The Experts below are selected from a list of 111 Experts worldwide ranked by ideXlab platform
Patrick Mehlen - One of the best experts on this subject based on the ideXlab platform.
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reciprocal antagonism between the netrin 1 Receptor uncoordinated phenotype 5a unc5a and the hepatitis c virus
Oncogene, 2017Co-Authors: Marielaure Plissonnier, Thomas Lahlali, M Raab, Maud Michelet, Cristina Romerolopez, Michel Rivoire, Klaus Strebhardt, David Durantel, Massimo Levrero, Patrick MehlenAbstract:Hepatitis C virus (HCV) infection is a leading cause of hepatocellular carcinoma (HCC), mainly through cirrhosis induction, spurring research for a deeper understanding of HCV versus host interactions in cirrhosis. The present study investigated crosstalks between HCV infection and UNC5A, a netrin-1 Dependence Receptor that is inactivated in cancer. UNC5A and HCV parameters were monitored in patients samples (n=550) as well as in in vitro. In patients, UNC5A mRNA expression is significantly decreased in clinical HCV(+) specimens irrespective of the viral genotype, but not in (HBV)(+) liver biopsies, as compared to uninfected samples. UNC5A mRNA is downregulated in F2 (3-fold; P=0.009), in F3 (10-fold, P=0.0004) and more dramatically so in F4/cirrhosis (44-fold; P<0.0001) histological stages of HCV(+) hepatic lesions compared to histologically matched HCV(-) tissues. UNC5A transcript was found strongly downregulated in HCC samples (33-fold; P<0.0001) as compared with non-HCC samples. In vivo, association of UNC5A transcripts with polyribosomes is decreased by 50% in HCV(+) livers. Consistent results were obtained in vitro showing HCV-dependent depletion of UNC5A in HCV-infected hepatocyte-like cells and in primary human hepatocytes. Using luciferase reporter constructs, HCV cumulatively decreased UNC5A transcription from the UNC5 promoter and translation in a UNC5A 5'UTR-dependent manner. Proximity ligation assays, kinase assays, as well as knockdown and forced expression experiments identified UNC5A as capable of impeding autophagy and promoting HCV restriction through specific impact on virion infectivity, in a cell death-independent and DAPK-related manner. In conclusion, while the UNC5A Dependence Receptor counteracts HCV persistence through regulation of autophagy in a DAPK-dependent manner, it is dramatically decreased in all instances in HCC samples, and specifically by HCV in cirrhosis. Such data argue for the evaluation of the implication of UNC5A in liver carcinogenesis.
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the patched Dependence Receptor triggers apoptosis through a dral caspase 9 complex
Nature Cell Biology, 2009Co-Authors: Frederic Mille, Nicolas Rama, Catherine Guix, Chantal Thibert, Joanna Fombonne, Hideki Hayashi, Veronique Corset, John C Reed, Patrick MehlenAbstract:Shh acts as a survival factor and in its absence its Receptor, Patched, induces cell death by recruiting a caspase-activating complex formed by the adaptor protein DRAL, the CARD domain containing proteins TUCAN or NALP1, and caspase-9. Sonic hedgehog (Shh) and its main Receptor, Patched (Ptc), are implicated in both neural development and tumorigenesis1,2. Besides its classic morphogenic activity, Shh is also a survival factor3,4. Along this line, Ptc has been shown to function as a Dependence Receptor; it induces apoptosis in the absence of Shh, whereas its pro-apoptotic activity is blocked in the presence of Shh5. Here we show that, in the absence of its ligand, Ptc interacts with the adaptor protein DRAL (downregulated in rhabdomyosarcoma LIM-domain protein; also known as FHL2). DRAL is required for the pro-apoptotic activity of Ptc both in immortalized cells and during neural tube development in chick embryos. We demonstrate that, in the absence of Shh, Ptc recruits a protein complex that includes DRAL, one of the caspase recruitment (CARD)-domain containing proteins TUCAN (family member, 8) or NALP1 (NLR family, pyrin domain containing 1) and apical caspase-9. Ptc triggers caspase-9 activation and enhances cell death through a caspase-9-dependent mechanism. Thus, we propose that in the absence of its ligand Shh the Dependence Receptor Ptc serves as the anchor for a caspase-activating complex that includes DRAL, and caspase-9.
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ephrinb3 is an anti apoptotic ligand that inhibits the Dependence Receptor functions of epha4 Receptors during adult neurogenesis
Biochimica et Biophysica Acta, 2009Co-Authors: Celine Furne, Jorge Ruben Cabrera, Patrick Mehlen, Laurent Pays, Jerome Ricard, John R Bethea, Daniel J LieblAbstract:Eph Receptors have been implicated in regulating a diverse array of cellular functions in the developing nervous system. Recently, Eph Receptors have been shown to promote cell death in adult germinal zones; however, their mechanisms of action remain ill-defined. In this study, we demonstrate that EphA4 is a new member of the Dependence Receptors family, which can initiate cell death in the absence of its ligand ephrinB3. Upon removal of its ligand, EphA4 triggers cell death that is dependent on caspase activation as caspase inhibitors prevent cell death. EphA4 itself is cleaved by caspase-3-like caspase in the intracellular domain at position D773/774, which is necessary for cell death initiation as mutation of the cleavage site abolishes apoptosis. In the adult subventricular zone, abolishing ephrinB3 results in increased cell death, while the absence of EphA4 results in excessive numbers of neuroblasts. Furthermore, infusion of soluble ephrinB3 into the lateral ventricle reduced cell death, and together these results support a Dependence role for EphA4 in adult neurogenesis.
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netrin 1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Julien Fitamant, Catherine Guix, Agnes Bernet, Isabelle Treilleux, Jean-yves Scoazec, Mariemay Coissieux, Celine Guenebeaud, Thomas Bachelot, Patrick MehlenAbstract:Netrin-1, an axon navigation cue was proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. The netrin-1 Receptors DCC and UNC5H were shown to belong to the family of Dependence Receptors that share the ability to induce apoptosis in the absence of their ligands. Such a trait confers on these Receptors a tumor suppressor activity. Expression of one of these Dependence Receptors at the surface of a tumor cell is indeed speculated to render this cell dependent on ligand availability for its survival, hence inhibiting uncontrolled cell proliferation or metastasis. Consequently, it is a selective advantage for a tumor cell to lose this Dependence Receptor activity, as previously described with losses of DCC and UNC5H expression in human cancers. However, the model predicts that a similar advantage may be obtained by gaining autocrine expression of the ligand. We describe here that, unlike human nonmetastatic breast tumors, a large fraction of metastatic breast cancers overexpress netrin-1. Moreover, we show that netrin-1-expressing mammary metastatic tumor cell lines undergo apoptosis when netrin-1 expression is experimentally decreased or when decoy soluble Receptor ectodomains are added. Such treatments prevent metastasis formation both in a syngenic mouse model of lung colonization of a mammary cancer cell line and in a model of spontaneous lung metastasis of xenografted human breast tumor. Thus, netrin-1 expression observed in a large fraction of human metastatic breast tumors confers a selective advantage for tumor cell survival and potentially represents a promising target for alternative anticancer therapeutic strategies.
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inactivation of the unc5c netrin 1 Receptor is associated with tumor progression in colorectal malignancies
Gastroenterology, 2007Co-Authors: Agnes Bernet, Patrick Mehlen, Nicolas Gadot, Laetitia Mazelin, Jean-yves Scoazec, Mariemay Coissieux, Susan L AckermanAbstract:Background & Aims: The UNC5H netrin-1 Receptors (UNC5H1-3 also called UNC5A-C) belong to the functional Dependence Receptors family, which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer a tumor-suppressor activity. Indeed, cells harboring these Receptors are thought to be dependent on ligand availability for their survival, thereby inhibiting uncontrolled tumor cell proliferation. We investigate here whether UNC5C acts as a tumor suppressor in colorectal malignancies. Methods: The level of UNC5C was analyzed in a panel of 86 primary sporadic colorectal carcinomas. Loss of heterozygosity in the UNC5C locus and epigenetic alterations in the UNC5C promoter were also analyzed. Intestinal tumor progression was monitored in mice bearing both UNC5C and APC1638N mutations, and apoptosis was measured in intestinal tumors developed in UNC5C/APC1638N mutant mice. Results: We show here that UNC5C expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, in mice, inactivation of UNC5C is associated with increased intestinal tumor progression and a decrease in tumor cell apoptosis. Conclusions: The loss of UNC5C expression observed in human colorectal cancer is a selective advantage for tumor progression, in agreement with the Dependence Receptor hypothesis. Thus, the UNC5C Dependence Receptor is a tumor suppressor that regulates sporadic colorectal cancer.
Catherine Guix - One of the best experts on this subject based on the ideXlab platform.
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the Dependence Receptor unc5h2 b triggers apoptosis via pp2a mediated dephosphorylation of dap kinase
Molecular Cell, 2010Co-Authors: Celine Guenebeaud, Catherine Guix, Marie Castets, Guillaume Chazot, David Goldschneider, Celine Delloyebourgeois, Avital Eisenberglerner, Galit Shohat, Mingjie Zhang, Vincent LaudetAbstract:The UNC5H Dependence Receptors promote apoptosis in the absence of their ligand, netrin-1, and this is important for neuronal and vascular development and for limitation of cancer progression. UNC5H2 (also called UNC5B) triggers cell death through the activation of the serine-threonine protein kinase DAPk. While performing a siRNA screen to identify genes implicated in UNC5H-induced apoptosis, we identified the structural subunit PR65β of the holoenzyme protein phosphatase 2A (PP2A). We show that UNC5H2/B recruits a protein complex that includes PR65β and DAPk and retains PP2A activity. PP2A activity is required for UNC5H2/B-induced apoptosis, since it activates DAPk by triggering its dephosphorylation. Moreover, netrin-1 binding to UNC5H2/B prevents this effect through interaction of the PP2A inhibitor CIP2A to UNC5H2/B. Thus we show here that, in the absence of netrin-1, recruitment of PP2A to UNC5H2/B allows the activation of DAPk via a PP2A-mediated dephosphorylation and that this mechanism is involved in angiogenesis regulation.
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the patched Dependence Receptor triggers apoptosis through a dral caspase 9 complex
Nature Cell Biology, 2009Co-Authors: Frederic Mille, Nicolas Rama, Catherine Guix, Chantal Thibert, Joanna Fombonne, Hideki Hayashi, Veronique Corset, John C Reed, Patrick MehlenAbstract:Shh acts as a survival factor and in its absence its Receptor, Patched, induces cell death by recruiting a caspase-activating complex formed by the adaptor protein DRAL, the CARD domain containing proteins TUCAN or NALP1, and caspase-9. Sonic hedgehog (Shh) and its main Receptor, Patched (Ptc), are implicated in both neural development and tumorigenesis1,2. Besides its classic morphogenic activity, Shh is also a survival factor3,4. Along this line, Ptc has been shown to function as a Dependence Receptor; it induces apoptosis in the absence of Shh, whereas its pro-apoptotic activity is blocked in the presence of Shh5. Here we show that, in the absence of its ligand, Ptc interacts with the adaptor protein DRAL (downregulated in rhabdomyosarcoma LIM-domain protein; also known as FHL2). DRAL is required for the pro-apoptotic activity of Ptc both in immortalized cells and during neural tube development in chick embryos. We demonstrate that, in the absence of Shh, Ptc recruits a protein complex that includes DRAL, one of the caspase recruitment (CARD)-domain containing proteins TUCAN (family member, 8) or NALP1 (NLR family, pyrin domain containing 1) and apical caspase-9. Ptc triggers caspase-9 activation and enhances cell death through a caspase-9-dependent mechanism. Thus, we propose that in the absence of its ligand Shh the Dependence Receptor Ptc serves as the anchor for a caspase-activating complex that includes DRAL, and caspase-9.
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netrin 1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Julien Fitamant, Catherine Guix, Agnes Bernet, Isabelle Treilleux, Jean-yves Scoazec, Mariemay Coissieux, Celine Guenebeaud, Thomas Bachelot, Patrick MehlenAbstract:Netrin-1, an axon navigation cue was proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. The netrin-1 Receptors DCC and UNC5H were shown to belong to the family of Dependence Receptors that share the ability to induce apoptosis in the absence of their ligands. Such a trait confers on these Receptors a tumor suppressor activity. Expression of one of these Dependence Receptors at the surface of a tumor cell is indeed speculated to render this cell dependent on ligand availability for its survival, hence inhibiting uncontrolled cell proliferation or metastasis. Consequently, it is a selective advantage for a tumor cell to lose this Dependence Receptor activity, as previously described with losses of DCC and UNC5H expression in human cancers. However, the model predicts that a similar advantage may be obtained by gaining autocrine expression of the ligand. We describe here that, unlike human nonmetastatic breast tumors, a large fraction of metastatic breast cancers overexpress netrin-1. Moreover, we show that netrin-1-expressing mammary metastatic tumor cell lines undergo apoptosis when netrin-1 expression is experimentally decreased or when decoy soluble Receptor ectodomains are added. Such treatments prevent metastasis formation both in a syngenic mouse model of lung colonization of a mammary cancer cell line and in a model of spontaneous lung metastasis of xenografted human breast tumor. Thus, netrin-1 expression observed in a large fraction of human metastatic breast tumors confers a selective advantage for tumor cell survival and potentially represents a promising target for alternative anticancer therapeutic strategies.
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the trkc Receptor induces apoptosis when the Dependence Receptor notion meets the neurotrophin paradigm
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Servane Tauszigdelamasure, Jimena Bouzasrodriguez, Jorge Ruben Cabrera, Catherine Mermetbouvier, Catherine Guix, Marieclaire Bordeaux, Urmas Arumae, Patrick MehlenAbstract:The TrkC/NT-3 Receptor/ligand pair is believed to be part of the classic neurotrophic theory claiming that neuronal death occurs by default when neurotrophic factors become limited, through loss of survival signals. Here, we show that TrkC is a Dependence Receptor and, as such, induces caspase-dependent apoptotic death in the absence of NT-3 in immortalized cells, a proapoptotic activity inhibited by the presence of NT-3. This proapoptotic activity of TrkC relies on the caspase-mediated cleavage of the intracellular domain of TrkC, which permits the release of a proapoptotic fragment. This fragment induces apoptosis through a caspase-9-dependent mechanism. Finally, we show that the death of dorsal root ganglion (DRG) neurons provoked by NT-3 withdrawal is inhibited when TrkC-proapoptotic activity is antagonized. Thus, the death of neurons upon disappearance of NT-3 is not only due to a loss of survival signals but also to the active proapoptotic activity of the unbound TrkC Dependence Receptor.
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the Dependence Receptor unc5h2 mediates apoptosis through dap kinase
The EMBO Journal, 2005Co-Authors: Fabien Llambi, Catherine Guix, Filipe Calheiros Lourenco, Devrim Gozuacik, Laurent Pays, Gabriel Del Rio, Adi Kimchi, Patrick MehlenAbstract:Netrin-1 Receptors UNC5H (UNC5H1–4) were originally proposed to mediate the chemorepulsive activity of netrin-1 during axonal guidance processes. However, UNC5H Receptors were more recently described as Dependence Receptors and, as such, able to trigger apoptosis in the absence of netrin-1. They were also proposed as putative tumor suppressors. Here, we show that UNC5H2 physically interacts with the serine/threonine kinase death-associated protein kinase (DAP-kinase) both in cell culture and in embryonic mouse brains. This interaction occurs in part through the respective death domains of UNC5H2 and DAP-kinase. Moreover, part of UNC5H2 proapoptotic activity occurs through this interaction because UNC5H2-induced cell death is partly impaired in the presence of dominant-negative mutants of DAP-kinase or in DAP-kinase mutant murine embryonic fibroblast cells. In the absence of netrin-1, UNC5H2 reduces DAP-kinase autophosphorylation on Ser308 and increases the catalytic activity of the kinase while netrin-1 blocks UNC5H2-dependent DAP-kinase activation. Thus, the pair netrin-1/UNC5H2 may regulate cell fate by controlling the proapoptotic kinase activity of DAP-kinase.
Jean-yves Scoazec - One of the best experts on this subject based on the ideXlab platform.
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DCC constrains tumour progression via its Dependence Receptor activity.
Nature, 2012Co-Authors: Marie Castets, Laura Broutier, Yann Molin, Marie Brevet, Guillaume Chazot, Nicolas Gadot, Armelle Paquet, Laetitia Mazelin, Loraine Jarrosson-wuilleme, Jean-yves ScoazecAbstract:The role of deleted in colorectal carcinoma (DCC) as a tumour suppressor has been a matter of debate for the past 15 years. DCC gene expression is lost or markedly reduced in the majority of advanced colorectal cancers and, by functioning as a Dependence Receptor, DCC has been shown to induce apoptosis unless engaged by its ligand, netrin-1 (ref. 2). However, so far no animal model has supported the view that the DCC loss-of-function is causally implicated as predisposing to aggressive cancer development. To investigate the role of DCC-induced apoptosis in the control of tumour progression, here we created a mouse model in which the pro-apoptotic activity of DCC is genetically silenced. Although the loss of DCC-induced apoptosis in this mouse model is not associated with a major disorganization of the intestines, it leads to spontaneous intestinal neoplasia at a relatively low frequency. Loss of DCC-induced apoptosis is also associated with an increase in the number and aggressiveness of intestinal tumours in a predisposing APC mutant context, resulting in the development of highly invasive adenocarcinomas. These results demonstrate that DCC functions as a tumour suppressor via its ability to trigger tumour cell apoptosis.
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netrin 1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Julien Fitamant, Catherine Guix, Agnes Bernet, Isabelle Treilleux, Jean-yves Scoazec, Mariemay Coissieux, Celine Guenebeaud, Thomas Bachelot, Patrick MehlenAbstract:Netrin-1, an axon navigation cue was proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. The netrin-1 Receptors DCC and UNC5H were shown to belong to the family of Dependence Receptors that share the ability to induce apoptosis in the absence of their ligands. Such a trait confers on these Receptors a tumor suppressor activity. Expression of one of these Dependence Receptors at the surface of a tumor cell is indeed speculated to render this cell dependent on ligand availability for its survival, hence inhibiting uncontrolled cell proliferation or metastasis. Consequently, it is a selective advantage for a tumor cell to lose this Dependence Receptor activity, as previously described with losses of DCC and UNC5H expression in human cancers. However, the model predicts that a similar advantage may be obtained by gaining autocrine expression of the ligand. We describe here that, unlike human nonmetastatic breast tumors, a large fraction of metastatic breast cancers overexpress netrin-1. Moreover, we show that netrin-1-expressing mammary metastatic tumor cell lines undergo apoptosis when netrin-1 expression is experimentally decreased or when decoy soluble Receptor ectodomains are added. Such treatments prevent metastasis formation both in a syngenic mouse model of lung colonization of a mammary cancer cell line and in a model of spontaneous lung metastasis of xenografted human breast tumor. Thus, netrin-1 expression observed in a large fraction of human metastatic breast tumors confers a selective advantage for tumor cell survival and potentially represents a promising target for alternative anticancer therapeutic strategies.
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inactivation of the unc5c netrin 1 Receptor is associated with tumor progression in colorectal malignancies
Gastroenterology, 2007Co-Authors: Agnes Bernet, Patrick Mehlen, Nicolas Gadot, Laetitia Mazelin, Jean-yves Scoazec, Mariemay Coissieux, Susan L AckermanAbstract:Background & Aims: The UNC5H netrin-1 Receptors (UNC5H1-3 also called UNC5A-C) belong to the functional Dependence Receptors family, which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer a tumor-suppressor activity. Indeed, cells harboring these Receptors are thought to be dependent on ligand availability for their survival, thereby inhibiting uncontrolled tumor cell proliferation. We investigate here whether UNC5C acts as a tumor suppressor in colorectal malignancies. Methods: The level of UNC5C was analyzed in a panel of 86 primary sporadic colorectal carcinomas. Loss of heterozygosity in the UNC5C locus and epigenetic alterations in the UNC5C promoter were also analyzed. Intestinal tumor progression was monitored in mice bearing both UNC5C and APC1638N mutations, and apoptosis was measured in intestinal tumors developed in UNC5C/APC1638N mutant mice. Results: We show here that UNC5C expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, in mice, inactivation of UNC5C is associated with increased intestinal tumor progression and a decrease in tumor cell apoptosis. Conclusions: The loss of UNC5C expression observed in human colorectal cancer is a selective advantage for tumor progression, in agreement with the Dependence Receptor hypothesis. Thus, the UNC5C Dependence Receptor is a tumor suppressor that regulates sporadic colorectal cancer.
Marielaure Plissonnier - One of the best experts on this subject based on the ideXlab platform.
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hepatocellular carcinoma associated depletion of the netrin 1 Receptor uncoordinated phenotype 5a unc5a skews the hepatic unfolded protein response towards prosurvival outcomes
Biochemical and Biophysical Research Communications, 2018Co-Authors: Marielaure Plissonnier, Thomas Lahlali, Cristina Romerolopez, Romain Barnault, Noemie Laverdure, Benjamin DucarougeAbstract:Abstract In the liver, HBV and HCV infections, exposure to toxics, genetic and metabolic disorders may induce endoplasmic reticulum (ER) stress and the unfolding protein response (UPR). The UPR allows cells to reach ER homeostasis after lumen overload, but also fosters survival of damaged cells and therefore HCC onset. Dependence Receptors such as UNC5A trigger apoptosis when unbound to their ligands. We have previously shown that the main Dependence Receptor ligand, netrin-1, could protect cells against UPR-induced apoptosis through sustained translation. In this study, we show that UNC5A is cumulatively downregulated by the UPR at the transcriptional level in vitro and at the translational level both in vitro and in vivo. We have found that the 5′-untranslated region of the UNC5A mRNA shares a certain homology degree with that of netrin-1, suggesting linked translational regulatory mechanisms, at least during the initial stages of the UPR. RNAi and forced expression studies identified UNC5A as a modulator of cell death in the context of the UPR. UNC5A decrease of association with polysomes and expression oriented cells towards UPR-associated hepatocytic survival. Such data indicate that cooperation between the UPR and UNC5A depletion as previously observed by ourselves in HCC patients samples may foster liver cancer development and growth.
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reciprocal antagonism between the netrin 1 Receptor uncoordinated phenotype 5a unc5a and the hepatitis c virus
Oncogene, 2017Co-Authors: Marielaure Plissonnier, Thomas Lahlali, M Raab, Maud Michelet, Cristina Romerolopez, Michel Rivoire, Klaus Strebhardt, David Durantel, Massimo Levrero, Patrick MehlenAbstract:Hepatitis C virus (HCV) infection is a leading cause of hepatocellular carcinoma (HCC), mainly through cirrhosis induction, spurring research for a deeper understanding of HCV versus host interactions in cirrhosis. The present study investigated crosstalks between HCV infection and UNC5A, a netrin-1 Dependence Receptor that is inactivated in cancer. UNC5A and HCV parameters were monitored in patients samples (n=550) as well as in in vitro. In patients, UNC5A mRNA expression is significantly decreased in clinical HCV(+) specimens irrespective of the viral genotype, but not in (HBV)(+) liver biopsies, as compared to uninfected samples. UNC5A mRNA is downregulated in F2 (3-fold; P=0.009), in F3 (10-fold, P=0.0004) and more dramatically so in F4/cirrhosis (44-fold; P<0.0001) histological stages of HCV(+) hepatic lesions compared to histologically matched HCV(-) tissues. UNC5A transcript was found strongly downregulated in HCC samples (33-fold; P<0.0001) as compared with non-HCC samples. In vivo, association of UNC5A transcripts with polyribosomes is decreased by 50% in HCV(+) livers. Consistent results were obtained in vitro showing HCV-dependent depletion of UNC5A in HCV-infected hepatocyte-like cells and in primary human hepatocytes. Using luciferase reporter constructs, HCV cumulatively decreased UNC5A transcription from the UNC5 promoter and translation in a UNC5A 5'UTR-dependent manner. Proximity ligation assays, kinase assays, as well as knockdown and forced expression experiments identified UNC5A as capable of impeding autophagy and promoting HCV restriction through specific impact on virion infectivity, in a cell death-independent and DAPK-related manner. In conclusion, while the UNC5A Dependence Receptor counteracts HCV persistence through regulation of autophagy in a DAPK-dependent manner, it is dramatically decreased in all instances in HCC samples, and specifically by HCV in cirrhosis. Such data argue for the evaluation of the implication of UNC5A in liver carcinogenesis.
Mariemay Coissieux - One of the best experts on this subject based on the ideXlab platform.
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Dependence Receptor trkc is a putative colon cancer tumor suppressor
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Annelaure Genevois, Gabriel Ichim, Mariemay Coissieux, Mariepierre Lambert, Fabrice Lavial, David Goldschneider, Loraine Jarrossonwuilleme, Florian Lepinasse, Geraldine Gouysse, Zdenko HercegAbstract:The TrkC neurotrophin Receptor belongs to the functional Dependence Receptor family, members of which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer tumor-suppressor activity. Indeed, cells that express these Receptors are thought to be dependent on ligand availability for their survival, a mechanism that inhibits uncontrolled tumor cell proliferation and migration. TrkC is a classic tyrosine kinase Receptor and therefore generally considered to be a proto-oncogene. We show here that TrkC expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, we show that TrkC silencing by promoter methylation is a selective advantage for colorectal cell lines to limit tumor cell death. Furthermore, reestablished TrkC expression in colorectal cancer cell lines is associated with tumor cell death and inhibition of in vitro characteristics of cell transformation, as well as in vivo tumor growth. Finally, we provide evidence that a mutation of TrkC detected in a sporadic cancer is a loss-of-proapoptotic function mutation. Together, these data support the conclusion that TrkC is a colorectal cancer tumor suppressor.
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variants in the netrin 1 Receptor unc5c prevent apoptosis and increase risk of familial colorectal cancer
Gastroenterology, 2011Co-Authors: Mariemay Coissieux, Marie Castets, Jerneja Tomsic, Heather Hampel, Sari Tuupanen, Nadine Andrieu, Ilene Comeras, Youenn Drouet, Christine Lasset, Sandya LiyanarachchiAbstract:Background & Aims Expression of the netrin-1 Dependence Receptor UNC5C is reduced in many colorectal tumors; mice with the UNC5C mutations have increased progression of intestinal tumors. We investigated whether specific variants in UNC5C increase risk of colorectal cancer (CRC). Methods We analyzed the sequence of UNC5C in blood samples from 1801 patients with CRC and 4152 controls from 3 cohorts (France, United States, and Finland). Almost all cases from France and the United States had familial CRC; of the Finnish cases, 92 of 984 were familial. We analyzed whether CRC segregates with the UNC5C variant A628K in 3 families with histories of CRC. We also performed haplotype analysis to determine the origin of this variant. Results Of 817 patients with familial CRC, 14 had 1 of 4 different, unreported missense variants in UNC5C . The variants p.Asp353Asn (encodes D353N), p.Arg603Cys (encodes R603C), and p.Gln630Glu (encodes Q630E) did not occur significantly more often in cases than controls. The variant p.Ala628Lys (A628K) was detected in 3 families in the French cohort (odds ratio, 8.8; Wald's 95% confidence interval, 1.47–52.93; P = .03) and in 2 families in the US cohort (odds ratio, 1.9; P = .6) but was not detected in the Finnish cohort; UNC5C A628K segregated with CRC in families. Three families with A628K had a 109-kilobase identical haplotype that spanned most of UNC5C , indicating recent origin of this variant in white subjects (14 generations; 95% confidence interval, 6–36 generations). Transfection of HEK293T cells with UNC5C-A628K significantly reduced apoptosis compared with wild-type UNC5C, measured in an assay of active caspase-3. Conclusions Inherited mutations in UNC5C prevent apoptosis and increase risk of CRC.
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netrin 1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Julien Fitamant, Catherine Guix, Agnes Bernet, Isabelle Treilleux, Jean-yves Scoazec, Mariemay Coissieux, Celine Guenebeaud, Thomas Bachelot, Patrick MehlenAbstract:Netrin-1, an axon navigation cue was proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. The netrin-1 Receptors DCC and UNC5H were shown to belong to the family of Dependence Receptors that share the ability to induce apoptosis in the absence of their ligands. Such a trait confers on these Receptors a tumor suppressor activity. Expression of one of these Dependence Receptors at the surface of a tumor cell is indeed speculated to render this cell dependent on ligand availability for its survival, hence inhibiting uncontrolled cell proliferation or metastasis. Consequently, it is a selective advantage for a tumor cell to lose this Dependence Receptor activity, as previously described with losses of DCC and UNC5H expression in human cancers. However, the model predicts that a similar advantage may be obtained by gaining autocrine expression of the ligand. We describe here that, unlike human nonmetastatic breast tumors, a large fraction of metastatic breast cancers overexpress netrin-1. Moreover, we show that netrin-1-expressing mammary metastatic tumor cell lines undergo apoptosis when netrin-1 expression is experimentally decreased or when decoy soluble Receptor ectodomains are added. Such treatments prevent metastasis formation both in a syngenic mouse model of lung colonization of a mammary cancer cell line and in a model of spontaneous lung metastasis of xenografted human breast tumor. Thus, netrin-1 expression observed in a large fraction of human metastatic breast tumors confers a selective advantage for tumor cell survival and potentially represents a promising target for alternative anticancer therapeutic strategies.
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inactivation of the unc5c netrin 1 Receptor is associated with tumor progression in colorectal malignancies
Gastroenterology, 2007Co-Authors: Agnes Bernet, Patrick Mehlen, Nicolas Gadot, Laetitia Mazelin, Jean-yves Scoazec, Mariemay Coissieux, Susan L AckermanAbstract:Background & Aims: The UNC5H netrin-1 Receptors (UNC5H1-3 also called UNC5A-C) belong to the functional Dependence Receptors family, which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer a tumor-suppressor activity. Indeed, cells harboring these Receptors are thought to be dependent on ligand availability for their survival, thereby inhibiting uncontrolled tumor cell proliferation. We investigate here whether UNC5C acts as a tumor suppressor in colorectal malignancies. Methods: The level of UNC5C was analyzed in a panel of 86 primary sporadic colorectal carcinomas. Loss of heterozygosity in the UNC5C locus and epigenetic alterations in the UNC5C promoter were also analyzed. Intestinal tumor progression was monitored in mice bearing both UNC5C and APC1638N mutations, and apoptosis was measured in intestinal tumors developed in UNC5C/APC1638N mutant mice. Results: We show here that UNC5C expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, in mice, inactivation of UNC5C is associated with increased intestinal tumor progression and a decrease in tumor cell apoptosis. Conclusions: The loss of UNC5C expression observed in human colorectal cancer is a selective advantage for tumor progression, in agreement with the Dependence Receptor hypothesis. Thus, the UNC5C Dependence Receptor is a tumor suppressor that regulates sporadic colorectal cancer.