signaling and ribosome composition, respectively. One human transcript can therefore express two sequence-independent polypeptides from overlapping ORFs that regulate the same processes via distinct mechanisms.
2020-12-07 | PXD018268 | Pride