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Leonard M Neckers - One of the best experts on this subject based on the ideXlab platform.

  • stabilization of Wild Type p53 by hypoxia inducible factor 1α
    Nature, 1998
    Co-Authors: Won G An, Meera Kanekal, Celeste M Simon, Emin Maltepe, Mikhail V Blagosklonny, Leonard M Neckers
    Abstract:

    Although hypoxia (lack of oxygen in body tissues) is perhaps the most physiological inducer of the Wild-Type p53 gene1, the mechanism of this induction is unknown. Cells may detect low oxygen levels through a haem-containing sensor protein2. The hypoxic state can be mimicked by using cobalt chloride and the iron chelator desferrioxamine2,3,4,5: like hypoxia, cobalt chloride and desferrioxamine activate hypoxia-inducible factor 1α (HIF-1α) (ref. 6), which stimulates the transcription of several genes that are associated with hypoxia6,7,8,9. Here we show that these treatments induce accumulation of Wild-Type p53 through HIF-1α-dependent stabilization of p53 protein. Induction of p53 does not occur in either a mutant hepatoma cell line that is unable to induce HIF-1α (ref. 10) or embryonic stem cells derived from mice lacking HIF-1β (ref. 11). HIF-1α is found in p53 immunoprecipitates from MCF7 cells that express Wild-Type p53 and are either hypoxic or have been exposed to desferrioxamine. Similarly, anti-haemagglutinin immunoprecipitates from lysates of normoxic PC3M cells that had been co-transfected with haemagglutinin-tagged HIF-1α and Wild-Type p53 also contain p53. Transfection of normoxic MCF7 cells with HIF-1α stimulates a co-transfected p53-dependent reporter plasmid and increases the amount of endogenous p53. Our results suggest that hypoxic induction of transcriptionally active Wild-Type p53 is achieved as a result of the stabilization of p53 by its association with HIF-1α.

  • stabilization of Wild Type p53 by hypoxia inducible factor 1α
    Nature, 1998
    Co-Authors: Meera Kanekal, Emin Maltepe, Mikhail V Blagosklonny, M C Simon, Leonard M Neckers
    Abstract:

    Although hypoxia (lack of oxygen in body tissues) is perhaps the most physiological inducer of the Wild-Type p53 gene, the mechanism of this induction is unknown. Cells may detect low oxygen levels through a haem-containing sensor protein. The hypoxic state can be mimicked by using cobalt chloride and the iron chelator desferrioxamine: like hypoxia, cobalt chloride and desferrioxamine activate hypoxia-inducible factor 1alpha (HIF-1alpha), which stimulates the transcription of several genes that are associated with hypoxia. Here we show that these treatments induce accumulation of Wild-Type p53 through HIF-1alpha-dependent stabilization of p53 protein. Induction of p53 does not occur in either a mutant hepatoma cell line that is unable to induce HIF-1alpha or embryonic stem cells derived from mice lacking HIF-1beta. HIF-1alpha is found in p53 immunoprecipitates from MCF7 cells that express Wild-Type p53 and are either hypoxic or have been exposed to desferrioxamine. Similarly, anti-haemagglutinin immunoprecipitates from lysates of normoxic PC3M cells that had been co-transfected with haemagglutinin-tagged HIF-1alpha and Wild-Type p53 also contain p53. Transfection of normoxic MCF7 cells with HIF-1alpha stimulates a co-transfected p53-dependent reporter plasmid and increases the amount of endogenous p53. Our results suggest that hypoxic induction of transcriptionally active Wild-Type p53 is achieved as a result of the stabilization of p53 by its association with HIF-1alpha.

Brian Myers - One of the best experts on this subject based on the ideXlab platform.

  • Wild Type fus corrects als like disease induced by cytoplasmic mutant fus through autoregulation
    Molecular Neurodegeneration, 2021
    Co-Authors: Inmaculada Sanjuanruiz, Noe Goveaperez, Melissa Mcalonisdownes, Stephane Dieterle, Salim Megat, Sylvie Dirriggrosch, Gina Picchiarelli, Diana Piol, Qiang Zhu, Brian Myers
    Abstract:

    Mutations in FUS, an RNA-binding protein involved in multiple steps of RNA metabolism, are associated with the most severe forms of amyotrophic lateral sclerosis (ALS). Accumulation of cytoplasmic FUS is likely to be a major culprit in the toxicity of FUS mutations. Thus, preventing cytoplasmic mislocalization of the FUS protein may represent a valuable therapeutic strategy. FUS binds to its own pre-mRNA creating an autoregulatory loop efficiently buffering FUS excess through multiple proposed mechanisms including retention of introns 6 and/or 7. Here, we introduced a Wild-Type FUS gene allele, retaining all intronic sequences, in mice whose heterozygous or homozygous expression of a cytoplasmically retained FUS protein (Fus∆NLS) was previously shown to provoke ALS-like disease or postnatal lethality, respectively. Wild-Type FUS completely rescued the early lethality caused by the two Fus∆NLS alleles, and improved the age-dependent motor deficits and reduced lifespan caused by heterozygous expression of mutant FUS∆NLS. Mechanistically, Wild-Type FUS decreased the load of cytoplasmic FUS, increased retention of introns 6 and 7 in the endogenous mouse Fus mRNA, and decreased expression of the mutant mRNA. Thus, the Wild-Type FUS allele activates the homeostatic autoregulatory loop, maintaining constant FUS levels and decreasing the mutant protein in the cytoplasm. These results provide proof of concept that an autoregulatory competent Wild-Type FUS expression could protect against this devastating, currently intractable, neurodegenerative disease.

  • Wild Type fus corrects als like disease induced by cytoplasmic mutant fus through autoregulation
    bioRxiv, 2020
    Co-Authors: Inmaculada Sanjuanruiz, Noe Goveaperez, Melissa Mcalonisdownes, Stephane Dieterle, Salim Megat, Sylvie Dirriggrosch, Gina Picchiarelli, Diana Piol, Qiang Zhu, Brian Myers
    Abstract:

    Abstract Mutations in FUS, an RNA-binding protein involved in multiple steps of RNA metabolism, are associated with the most severe forms of amyotrophic lateral sclerosis (ALS). Accumulation of cytoplasmic FUS is likely to be a major culprit in the toxicity of FUS mutations. Thus, preventing cytoplasmic mislocalization of the FUS protein may represent a valuable therapeutic strategy. FUS binds to its own pre-mRNA creating an autoregulatory loop efficiently buffering FUS excess through multiple proposed mechanisms including retention of introns 6 and/or 7. Here, we introduced a Wild-Type FUS gene allele, retaining all intronic sequences, in mice whose heterozygous or homozygous expression of a cytoplasmically retained FUS protein (FusΔNLS) was previously shown to provoke ALS-like disease or postnatal lethality, respectively. Wild-Type FUS completely rescued the early lethality caused by the two FusΔNLS alleles, and improved age-dependent motor deficit and reduced lifespan associated with the heterozygous expression of FusΔNLS. Mechanistically, Wild-Type FUS decreased the load of cytoplasmic FUS, increased exon 7 skipping and retention of introns 6 and 7 in the endogenous mouse Fus mRNA, leading to decreased expression of the mutant mRNA. Thus, the Wild-Type FUS allele activates the homeostatic autoregulatory loop, maintaining constant FUS levels and decreasing the mutant protein in the cytoplasm. These results provide proof of concept that an autoregulatory competent Wild-Type FUS expression could protect against this devastating, currently intractable, neurodegenerative disease.

Jonathan Kipnis - One of the best experts on this subject based on the ideXlab platform.

  • Wild Type microglia arrest pathology in a mouse model of rett syndrome
    Nature, 2012
    Co-Authors: Noel C Derecki, James C Cronk, Zhenjie Lu, Eric Xu, Stephen B G Abbott, Patrice G Guyenet, Jonathan Kipnis
    Abstract:

    Transplanting bone marrow from Wild-Type mice into MECP2-lacking mice results in Wild-Type microglial engraftment, extends lifespan and reduces symptoms of disease such as breathing and locomotor abnormalities, implicating microglia in the pathophysiology of Rett syndrome. The X-linked autism spectrum disorder known as Rett syndrome is predominantly linked to mutations in the MECP2 gene. It is typically associated with neuronal dysfunction, almost exclusively in girls, but new evidence suggests that restoring MECP2 function in other cell Types may also arrest disease development. Here, the authors show in a mouse model that transplanting bone marrow from Wild-Type mice into mice lacking Mecp2 results in an invasion of donor-derived microglial cells into the brain, accompanied by increased lifespan and reduced signs of disease, including improved breathing and locomotion. The donor cells expressed normal MECP2 and high levels of the neurotrophic factor IGF-1. These results point to a crucial role for microglia in Rett syndrome, and open the possibility that bone-marrow implants might be of therapeutic benefit. Rett syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein1,2,3,4,5. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction6. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett syndrome. Transplantation of Wild-Type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenoType, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysmcre on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, Wild-Type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of Wild Type, and locomotor activity was improved. Mecp2+/− females also showed significant improvements as a result of Wild-Type microglial engraftment. These benefits mediated by Wild-Type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.

  • Wild Type microglia arrest pathology in a mouse model of rett syndrome
    Nature, 2012
    Co-Authors: Noel C Derecki, James C Cronk, Stephen B G Abbott, Patrice G Guyenet, Jonathan Kipnis
    Abstract:

    Rett syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett syndrome. Transplantation of Wild-Type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenoType, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, Wild-Type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of Wild Type, and locomotor activity was improved. Mecp2(+/-) females also showed significant improvements as a result of Wild-Type microglial engraftment. These benefits mediated by Wild-Type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.

Meera Kanekal - One of the best experts on this subject based on the ideXlab platform.

  • stabilization of Wild Type p53 by hypoxia inducible factor 1α
    Nature, 1998
    Co-Authors: Won G An, Meera Kanekal, Celeste M Simon, Emin Maltepe, Mikhail V Blagosklonny, Leonard M Neckers
    Abstract:

    Although hypoxia (lack of oxygen in body tissues) is perhaps the most physiological inducer of the Wild-Type p53 gene1, the mechanism of this induction is unknown. Cells may detect low oxygen levels through a haem-containing sensor protein2. The hypoxic state can be mimicked by using cobalt chloride and the iron chelator desferrioxamine2,3,4,5: like hypoxia, cobalt chloride and desferrioxamine activate hypoxia-inducible factor 1α (HIF-1α) (ref. 6), which stimulates the transcription of several genes that are associated with hypoxia6,7,8,9. Here we show that these treatments induce accumulation of Wild-Type p53 through HIF-1α-dependent stabilization of p53 protein. Induction of p53 does not occur in either a mutant hepatoma cell line that is unable to induce HIF-1α (ref. 10) or embryonic stem cells derived from mice lacking HIF-1β (ref. 11). HIF-1α is found in p53 immunoprecipitates from MCF7 cells that express Wild-Type p53 and are either hypoxic or have been exposed to desferrioxamine. Similarly, anti-haemagglutinin immunoprecipitates from lysates of normoxic PC3M cells that had been co-transfected with haemagglutinin-tagged HIF-1α and Wild-Type p53 also contain p53. Transfection of normoxic MCF7 cells with HIF-1α stimulates a co-transfected p53-dependent reporter plasmid and increases the amount of endogenous p53. Our results suggest that hypoxic induction of transcriptionally active Wild-Type p53 is achieved as a result of the stabilization of p53 by its association with HIF-1α.

  • stabilization of Wild Type p53 by hypoxia inducible factor 1α
    Nature, 1998
    Co-Authors: Meera Kanekal, Emin Maltepe, Mikhail V Blagosklonny, M C Simon, Leonard M Neckers
    Abstract:

    Although hypoxia (lack of oxygen in body tissues) is perhaps the most physiological inducer of the Wild-Type p53 gene, the mechanism of this induction is unknown. Cells may detect low oxygen levels through a haem-containing sensor protein. The hypoxic state can be mimicked by using cobalt chloride and the iron chelator desferrioxamine: like hypoxia, cobalt chloride and desferrioxamine activate hypoxia-inducible factor 1alpha (HIF-1alpha), which stimulates the transcription of several genes that are associated with hypoxia. Here we show that these treatments induce accumulation of Wild-Type p53 through HIF-1alpha-dependent stabilization of p53 protein. Induction of p53 does not occur in either a mutant hepatoma cell line that is unable to induce HIF-1alpha or embryonic stem cells derived from mice lacking HIF-1beta. HIF-1alpha is found in p53 immunoprecipitates from MCF7 cells that express Wild-Type p53 and are either hypoxic or have been exposed to desferrioxamine. Similarly, anti-haemagglutinin immunoprecipitates from lysates of normoxic PC3M cells that had been co-transfected with haemagglutinin-tagged HIF-1alpha and Wild-Type p53 also contain p53. Transfection of normoxic MCF7 cells with HIF-1alpha stimulates a co-transfected p53-dependent reporter plasmid and increases the amount of endogenous p53. Our results suggest that hypoxic induction of transcriptionally active Wild-Type p53 is achieved as a result of the stabilization of p53 by its association with HIF-1alpha.

Inmaculada Sanjuanruiz - One of the best experts on this subject based on the ideXlab platform.

  • Wild Type fus corrects als like disease induced by cytoplasmic mutant fus through autoregulation
    Molecular Neurodegeneration, 2021
    Co-Authors: Inmaculada Sanjuanruiz, Noe Goveaperez, Melissa Mcalonisdownes, Stephane Dieterle, Salim Megat, Sylvie Dirriggrosch, Gina Picchiarelli, Diana Piol, Qiang Zhu, Brian Myers
    Abstract:

    Mutations in FUS, an RNA-binding protein involved in multiple steps of RNA metabolism, are associated with the most severe forms of amyotrophic lateral sclerosis (ALS). Accumulation of cytoplasmic FUS is likely to be a major culprit in the toxicity of FUS mutations. Thus, preventing cytoplasmic mislocalization of the FUS protein may represent a valuable therapeutic strategy. FUS binds to its own pre-mRNA creating an autoregulatory loop efficiently buffering FUS excess through multiple proposed mechanisms including retention of introns 6 and/or 7. Here, we introduced a Wild-Type FUS gene allele, retaining all intronic sequences, in mice whose heterozygous or homozygous expression of a cytoplasmically retained FUS protein (Fus∆NLS) was previously shown to provoke ALS-like disease or postnatal lethality, respectively. Wild-Type FUS completely rescued the early lethality caused by the two Fus∆NLS alleles, and improved the age-dependent motor deficits and reduced lifespan caused by heterozygous expression of mutant FUS∆NLS. Mechanistically, Wild-Type FUS decreased the load of cytoplasmic FUS, increased retention of introns 6 and 7 in the endogenous mouse Fus mRNA, and decreased expression of the mutant mRNA. Thus, the Wild-Type FUS allele activates the homeostatic autoregulatory loop, maintaining constant FUS levels and decreasing the mutant protein in the cytoplasm. These results provide proof of concept that an autoregulatory competent Wild-Type FUS expression could protect against this devastating, currently intractable, neurodegenerative disease.

  • Wild Type fus corrects als like disease induced by cytoplasmic mutant fus through autoregulation
    bioRxiv, 2020
    Co-Authors: Inmaculada Sanjuanruiz, Noe Goveaperez, Melissa Mcalonisdownes, Stephane Dieterle, Salim Megat, Sylvie Dirriggrosch, Gina Picchiarelli, Diana Piol, Qiang Zhu, Brian Myers
    Abstract:

    Abstract Mutations in FUS, an RNA-binding protein involved in multiple steps of RNA metabolism, are associated with the most severe forms of amyotrophic lateral sclerosis (ALS). Accumulation of cytoplasmic FUS is likely to be a major culprit in the toxicity of FUS mutations. Thus, preventing cytoplasmic mislocalization of the FUS protein may represent a valuable therapeutic strategy. FUS binds to its own pre-mRNA creating an autoregulatory loop efficiently buffering FUS excess through multiple proposed mechanisms including retention of introns 6 and/or 7. Here, we introduced a Wild-Type FUS gene allele, retaining all intronic sequences, in mice whose heterozygous or homozygous expression of a cytoplasmically retained FUS protein (FusΔNLS) was previously shown to provoke ALS-like disease or postnatal lethality, respectively. Wild-Type FUS completely rescued the early lethality caused by the two FusΔNLS alleles, and improved age-dependent motor deficit and reduced lifespan associated with the heterozygous expression of FusΔNLS. Mechanistically, Wild-Type FUS decreased the load of cytoplasmic FUS, increased exon 7 skipping and retention of introns 6 and 7 in the endogenous mouse Fus mRNA, leading to decreased expression of the mutant mRNA. Thus, the Wild-Type FUS allele activates the homeostatic autoregulatory loop, maintaining constant FUS levels and decreasing the mutant protein in the cytoplasm. These results provide proof of concept that an autoregulatory competent Wild-Type FUS expression could protect against this devastating, currently intractable, neurodegenerative disease.