Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration
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...
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| مؤلفون آخرون: | , , , , , , , , , , , , , |
| التنسيق: | article |
| منشور في: |
2011
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| الوصول للمادة أونلاين: | http://hdl.handle.net/10725/6141 https://doi.org/10.1523/JNEUROSCI.0710-11.2011 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://www.jneurosci.org/content/31/18/6858.short |
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| _version_ | 1864513478585221120 |
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| author | Sleiman, Sama F. |
| author2 | Langley, Brett C. Berlin, Jill Xia, Li Payappilly, Jimmy B. Kharel, Madan K. Guo, Hengchang Thonpson, Leslie Michels Mahishi, Lata Ahuja, Preeti Maclellan, W. Robb Geschwind, Daniel H. Coppola, Giovanni Rohr, Jurgen Ratan, Rajiv R. |
| author2_role | author author author author author author author author author author author author author author |
| author_facet | Sleiman, Sama F. Langley, Brett C. Berlin, Jill Xia, Li Payappilly, Jimmy B. Kharel, Madan K. Guo, Hengchang Thonpson, Leslie Michels Mahishi, Lata Ahuja, Preeti Maclellan, W. Robb Geschwind, Daniel H. Coppola, Giovanni Rohr, Jurgen Ratan, Rajiv R. |
| author_role | author |
| dc.creator.none.fl_str_mv | Sleiman, Sama F. Langley, Brett C. Berlin, Jill Xia, Li Payappilly, Jimmy B. Kharel, Madan K. Guo, Hengchang Thonpson, Leslie Michels Mahishi, Lata Ahuja, Preeti Maclellan, W. Robb Geschwind, Daniel H. Coppola, Giovanni Rohr, Jurgen Ratan, Rajiv R. |
| dc.date.none.fl_str_mv | 2011 2017-09-06T07:34:16Z 2017-09-06T07:34:16Z 2017-10-12 |
| dc.identifier.none.fl_str_mv | 1529-2401 http://hdl.handle.net/10725/6141 https://doi.org/10.1523/JNEUROSCI.0710-11.2011 Sleiman, S. F., Langley, B. C., Basso, M., Berlin, J., Xia, L., Payappilly, J. B., ... & Mahishi, L. (2011). Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration. Journal of Neuroscience, 31(18), 6858-6870. http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://www.jneurosci.org/content/31/18/6858.short |
| dc.language.none.fl_str_mv | en |
| dc.relation.none.fl_str_mv | Journal of Neuroscience |
| dc.rights.*.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.title.none.fl_str_mv | Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration |
| dc.type.none.fl_str_mv | Article info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/article |
| description | 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | LAURepo_da75bd207e89ee3d5dcbe42d6b6df882 |
| identifier_str_mv | 1529-2401 Sleiman, S. F., Langley, B. C., Basso, M., Berlin, J., Xia, L., Payappilly, J. B., ... & Mahishi, L. (2011). Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration. Journal of Neuroscience, 31(18), 6858-6870. |
| language_invalid_str_mv | en |
| network_acronym_str | LAURepo |
| network_name_str | Lebanese American University repository |
| oai_identifier_str | oai:laur.lau.edu.lb:10725/6141 |
| publishDate | 2011 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| spelling | Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegenerationSleiman, Sama F.Langley, Brett C.Berlin, JillXia, LiPayappilly, Jimmy B.Kharel, Madan K.Guo, HengchangThonpson, Leslie MichelsMahishi, LataAhuja, PreetiMaclellan, W. RobbGeschwind, Daniel H.Coppola, GiovanniRohr, JurgenRatan, Rajiv R.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.PublishedN/A2017-09-06T07:34:16Z2017-09-06T07:34:16Z20112017-10-12Articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1529-2401http://hdl.handle.net/10725/6141https://doi.org/10.1523/JNEUROSCI.0710-11.2011Sleiman, S. F., Langley, B. C., Basso, M., Berlin, J., Xia, L., Payappilly, J. B., ... & Mahishi, L. (2011). Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration. Journal of Neuroscience, 31(18), 6858-6870.http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.phphttp://www.jneurosci.org/content/31/18/6858.shortenJournal of Neuroscienceinfo:eu-repo/semantics/openAccessoai:laur.lau.edu.lb:10725/61412021-03-19T10:00:49Z |
| spellingShingle | Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration Sleiman, Sama F. |
| status_str | publishedVersion |
| title | Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration |
| title_full | Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration |
| title_fullStr | Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration |
| title_full_unstemmed | Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration |
| title_short | Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration |
| title_sort | Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration |
| url | http://hdl.handle.net/10725/6141 https://doi.org/10.1523/JNEUROSCI.0710-11.2011 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://www.jneurosci.org/content/31/18/6858.short |