Origin and development of hematopoietic tumors in sumoylation mutants of Drosophila melanogaster
Item
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Title
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Origin and development of hematopoietic tumors in sumoylation mutants of Drosophila melanogaster
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Identifier
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d_2009_2013:8f219cb82764:11062
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identifier
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10914
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Creator
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Kalamarz, Marta Elzbieta,
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Contributor
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Shubha Govind
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Date
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2010
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Language
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English
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Publisher
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City University of New York.
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Subject
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Genetics | Developmental biology | Cellular biology | Oncology | hematopoiesis | progenitor maintenance | proliferation | sumoylation | tumor | Ubc9
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Abstract
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The larval hematopoietic system of Drosophila melanogaster consists of freely circulating cells, the sessile population, and the hematopoietic organ called the lymph gland. Most hemocytes function as macrophages and play a significant role in innate immunity. Hemocytes also remodel tissues, aiding in development of the organism. Constitutive activation of immune signaling pathways, as well as various mutations in genes which are not linked to immune pathways, result in the overabundance of circulating hemocytes and tumor formation. Many aspects of tumor development, such as the identity of the affected hematopoietic population and mechanisms of tumor growth are either not characterized or not well understood. The overall goal of this project was to understand the origin and development of hematopoietic tumor formation in Ubc9 mutants.;Ubc9 is an E2 enzyme, which conjugates SUMO (small ubiquitin-like modifier) to a range of target proteins. Sumoylation targets vary in function from structural components to enzymes and transcription factors. Thus, sumoylation affects multiple cellular functions via modification of protein localization, stability or activity. Loss-of-function Ubc9 mutants of Drosophila exhibit severe defects in hematopoietic and immune tissues, including hemocyte overproliferation and tumor formation during larval stages.;In this dissertation, we report that the hemolymph of Ubc9 mutants contains hematopoietic cells and structures that range from aggregates (composed of only few cells) to small and large tumors. The largest tumors are less than 1 mm³ in volume. Most cells and aggregates exhibit high ration of mitotic cells, but only a few of the largest tumors in the hemolymph contain actively dividing cells. Based on staining patterns and genetic rescue experiments, we propose that the large tumors are derived specifically from overgrown posterior lobes of the hematopoietic organ. The origin of smaller tumors and aggregates is less clear. Our data suggest that these structures likely derive from circulating hemocytes and fragments of dispersed anterior lobes.;Microtumors in Ubc9 mutants arise from the highly-mitotic mutant stem/progenitor cells of the lymph gland. Loss of sumoylation cascade enzymes E1 (Aos1/Uba2), E2 (Ubc9), or E3 (PIAS) leads to loss of proliferative quiescence in hematopoietic precursors localized within the lymph gland. Proliferative quiescence of these precursors is at least in part mediated by the activity of the cyclin-dependent kinase inhibitor Dacapo/p21. Expression of Dacapo homolog, human p21, in the Ubc9 progenitor cells relieves tumor formation. These studies suggest that sumoylation provides a cell-intrinsic mechanism to preserve stem/progenitor cell states for stress response, immunity and development of the fly.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biology
