Get started
Work

Mithramycin Is a Gene-Selective Sp1 Inhibitor That Identifies a Biological Intersection between Cancer and Neurodegeneration

Year: 2011
Type: article
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.
DOI: 10.1523/jneurosci.0710-11.2011
Authors: Sama F. Sleiman, Brett C. Langley, Manuela Basso, Jill Berlin, Li Xia, Jimmy B. Payappilly, Madan K. Kharel, Hengchang Guo, J. Lawrence Marsh, Leslie Michels Thompson, Lata Mahishi, Preeti Ahuja, W. Robb MacLellan, Daniel H. Geschwind, Giovanni Coppola, Jürgen Rohr, Rajiv R. Ratan
Institutions: Burke Medical Research Institute, Cornell University, Weill Cornell Medicine, University of Kentucky, University of California, Irvine, University of California, Los Angeles
Language: English
Open Access status: hybrid
Awards: G2291631073, Mitochondrial and Metabolic Dysfunction in Age-related Neurodegeneration, Novel aureolic acid type antitumor agents, Transcription and Therapy for HD: from Molecules to Man, Role of chromatin remodeling in Huntington's disease, Cancer Center Support Grant
OpenAlex ID: W2049612034
FWCI: 6.097
Cites: 74
Cited by: 137
Related to: 10