TY - JOUR
T1 - Mithramycin is a gene-selective sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration
AU - Sleiman, Sama F.
AU - Langley, Brett C.
AU - Basso, Manuela
AU - Berlin, Jill
AU - Xia, Li
AU - Payappilly, Jimmy B.
AU - Kharel, Madan K.
AU - Guo, Hengchang
AU - Marsh, J. Lawrence
AU - Thompson, Leslie Michels
AU - Mahishi, Lata
AU - Ahuja, Preeti
AU - Maclellan, W. Robb
AU - Geschwind, Daniel H.
AU - Coppola, Giovanni
AU - Rohr, Jürgen
AU - Ratan, Rajiv R.
PY - 2011/5/4
Y1 - 2011/5/4
N2 - 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 p21waf1/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.
AB - 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 p21waf1/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.
UR - http://www.scopus.com/inward/record.url?scp=79955755623&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955755623&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0710-11.2011
DO - 10.1523/JNEUROSCI.0710-11.2011
M3 - Article
C2 - 21543616
AN - SCOPUS:79955755623
SN - 0270-6474
VL - 31
SP - 6858
EP - 6870
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 18
ER -