Proteasomal Degradation in Stem Cells of C. elegans

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atmire.migration.oldid3503
dc.contributor.advisorHansen, David
dc.contributor.authorGupta, Pratyush
dc.date.accessioned2015-09-02T20:55:01Z
dc.date.available2015-11-20T08:00:36Z
dc.date.issued2015-09-02
dc.date.submitted2015en
dc.description.abstractThe level of stem cell proliferation must be tightly controlled for proper development and tissue homeostasis. Multiple levels of gene regulation are often employed to regulate stem cell proliferation to ensure that the amount of proliferation is aligned with the needs of the tissue. I focus on proteasome-mediated protein degradation as a means of regulating the activities of proteins involved in controlling the stem cell proliferative fate in the C. elegans germline. Previously, RFP-1 (RING finger protein), a putative E3 ubiquitin ligase was identified as being involved in regulating the proliferative fate. I demonstrated that RFP-1 binds to and causes proteasome-mediated degradation of MRG-1 (mortality related gene), a homologue of the mammalian chromodomain-containing protein MRG15 (MORF4L1), which has been implicated in promoting proliferation of neural precursor cells. I have demonstrated that C. elegans with reduced proteasome activity, or that lack RFP-1 expression, have increased levels of MRG-1 and cause a shift towards increased proliferation in sensitized genetic backgrounds. Likewise, reduction of MRG-1 partially suppresses stem cell over-proliferation. Analysis in tissue culture cells further supports that RFP-1 ubiquitinates and directly targets MRG-1 for degradation by the proteasome. I discovered that MRG-1 levels are controlled independently of the spatially regulated GLP-1/Notch signaling pathway, which is the primary signal controlling the extent of stem cell proliferation in the C. elegans germline. Therefore, I have identified MRG-1 as a key player in regulating the proliferation versus differentiation decision and determined that its activity is controlled, at least in part, through proteasomal degradation. Furthermore in a second project, using Stable Isotope Labeling of Amino Acids in C. elegans (SILAC) proteomics, I have identified proteins in the C. elegans germline and quantified the abundance of proteins that are enriched in the stem cell population. I have identified eight putative proliferation-promoting proteins that cause suppression of proliferation when their function is reduced. Stem cells contain the therapeutic power to rejuvenate human life. However, this is possible only if we can clearly understand their behaviour. Through this kind of research we can obtain deeper insight into the functioning of stem cells, necessary to harness their untapped potential.en_US
dc.identifier.citationGupta, P. (2015). Proteasomal Degradation in Stem Cells of C. elegans (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/27467en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/27467
dc.identifier.urihttp://hdl.handle.net/11023/2423
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectBiology
dc.subjectBiology--Cell
dc.subjectGenetics
dc.subjectBiology--Molecular
dc.subject.classificationStem Cellsen_US
dc.subject.classificationC. elegansen_US
dc.subject.classificationProteasomal Degradationen_US
dc.subject.classificationMRG-1/MORFen_US
dc.subject.classificationCancer/Tumoren_US
dc.titleProteasomal Degradation in Stem Cells of C. elegans
dc.typedoctoral thesis
thesis.degree.disciplineBiological Sciences
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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