Mithramycin is a gene-selective sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration Academic Article uri icon

Overview

MeSH Major

  • Antibiotics, Antineoplastic
  • Neurons
  • Plicamycin
  • Sp1 Transcription Factor

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.

publication date

  • May 4, 2011

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3717375

Digital Object Identifier (DOI)

  • 10.1523/JNEUROSCI.0710-11.2011

PubMed ID

  • 21543616

Additional Document Info

start page

  • 6858

end page

  • 70

volume

  • 31

number

  • 18