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dc.contributor.advisor Gomer, Richard H.
dc.creatorPhillips, Jonathan
dc.date.accessioned 2013-09-16T16:06:41Z
dc.date.accessioned 2013-09-16T16:07:08Z
dc.date.available 2013-09-16T16:06:41Z
dc.date.available 2013-09-16T16:07:08Z
dc.date.created 2013-05
dc.date.issued 2013-09-16
dc.date.submitted May 2013
dc.identifier.citation Phillips, Jonathan. "Regulation of cell number and cell movement in Dictyostelium discoideum." (2013) Diss., Rice University. https://hdl.handle.net/1911/72020.
dc.identifier.urihttps://hdl.handle.net/1911/72020
dc.description.abstract Little is known about how the size of a tissue is established during development and maintained subsequently. Proliferation-inhibiting signals secreted by cells within a tissue that act specifically on cells within that tissue can provide negative feedback on cell number, thus regulating tissue size. A better understanding of tissue-specific inhibitors of proliferation could be useful for designing therapies for cancer and other diseases. However, few signals of this sort have been identified, and little is known about how these signals function. Two examples of such signals are the proteins AprA and CfaD, which are secreted by the social amoeba Dictyostelium discoideum and inhibit cell proliferation in a concentration-dependent manner. Cells lacking either AprA or CfaD proliferate rapidly, and adding recombinant AprA or CfaD to cells reduces proliferation. However, little is known about the signal transduction pathways downstream of AprA and CfaD. I identified three proteins that are required for the normal function of AprA and CfaD: the kinase QkgA, the putative transcription factor BzpN, and the putative kinase PakD. Cells lacking any one of these proteins proliferate rapidly, and adding AprA or CfaD to cells lacking these proteins does not cause reduced proliferation, indicating that these proteins are involved in AprA/CfaD signal transduction. I also found that, in addition to its proliferation-inhibiting activity, AprA also functions as an autocrine chemorepellant. Colonies of cells lacking AprA expand less rapidly than wild-type colonies, despite the fact that individual cells lacking AprA show a random motility like that of wild-type cells. Further, two independent assays demonstrate that cells show a biased movement away from a source of AprA. The chemorepellant activity of AprA requires CfaD, QkgA, and PakD, but not BzpN, indicating that AprA affects proliferation and chemorepulsion through distinct but overlapping pathways. These results suggest that AprA functions as a readout of local cell density, to which cells respond by slowing proliferation and chemotaxing to regions of lower cell density, where nutrients are more likely to be present. The study of human AprA, CfaD, QkgA, BzpN, and PakD orthologs may serve to guide therapeutic approaches that modulate chemorepulsive or antiproliferative processes.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.subjectAutocrine signaling
Proliferation
Chalone
Dictyostelium
Chemorepellent
dc.title Regulation of cell number and cell movement in Dictyostelium discoideum
dc.contributor.committeeMember Braam, Janet
dc.contributor.committeeMember Beckingham, Kathleen M.
dc.contributor.committeeMember Farach-Carson, Cindy
dc.contributor.committeeMember Tabor, Jeffrey J.
dc.date.updated 2013-09-16T16:07:09Z
dc.identifier.slug 123456789/ETD-2013-05-426
dc.type.genre Thesis
dc.type.material Text
thesis.degree.department Biochemistry and Cell Biology
thesis.degree.discipline Natural Sciences
thesis.degree.grantor Rice University
thesis.degree.level Doctoral
thesis.degree.name Doctor of Philosophy


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