title: Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration.
abstract: Oncogenic transformation of postmitotic neurons triggers cell death, but the identity of genes critical for degeneration remain unclear. The antitumor antibiotic mithramycin prolongs survival of mouse models of Huntington's disease in vivo and inhibits oxidative stress-induced death in cortical neurons in vitro. We had correlated protection by mithramycin with its ability to bind to GC-rich DNA and globally displace Sp1 family transcription factors. To understand how antitumor drugs prevent neurodegeneration, here we use structure-activity relationships of mithramycin analogs to discover that selective DNA-binding inhibition of the drug is necessary for its neuroprotective effect. We identify several genes (Myc, c-Src, Hif1α, and p21(waf1/cip1)) involved in neoplastic transformation, whose altered expression correlates with protective doses of mithramycin or its analogs. Most interestingly, inhibition of one these genes, Myc, is neuroprotective, whereas forced expression of Myc induces Rattus norvegicus neuronal cell death. These results support a model in which cancer cell transformation shares key genetic components with neurodegeneration.
authors.affiliation: Burke Medical Research Institute, White Plains, New York 10605, USA.
authors.forename: Sama F
authors.initials: SF
authors.lastname: Sleiman
authors.forename: Brett C
authors.initials: BC
authors.lastname: Langley
authors.forename: Manuela
authors.initials: M
authors.lastname: Basso
authors.forename: Jill
authors.initials: J
authors.lastname: Berlin
authors.forename: Li
authors.initials: L
authors.lastname: Xia
authors.forename: Jimmy B
authors.initials: JB
authors.lastname: Payappilly
authors.forename: Madan K
authors.initials: MK
authors.lastname: Kharel
authors.forename: Hengchang
authors.initials: H
authors.lastname: Guo
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
authors.forename: Leslie Michels
authors.initials: LM
authors.lastname: Thompson
authors.forename: Lata
authors.initials: L
authors.lastname: Mahishi
authors.forename: Preeti
authors.initials: P
authors.lastname: Ahuja
authors.forename: W Robb
authors.initials: WR
authors.lastname: MacLellan
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.forename: Jürgen
authors.initials: J
authors.lastname: Rohr
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Ratan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004330:Drosophila; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000903:Antibiotics, Antineoplastic; D016329:Sp1 Transcription Factor; D008926:Plicamycin