Perret C

References (9)

Title : NOTUM from Apc-mutant cells biases clonal competition to initiate cancer - Flanagan_2021_Nature__
Author(s) : Flanagan DJ , Pentinmikko N , Luopajarvi K , Willis NJ , Gilroy K , Raven AP , McGarry L , Englund JI , Webb AT , Scharaw S , Nasreddin N , Hodder MC , Ridgway RA , Minnee E , Sphyris N , Gilchrist E , Najumudeen AK , Romagnolo B , Perret C , Williams AC , Clevers H , Nummela P , Lahde M , Alitalo K , Hietakangas V , Hedley A , Clark W , Nixon C , Kirschner K , Jones EY , Ristimaki A , Leedham SJ , Fish PV , Vincent JP , Katajisto P , Sansom OJ
Ref : Nature , : , 2021
Abstract : The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling(1), but reduced secretion of WNT ligands increases the ability of Apc-mutant intestinal stem cells to colonize a crypt (known as fixation)(2). Here we investigated how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We found that Apc-mutant cells are enriched for transcripts that encode several secreted WNT antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppressed the growth of wild-type organoids in a NOTUM-dependent manner. Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the proliferation of surrounding wild-type crypt cells and drove their differentiation, thereby outcompeting crypt cells from the niche. Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expand and form intestinal adenomas. We identify NOTUM as a key mediator during the early stages of mutation fixation that can be targeted to restore wild-type cell competitiveness and provide preventative strategies for people at a high risk of developing colorectal cancer.
ESTHER : Flanagan_2021_Nature__
PubMedSearch : Flanagan_2021_Nature__
PubMedID: 34079124
Gene_locus related to this paper: human-NOTUM

Title : Notum Deacylates Octanoylated Ghrelin - Zhao_2021_Mol.Metab__101201
Author(s) : Zhao Y , Schuhmacher LN , Roberts M , Kakugawa S , Bineva-Todd G , Howell S , O'Reilly N , Perret C , Snijders AP , Vincent JP , Jones EY
Ref : Mol Metab , :101201 , 2021
Abstract : OBJECTIVES: The only proteins known to be modified by O-linked lipidation are Wnts and ghrelin, and enzymatic removal of this post-translational modification inhibits ligand activity. Indeed, the Wnt-deacylase activity of Notum is the basis of its ability to act as a feedback inhibitor of Wnt signalling. Whether Notum also deacylates ghrelin has not been determined. METHODS: We used mass-spectrometry to assay ghrelin deacylation by Notum and co-crystallisation to reveal enzyme-substrate interactions at the atomic level. CRISPR/Cas technology was used to tag endogenous Notum and assess its localisation in mice while liver-specific Notum knock-out mice allowed us to investigate the physiological role of Notum in modulating the level of ghrelin deacylation. RESULTS: Mass-spectrometry detected the removal of octanoyl from ghrelin by purified active Notum, but not by an inactive mutant. The 2.2 A resolution crystal structure of the Notum-ghrelin complex shows the octanoyl lipid is accommodated in the hydrophobic pocket of Notum. The knock-in allele expressing HA-tagged Notum reveals that Notum is produced in the liver and present in the bloodstream, albeit at a low level. Liver-specific inactivation of Notum in animals fed with a high fat diet leads to a small but significant increase in acylated ghrelin in the circulation, while no such increase is seen in wildtype animals on the same diet. CONCLUSIONS: Overall our data demonstrate Notum can act as a ghrelin deacylase, and that this may be physiologically relevant under high fat diet conditions. Our work therefore adds Notum to the list of enzymes, including butylcholineasterase and other carboxylesterases, that modulate the acylation state of ghrelin. The contribution of multiple enzymes could help tune the activity of this important hormone to a wide range of physiological conditions.
ESTHER : Zhao_2021_Mol.Metab__101201
PubMedSearch : Zhao_2021_Mol.Metab__101201
PubMedID: 33647468
Gene_locus related to this paper: human-NOTUM

Title : Osteocyte- and late Osteoblast-derived NOTUM Reduces Cortical Bone Mass in Mice - Nilsson_2021_Am.J.Physiol.Endocrinol.Metab__
Author(s) : Nilsson KH , Henning P , El Shahawy M , Wu J , Koskela A , Tuukkanen J , Perret C , Lerner UH , Ohlsson C , Moverare-Skrtic S
Ref : American Journal of Physiology Endocrinol Metab , : , 2021
Abstract : Osteoporosis is a common skeletal disease, with increased risk of fractures. Currently available osteoporosis treatments reduce the risk of vertebral fractures, mainly dependent on trabecular bone, whereas the effect on non-vertebral fractures, mainly dependent on cortical bone, is less pronounced. WNT signaling is a crucial regulator of bone homeostasis, and the activity of WNTs is inhibited by NOTUM, a secreted WNT lipase. We previously demonstrated that conditional inactivation of NOTUM in all osteoblast lineage cells increases the cortical but not the trabecular bone mass. The aim of the present study was to determine if NOTUM increasing cortical bone is derived from osteoblast precursors/early osteoblasts or from osteocytes/late osteoblasts. First, we demonstrated Notum mRNA expression in Dmp1-expressing osteocytes and late osteoblasts in cortical bone using in situ hybridization. We then developed a mouse model with inactivation of NOTUM in Dmp1 expressing osteocytes and late osteoblasts (Dmp1-creNotum(flox/flox) mice). We observed that the Dmp1-creNotum(flox/flox) mice displayed a substantial reduction of Notum mRNA in cortical bone, resulting in increased cortical bone mass and decreased cortical porosity in femur, but no change in trabecular bone volume fraction (BV/TV) in femur or in the lumbar vertebrae L5 in Dmp1-creNotum(flox/flox) mice as compared to control mice. In conclusion, osteocytes and late osteoblasts are the principal source of NOTUM in cortical bone, and NOTUM derived from osteocytes/late osteoblasts reduces cortical bone mass. These findings demonstrate that inhibition of osteocyte/late osteoblast-derived NOTUM might be an interesting pharmacological target to increase cortical bone mass and reduce non-vertebral fracture risk.
ESTHER : Nilsson_2021_Am.J.Physiol.Endocrinol.Metab__
PubMedSearch : Nilsson_2021_Am.J.Physiol.Endocrinol.Metab__
PubMedID: 33749332
Gene_locus related to this paper: human-NOTUM , mouse-notum

Title : Osteoblast-derived NOTUM reduces cortical bone mass in mice and the NOTUM locus is associated with bone mineral density in humans - Moverare-Skrtic_2019_FASEB.J__fj201900707R
Author(s) : Moverare-Skrtic S , Nilsson KH , Henning P , Funck-Brentano T , Nethander M , Rivadeneira F , Coletto Nunes G , Koskela A , Tuukkanen J , Tuckermann J , Perret C , Souza PPC , Lerner UH , Ohlsson C
Ref : FASEB Journal , :fj201900707R , 2019
Abstract : Osteoporosis is a common skeletal disease, affecting millions of individuals worldwide. Currently used osteoporosis treatments substantially reduce vertebral fracture risk, whereas nonvertebral fracture risk, mainly caused by reduced cortical bone mass, has only moderately been improved by the osteoporosis drugs used, defining an unmet medical need. Because several wingless-type MMTV integration site family members (WNTs) and modulators of WNT activity are major regulators of bone mass, we hypothesized that NOTUM, a secreted WNT lipase, might modulate bone mass via an inhibition of WNT activity. To characterize the possible role of endogenous NOTUM as a physiologic modulator of bone mass, we developed global, cell-specific, and inducible Notum-inactivated mouse models. Notum expression was high in the cortical bone in mice, and conditional Notum inactivation revealed that osteoblast lineage cells are the principal source of NOTUM in the cortical bone. Osteoblast lineage-specific Notum inactivation increased cortical bone thickness via an increased periosteal circumference. Inducible Notum inactivation in adult mice increased cortical bone thickness as a result of increased periosteal bone formation, and silencing of Notum expression in cultured osteoblasts enhanced osteoblast differentiation. Large-scale human genetic analyses identified genetic variants mapping to the NOTUM locus that are strongly associated with bone mineral density (BMD) as estimated with quantitative ultrasound in the heel. Thus, osteoblast-derived NOTUM is an essential local physiologic regulator of cortical bone mass via effects on periosteal bone formation in adult mice, and genetic variants in the NOTUM locus are associated with BMD variation in adult humans. Therapies targeting osteoblast-derived NOTUM may prevent nonvertebral fractures.-Moverare-Skrtic, S., Nilsson, K. H., Henning, P., Funck-Brentano, T., Nethander, M., Rivadeneira, F., Coletto Nunes, G., Koskela, A., Tuukkanen, J., Tuckermann, J., Perret, C., Souza, P. P. C., Lerner, U. H., Ohlsson, C. Osteoblast-derived NOTUM reduces cortical bone mass in mice and the NOTUM locus is associated with bone mineral density in humans.
ESTHER : Moverare-Skrtic_2019_FASEB.J__fj201900707R
PubMedSearch : Moverare-Skrtic_2019_FASEB.J__fj201900707R
PubMedID: 31307226
Gene_locus related to this paper: human-NOTUM

Title : Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity - Soethoudt_2017_Nat.Commun_8_13958
Author(s) : Soethoudt M , Grether U , Fingerle J , Grim TW , Fezza F , De Petrocellis L , Ullmer C , Rothenhausler B , Perret C , van Gils N , Finlay D , MacDonald C , Chicca A , Gens MD , Stuart J , de Vries H , Mastrangelo N , Xia L , Alachouzos G , Baggelaar MP , Martella A , Mock ED , Deng H , Heitman LH , Connor M , Di Marzo V , Gertsch J , Lichtman AH , Maccarrone M , Pacher P , Glass M , van der Stelt M
Ref : Nat Commun , 8 :13958 , 2017
Abstract : The cannabinoid CB2 receptor (CB2R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed and widely used to target CB2R, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CB2R ligands to date. In a collaborative effort between multiple academic and industry laboratories, we identify marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects. We reach a consensus that HU910, HU308 and JWH133 are the recommended selective CB2R agonists to study the role of CB2R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research.
ESTHER : Soethoudt_2017_Nat.Commun_8_13958
PubMedSearch : Soethoudt_2017_Nat.Commun_8_13958
PubMedID: 28045021

Title : Generation of Mice with Hepatocyte-Specific Conditional Deletion of Notum - Canal_2016_PLoS.One_11_e0150997
Author(s) : Canal F , Charawi S , Grimber G , Houbron C , Drouet V , Colnot S , Terris B , Cavard C , Perret C
Ref : PLoS ONE , 11 :e0150997 , 2016
Abstract : BACKGROUND: Fine tuning of the Wnt/beta-catenin signaling pathway is essential for the proper development and function of the liver. Aberrant activation of this pathway is observed in 20%-40% of hepatocellular carcinomas (HCC). Notum encodes a secreted Wnt deacylase that inhibits Wnt activity and thereby restricts the zone of activation of Wnt/beta-catenin signaling. An important role of NOTUM has been described in development in drosophila, planaria and zebrafish, but its role in the mammalian liver is unknown. Notum is required for spatial control of the Wnt/beta-catenin signaling in several animal models and the Wnt/beta-catenin pathway contributes to liver patterning involved in metabolic zonation. Therefore, Notum may be involved in the liver patterning induced by the Wnt/beta-catenin signaling during the adult stage. METHODOLOGY/PRINCIPAL FINDINGS: We generated a conditional Notum knockout mouse mutant to study the effect of the deletion of Notum in the liver. We show that Notum is a direct target of the Wnt/beta-catenin signaling in the liver. Liver-specific deletion of Notum did not modify liver zonation, but Notum deletion had a long-term effect on mouse physiology. In particular, male mutant mice developed metabolic disorders. CONCLUSION: We show that Notum is not a key actor of Wnt/beta-catenin-dependent liver patterning of adult mice, but has role in liver glucose homeostasis. Male mice deficient in Notum specifically in the liver develop metabolic dysfunctions implicating Notum in the development of Type 2 diabetes.
ESTHER : Canal_2016_PLoS.One_11_e0150997
PubMedSearch : Canal_2016_PLoS.One_11_e0150997
PubMedID: 26974334
Gene_locus related to this paper: mouse-notum

Title : Whole-Genome Sequence of Mycobacterium abscessus Clinical Strain V06705 - Pang_2013_Genome.Announc_1_e00690
Author(s) : Pang S , Renvoise A , Perret C , Guinier M , Chelghoum N , Brossier F , Capton E , Jarlier V , Sougakoff W
Ref : Genome Announc , 1 : , 2013
Abstract : Infection caused by Mycobacterium abscessus strains is a growing cause of concern in both community-acquired and health care-associated diseases, as these organisms naturally display multiple drug resistances. We report an annotated draft genome sequence of M. abscessus strain V06705 obtained from a patient in France.
ESTHER : Pang_2013_Genome.Announc_1_e00690
PubMedSearch : Pang_2013_Genome.Announc_1_e00690
PubMedID: 24009121
Gene_locus related to this paper: mycab-b1mch4 , mycab-b1mdu3 , mycab-b1mes2 , mycab-b1mes3 , mycab-b1mfj3 , mycab-b1mfk0 , mycab-b1mgd3 , mycab-b1mkl9 , mycab-i9cu79 , myca9-b1miq0 , mycab-r4v1a9 , mycab-x8en65

Title : A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease - Wild_2011_Circ.Cardiovasc.Genet_4_403
Author(s) : Wild PS , Zeller T , Schillert A , Szymczak S , Sinning CR , Deiseroth A , Schnabel RB , Lubos E , Keller T , Eleftheriadis MS , Bickel C , Rupprecht HJ , Wilde S , Rossmann H , Diemert P , Cupples LA , Perret C , Erdmann J , Stark K , Kleber ME , Epstein SE , Voight BF , Kuulasmaa K , Li M , Schafer AS , Klopp N , Braund PS , Sager HB , Demissie S , Proust C , Konig IR , Wichmann HE , Reinhard W , Hoffmann MM , Virtamo J , Burnett MS , Siscovick D , Wiklund PG , Qu L , El Mokthari NE , Thompson JR , Peters A , Smith AV , Yon E , Baumert J , Hengstenberg C , Marz W , Amouyel P , Devaney J , Schwartz SM , Saarela O , Mehta NN , Rubin D , Silander K , Hall AS , Ferrieres J , Harris TB , Melander O , Kee F , Hakonarson H , Schrezenmeir J , Gudnason V , Elosua R , Arveiler D , Evans A , Rader DJ , Illig T , Schreiber S , Bis JC , Altshuler D , Kavousi M , Witteman JC , Uitterlinden AG , Hofman A , Folsom AR , Barbalic M , Boerwinkle E , Kathiresan S , Reilly MP , O'Donnell CJ , Samani NJ , Schunkert H , Cambien F , Lackner KJ , Tiret L , Salomaa V , Munzel T , Ziegler A , Blankenberg S
Ref : Circ Cardiovasc Genet , 4 :403 , 2011
Abstract : BACKGROUND: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). METHODS AND RESULTS: In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7x10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3x10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4x10(-3)). CONCLUSIONS: The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.
ESTHER : Wild_2011_Circ.Cardiovasc.Genet_4_403
PubMedSearch : Wild_2011_Circ.Cardiovasc.Genet_4_403
PubMedID: 21606135
Gene_locus related to this paper: human-LIPA

Title : Platelet-activating factor-acetylhydrolase and PAF-receptor gene haplotypes in relation to future cardiovascular event in patients with coronary artery disease - Ninio_2004_Hum.Mol.Genet_13_1341
Author(s) : Ninio E , Tregouet D , Carrier JL , Stengel D , Bickel C , Perret C , Rupprecht HJ , Cambien F , Blankenberg S , Tiret L
Ref : Hum Mol Genet , 13 :1341 , 2004
Abstract : Oxidation of low density lipoproteins is an initial step of atherogenesis that generates pro-inflammatory phospholipids, including platelet-activating factor (PAF) and its analogs. PAF is degraded by PAF-acetylhydrolase (PAF-AH), a circulating enzyme having both pro- and anti-inflammatory activities. PAF-AH activity has been postulated to be a risk factor for coronary artery disease (CAD); however, whether PAF-AH has a causal role or is simply a marker of risk is unclear. The aim of this study was to relate the variability of the genes encoding PAF-AH (PLA2G7) and the PAF-receptor (PTAFR) to the risk of CAD and its complications. All polymorphisms located in putatively functional regions were investigated in a prospective cohort of CAD patients (n = 1314) and a group of healthy controls (n = 485). The whole gene variability was investigated in relation to case-control status, prospective cardiovascular outcome and plasma PAF-AH levels by means of haplotype analyses. All analyses indicated an effect of the PLA2G7/A379V polymorphism independent of the other polymorphisms. The V379 allele was less frequent in CAD patients than in controls and was associated with a lower risk of future cardiovascular events, suggesting that this allele might be protective against the development of CAD. The V379 allele was also associated with a weak increase of plasma PAF-AH activity that was unlikely to explain the protective effect of the allele on risk. A more likely interpretation is that the A379V polymorphism might modify the enzyme function towards a more anti-atherogenic form. Polymorphisms of the PTAFR gene were not related to any phenotype.
ESTHER : Ninio_2004_Hum.Mol.Genet_13_1341
PubMedSearch : Ninio_2004_Hum.Mol.Genet_13_1341
PubMedID: 15115767
Gene_locus related to this paper: human-PLA2G7