Regulation of cell number and cell movement in Dictyostelium discoideum

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dc.contributor.advisorGomer, Richard H.en_US
dc.contributor.committeeMemberBraam, Janeten_US
dc.contributor.committeeMemberBeckingham, Kathleen M.en_US
dc.contributor.committeeMemberFarach-Carson, Cindyen_US
dc.contributor.committeeMemberTabor, Jeffrey J.en_US
dc.creatorPhillips, Jonathanen_US
dc.date.accessioned2013-09-16T16:06:41Zen_US
dc.date.accessioned2013-09-16T16:07:08Zen_US
dc.date.available2013-09-16T16:06:41Zen_US
dc.date.available2013-09-16T16:07:08Zen_US
dc.date.created2013-05en_US
dc.date.issued2013-09-16en_US
dc.date.submittedMay 2013en_US
dc.date.updated2013-09-16T16:07:09Zen_US
dc.description.abstractLittle 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.en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.citationPhillips, Jonathan. "Regulation of cell number and cell movement in Dictyostelium discoideum." (2013) Diss., Rice University. <a href="https://hdl.handle.net/1911/72020">https://hdl.handle.net/1911/72020</a>.en_US
dc.identifier.slug123456789/ETD-2013-05-426en_US
dc.identifier.urihttps://hdl.handle.net/1911/72020en_US
dc.language.isoengen_US
dc.rightsCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.subjectAutocrine signalingen_US
dc.subjectProliferationen_US
dc.subjectChaloneen_US
dc.subjectDictyosteliumen_US
dc.subjectChemorepellenten_US
dc.titleRegulation of cell number and cell movement in Dictyostelium discoideumen_US
dc.typeThesisen_US
dc.type.materialTexten_US
thesis.degree.departmentBiochemistry and Cell Biologyen_US
thesis.degree.disciplineNatural Sciencesen_US
thesis.degree.grantorRice Universityen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
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