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dc.contributor.authorMakarevich, Oleg
dc.contributor.authorSabirzhanov, Boris
dc.contributor.authorAubrecht, Taryn G
dc.contributor.authorGlaser, Ethan P
dc.contributor.authorPolster, Brian M
dc.contributor.authorHenry, Rebecca J
dc.contributor.authorFaden, Alan I
dc.contributor.authorStoica, Bogdan A
dc.date.accessioned2020-08-06T17:21:20Z
dc.date.available2020-08-06T17:21:20Z
dc.date.issued2020-07-27
dc.identifier.urihttp://hdl.handle.net/10713/13493
dc.description.abstractDNA damage triggers cell death mechanisms contributing to neuronal loss and cognitive decline in neurological disorders, including traumatic brain injury (TBI), and as a side effect of chemotherapy. Mithramycin, which competitively targets chromatin-binding sites of specificity protein 1 (Sp1), was used to examine previously unexplored neuronal cell death regulatory mechanisms via rat primary neurons in vitro and after TBI in mice (males). In primary neurons exposed to DNA-damage-inducing chemotherapy drugs in vitro we showed that DNA breaks sequentially initiate DNA-damage responses, including phosphorylation of ATM, H2AX and tumor protein 53 (p53), transcriptional activation of pro-apoptotic BH3-only proteins, and mitochondrial outer membrane permeabilization (MOMP), activating caspase-dependent and caspase-independent intrinsic apoptosis. Mithramycin was highly neuroprotective in DNA-damage-dependent neuronal cell death, inhibiting chemotherapeutic-induced cell death cascades downstream of ATM and p53 phosphorylation/activation but upstream of p53-induced expression of pro-apoptotic molecules. Mithramycin reduced neuronal upregulation of BH3-only proteins and mitochondrial dysfunction, attenuated caspase-3/7 activation and caspase substrates' cleavage, and limited c-Jun activation. Chromatin immunoprecipitation indicated that mithramycin attenuates Sp1 binding to pro-apoptotic gene promoters without altering p53 binding suggesting it acts by removing cofactors required for p53 transactivation. In contrast, the DNA-damage-independent neuronal death models displayed caspase initiation in the absence of p53/BH3 activation and were not protected even when mithramycin reduced caspase activation. Interestingly, experimental TBI triggers a multiplicity of neuronal death mechanisms. Although markers of DNA-damage/p53-dependent intrinsic apoptosis are detected acutely in the injured cortex and are attenuated by mithramycin, these processes may play a reduced role in early neuronal death after TBI, as caspase-dependent mechanisms are repressed in mature neurons while other, mithramycin-resistant mechanisms are active. Our data suggest that Sp1 is required for p53-mediated transactivation of neuronal pro-apoptotic molecules and that mithramycin may attenuate neuronal cell death in conditions predominantly involving DNA-damage-induced p53-dependent intrinsic apoptosis.en_US
dc.description.urihttps://doi.org/10.1038/s41419-020-02774-6en_US
dc.language.isoen_USen_US
dc.publisherSpringer Natureen_US
dc.relation.ispartofCell Death and Diseaseen_US
dc.subjectmithramycinen_US
dc.subject.meshCell Deathen_US
dc.subject.meshDNA Damage--physiology
dc.subject.meshPlicamycinen_US
dc.titleMithramycin selectively attenuates DNA-damage-induced neuronal cell deathen_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41419-020-02774-6
dc.identifier.pmid32719328
dc.source.volume11
dc.source.issue7
dc.source.beginpage587
dc.source.endpage
dc.source.countryEngland


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