Causes and Consequences of Centrosome Amplification in Cancer
Başlık:
Causes and Consequences of Centrosome Amplification in Cancer
Yazar:
Denu, Ryan Austin, author.
ISBN:
9780355992717
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (441 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Mark E. Burkard Committee members: Fotis A. Asimakopoulos; Joshua M. Lang; Gary E. Lyons; David A. Wassarman.
Özet:
The centrosome is the major microtubule organizing center of animal cells and consists of two orthogonally-positioned centrioles surrounded by a complex network of proteins called the pericentriolar material. Centrosome amplification (CA), or the numerical increase of centrosomes, occurs in many human cancers and correlates with worse outcomes. However, the causes and consequences of centrosome amplification in cancer have been underexplored. Herein, I attempt to fill this crucial gap in knowledge.
CA can arise by either centriole overduplication or cell doubling events (e.g. cytokinesis failure or cell-cell fusion). The relative contribution of these mechanisms has been unclear. Herein I attempt to answer this question by assessing centrioles in human cancer tissue. We find that centriole overduplication is the predominant mechanism leading to CA. Given this, we attempt to identify the molecular drivers of centriole overduplication in human cancer. To that end, we investigate genomic and transcriptomic alterations in the 366 known centrosome proteins. We identify the most commonly altered centrosome genes in human cancer using publicly-available data sets and test these in vitro. We find that genomic deletion of MCPH1 is a common and penetrant cause of CA in human cancer.
Given that CA is very specific to cancer cells, it represents a potentially good therapeutic target for treating cancer. To that end, we examined the cellular and physiological consequences of CA. As previously shown, we observe that CA induces mitotic errors, including an increase in multipolar spindles and lagging chromosomes. Furthermore, we find that CA impairs autophagy, the cell's recycling pathway, rendering cells with CA more susceptible to autophagy inhibition.
As PLK4 is a potential driver of CA in human cancer and a potential drug target to better treat human cancer, we engineered a PLK4 analog sensitive human epithelial cell line to interrogate PLK4 signaling. We identify many putative substrates of PLK4, including known substrates CEP152 and PCM1, in addition to unknown substrates. We find that PLK4 phosphorylates CEP131 S78 to control the integrity of centriolar satellites. Centriolar satellites are protein-rich granules that surround the centrosome and regulate protein movement to and from the centrosome. Further, we identify CEP170 and CDK5RAP2 as substrates of PLK4.
Lastly, we explore centriolar satellites in human cancer by assessing genomic and transcriptomic alterations in the 44 known centriolar satellite proteins. We identify genomic deletions. To model this, we engineered PCM1 knockout cells, and find that these cells have greater rates of multipolar spindles and lagging chromosomes. Furthermore, PCM1 knockout cells are more sensitive to autophagy inhibitors, consistent with our findings in cells with CA.
Overall, this work expands our knowledge of centrosome biology and PLK4 signaling at the centrosome. Furthermore, this work has identified some of the major causes and consequences of CA in human cancer.
Notlar:
School code: 0262
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(682296.1) | 682296-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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