Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration.
|Title||Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration.|
|Publication Type||Journal Article|
|Year of Publication||2011|
|Authors||Sleiman, SF, Langley BC, Basso M, Berlin J, Xia L, Payappilly JB, Kharel MK, Guo H, Marsh LJ, Thompson LM, Mahishi L, Ahuja P, MacLellan RW, Geschwind DH, Coppola G, Rohr J, Ratan RR|
|Journal||The Journal of neuroscience : the official journal of the Society for Neuroscience|
|Date Published||2011 May 4|
|Keywords||Analysis of Variance, Animals, Animals, Genetically Modified, Antibiotics, Antineoplastic, Blotting, Western, Cell Survival, Cells, Cultured, cerebral cortex, Chromatin Immunoprecipitation, Drosophila, Neurons, Plicamycin, Rats, Rats, Sprague-Dawley, Sp1 Transcription Factor, Structure-Activity Relationship|
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.
|Alternate Journal||J. Neurosci.|