Show simple item record

dc.contributor.advisorSoboloff, Jonathan
dc.creatorGo, Christina Karen
dc.date.accessioned2020-10-26T18:26:12Z
dc.date.available2020-10-26T18:26:12Z
dc.date.issued2018
dc.identifier.urihttp://hdl.handle.net/20.500.12613/1310
dc.description.abstractMy studies seek to understand how Ca2+ signals are controlled by entry and clearance mechanisms, leading to pluripotent changes in cell fate. The Ca2+-dependent activity of transcription factor NFAT, which drives many changes in gene expression, was examined. Remarkably, overexpression of Ca2+-extruder PMCA4 increased NFAT activation in a splice variant-dependent manner. Partner of STIM1 (POST), rather than facilitating STIM1-mediated inhibition of PMCA4, accelerated clearance via close associations with PMCA4b and Orai1. Furthermore, it was found that PMCA4b markedly depressed near-PM Ca2+ while raising global levels. These observations define the role of POST in facilitating sustained SOCE and spontaneous Ca2+ oscillations by coupling PMCA4 and Orai1 activity. EGR4 was found to upregulate POST during T cell activation, and knocking out Egr4 resulted in dysregulated Ca2+ oscillations. Moreover, knockout of Egr4 induced strong IFN-γ expression independent of T cell polarization. The dysregulation of Ca2+ signals and cytokine production support a new role for EGR4 in T cell differentiation. Finally, SOCE was found to be reduced in invasive melanoma cell lines. Correlation of diminished SOCE with increased invasiveness support a model in which invasiveness can be driven by reduced SOCE downstream of non-canonical Wnt5a signaling. These novel findings present new mechanisms governing sustained Ca2+ responses, and their ramifications on T cell development and progression of neoplastic disease.
dc.format.extent186 pages
dc.language.isoeng
dc.publisherTemple University. Libraries
dc.relation.ispartofTheses and Dissertations
dc.rightsIN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectBiochemistry
dc.subjectMedicine
dc.subjectBiology, Molecular
dc.titlePHYSIOLOGICAL IMPLICATIONS AND MOLECULAR INSIGHTS INTO CA2+ ENTRY AND CLEARANCE MECHANISMS
dc.typeText
dc.type.genreThesis/Dissertation
dc.contributor.committeememberRothberg, Brad S.
dc.contributor.committeememberChong, Parkson Lee-Gau
dc.contributor.committeememberZaidi, M. Raza
dc.contributor.committeememberRen, Dejian
dc.description.departmentBiochemistry
dc.relation.doihttp://dx.doi.org/10.34944/dspace/1292
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.degreePh.D.
refterms.dateFOA2020-10-26T18:26:12Z


Files in this item

Thumbnail
Name:
Go_temple_0225E_13503.pdf
Size:
5.880Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record