Investigation of the molecular mechanisms and therapeutic potential of oncogene-induced kinetochore-microtubule defects
| dc.contributor.author | Herman, Jacob A., author | |
| dc.contributor.author | DeLuca, Jenniver G., advisor | |
| dc.contributor.author | Bamburg, James, committee member | |
| dc.contributor.author | Stargell, Laurie, committee member | |
| dc.contributor.author | Nickoloff, Jac, committee member | |
| dc.date.accessioned | 2015-08-27T03:57:11Z | |
| dc.date.available | 2016-06-03T03:56:54Z | |
| dc.date.issued | 2015 | |
| dc.description.abstract | Kinetochores, large protein structures assembled on centromeric DNA during mitosis, bind to microtubules of the mitotic spindle to orchestrate and power chromosome movements. Deregulation of kinetochore-microtubule (kinetochore-MT) attachments has been implicated in driving chromosome instability and cancer evolution; however, the nature and source of kinetochore-MT attachment defects in cancer cells remain largely unknown. Here, we identify kinetochore-MT attachments, and their regulation by Aurora B kinase (ABK) as key targets for selective therapeutic intervention in glioblastoma and other cancers. We observe that accessory regulators of ABK and kinetochore-microtubule attachment stability are compromised in some cancers and fundamentally alter kinetochore signaling. First we identify RAS/MAPK oncogenic transformation as sufficient to induce these defects through an enzymatic cascade targeting the kinetochore. We then identify BUBR1 kinetochore recruitment and kinetochore-associated PP2A activity as cancer-essential activities, which are required for some cancers to form robust physical interactions between kinetochores and MTs. We also verify previous findings that many cancers are characterized by chromosome segregation errors arising from merotelic kinetochore-microtubule attachments (a single kinetochore bound to microtubules emanating from both spindle poles). We attribute the cause of these errors to be a decrease in MT dynamics independent of the physical attachments status. Finally we characterize a novel kinetochore component, BUGZ, which serves as a molecular chaperone for BUB3 and thus indirectly stimulates ABK activity. We find that BUGZ binds to BUB3 through a conserved GLEBS domain, and this interaction is required for BUB3 kinetochore localization. BUGZ depletion decreases ABK activity resulting in lethal chromosome alignment defects in glioblastoma cells and genetically transformed cells. Together these findings further elucidate the molecular mechanism by which kinetochore-MT attachments are regulated and importantly, how this mechanism is perturbed upon transformation. These results will make the design and application of novel anti-cancer drugs with reduced side effects possible because the specifically target cancer populations. | |
| dc.format.medium | born digital | |
| dc.format.medium | doctoral dissertations | |
| dc.identifier.uri | http://hdl.handle.net/10217/166957 | |
| dc.language | English | |
| dc.language.iso | eng | |
| dc.publisher | Colorado State University. Libraries | |
| dc.relation.ispartof | 2000-2019 | |
| dc.rights | Copyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright. | |
| dc.subject | BubR1 | |
| dc.subject | MAPK | |
| dc.subject | RAS | |
| dc.subject | kinetochore | |
| dc.subject | Aurora B | |
| dc.subject | PP2A | |
| dc.title | Investigation of the molecular mechanisms and therapeutic potential of oncogene-induced kinetochore-microtubule defects | |
| dc.type | Text | |
| dcterms.embargo.expires | 2016-06-03 | |
| dcterms.embargo.terms | 2016-06-03 | |
| dcterms.rights.dpla | This Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). | |
| thesis.degree.discipline | Biochemistry and Molecular Biology | |
| thesis.degree.grantor | Colorado State University | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) |
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