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Nadler, Monica

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Nadler

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Monica

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Nadler, Monica
Author's Publications: search.filters.isAuthorOfPublication.87cf1d47-414e-4de5-b79d-89698856e596

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    A Peroxidase Peroxiredoxin 1-Specific Redox Regulation of the Novel FOXO3 microRNA Target let-7
    (Mary Ann Liebert, Inc., 2018) Hopkins, Barbara L.; Nadler, Monica; Skoko, John J.; Bertomeu, Thierry; Pelosi, Andrea; Shafaei, Parisa Mousavi; Levine, Kevin; Schempf, Anja; Pennarun, Bodvael; Yang, Bo; Datta, Dipak; Bucur, Octavian; Ndebele, Kenneth; Oesterreich, Steffi; Yang, Da; Giulia Rizzo, Maria; Khosravi-Far, Roya; Neumann, Carola A.
    Abstract Precision in redox signaling is attained through posttranslational protein modifications such as oxidation of protein thiols. The peroxidase peroxiredoxin 1 (PRDX1) regulates signal transduction through changes in thiol oxidation of its cysteines. We demonstrate here that PRDX1 is a binding partner for the tumor suppressive transcription factor FOXO3 that directly regulates the FOXO3 stress response. Heightened oxidative stress evokes formation of disulfide-bound heterotrimers linking dimeric PRDX1 to monomeric FOXO3. Absence of PRDX1 enhances FOXO3 nuclear localization and transcription that are dependent on the presence of Cys31 or Cys150 within FOXO3. Notably, FOXO3-T32 phosphorylation is constitutively enhanced in these mutants, but nuclear translocation of mutant FOXO3 is restored with PI3K inhibition. Here we show that on H2O2 exposure, transcription of tumor suppressive miRNAs let-7b and let-7c is regulated by FOXO3 or PRDX1 expression levels and that let-7c is a novel target for FOXO3. Conjointly, inhibition of let-7 microRNAs increases let-7-phenotypes in PRDX1-deficient breast cancer cells. Altogether, these data ascertain the existence of an H2O2-sensitive PRDX1-FOXO3 signaling axis that fine tunes FOXO3 activity toward the transcription of gene targets in response to oxidative stress. Antioxid. Redox Signal. 28, 62–77.
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    Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1
    (2017) Krishnan, Vaishnav; Stoppel, David C.; Nong, Yi; Johnson, Mark; Nadler, Monica; Ozkaynak, Ekim; Teng, Brian L.; Nagakura, Ikue; Mohammad, Fahim; Silva, Michael; Peterson, Sally; Cruz, Tristan J.; Kasper, Ekkehard; Arnaout, Ramy; Anderson, Matthew
    Summary Maternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant autism linked to increased gene dosages of UBE3A, which both possesses ubiquitin-ligase and transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus down-regulates glutamatergic synapse organizer cerebellin-1 (Cbln1) that is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in mice with asymptomatic increases of UBE3A. This Ube3a-seizure synergy maps to glutamate neurons of the midbrain ventral tegmental area (VTA) where Cbln1 deletions impair sociability and weaken glutamatergic transmission. We provide preclinical evidence that viral-vector-based chemogenetic activations of, or Cbln1 restorations in VTA glutamatergic neurons rescues sociability deficits induced by Ube3a and/or seizures. Our results suggest a gene × seizure interaction in VTA glutamatergic neurons that impairs sociability by downregulating Cbln1, a key node in the expanding protein interaction network of autism genes.
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    Members of the thrombospondin gene family bind stromal interaction molecule 1 and regulate calcium channel activity
    (2014) Duquette, Mark; Nadler, Monica; Okuhara, Dayne; Thompson, Jill; Shuttleworth, Trevor; Lawler, Jack
    The thrombospondins (TSPs) are a family of matricellular proteins that regulate cellular phenotype through interactions with a myriad of other proteins and proteoglycans. We have identified a novel interaction of the members of the TSP gene family with stromal interaction molecule 1 (STIM1). This association is robust since it is preserved in Triton X-100, can be detected with multiple anti-TSP-1 and anti-STIM1 antibodies, and is detected in a wide range of cell types. We have also found that STIM1 co-immunoprecipitates with TSP-4 and cartilage oligomeric matrix protein (COMP), and that a recombinant version of the N-terminal domain of STIM1 binds to the signature domain of TSP-1 and COMP. The association of the TSPs with STIM1 is observed in both the presence and absence of calcium indicating that the calcium-dependent conformation of the signature domain of TSPs is not required for binding. Thus, this interaction could occur in the ER under conditions of normal or low calcium concentration. Furthermore, we observed that the expression of COMP in HEK 293 cells decreases STIM1-mediated calcium release activated calcium (CRAC) channel currents and increases arachidonic acid calcium (ARC) channel currents. These data indicate that the TSPs regulate STIM1 function and participate in the reciprocal regulation of two channels that mediate calcium entry into the cell.