The Role of CDCA7 in Akt-mediated Myc-Dependent Apoptosis and Proliferation

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dc.contributor.advisorScheid, Michael P.
dc.creatorGabor, Tim Vincent
dc.date.accessioned2018-08-27T16:42:37Z
dc.date.available2018-08-27T16:42:37Z
dc.date.copyright2018-05-15
dc.date.issued2018-08-27
dc.date.updated2018-08-27T16:42:37Z
dc.degree.disciplineBiology
dc.degree.levelDoctoral
dc.degree.namePhD - Doctor of Philosophy
dc.description.abstractCDCA7, or cell division cycle associated protein A7, was described in 2001 by Prescott and colleagues as a target of Myc-dependent transcriptional regulation (Prescott et al., 2001). We have identified CDCA7 as associating with the transcription factor Myc and is the target of phosphorylation by the prosurvival serine/threonine kinase Akt. Phosphorylation by Akt at threonine 163 disrupts CDCA7 association with Myc, promotes binding to 14-3-3 and sequestration in the cytoplasm. Coexpression of CDCA7 and Myc in fibroblasts potentiates Myc-dependent apoptosis upon serum withdrawal. In contrast, knockdown of CDCA7 by shRNA abrogated Myc-dependent apoptosis. Myc induced transformation of fibroblasts was reduced in the presence of CDCA7 and significantly inhibited by the expression of the non-Myc binding mutant (156-187) CDCA7. We have shown that CDCA7 enhances the activation of an E-box in a Myc-binding dependent manner. CDCA7 increases Myc occupancy of the proapoptotic BAX promoter, elevates BAX and Cyclin B1 mRNA levels while reducing p15INK4B mRNA levels. This data points to a novel mechanism which implicates Akt phosphorylation of CDCA7 as participating in the dual signal model of Myc of function and thus affecting Myc-dependent growth and transformation. In this study, we have also shown that expression of CDCA7 reduces proliferation rates and shifts cell cycle distribution towards G2/M phase and that phosphorylation of CDCA7 at T163 occurs strictly in G2/M. CDCA7 phosphorylated at threonine 163 colocalizes with the centrosomal protein marker -Tubulin and activated Akt (phospho-serine 473) in mitotic cells. Finally, we have shown that CDCA7 co-associates with monomers of itself which is dependent on amino acids 187-234, adding to the possible mechanisms by which CDCA7 function may be regulated.
dc.identifier.urihttp://hdl.handle.net/10315/35022
dc.language.isoen
dc.rightsAuthor owns copyright, except where explicitly noted. Please contact the author directly with licensing requests.
dc.subjectBiochemistry
dc.subject.keywordsCDCA7
dc.subject.keywordsGill
dc.subject.keywordsProliferation
dc.subject.keywordsApoptosis
dc.subject.keywordsMyc
dc.subject.keywordsAkt
dc.subject.keywordsPI3K
dc.subject.keywordsCancer
dc.subject.keywordsImmunohistochemistry
dc.subject.keywordsWestern blot
dc.subject.keywordsImmunoprecipitation
dc.subject.keywordsCell culture
dc.subject.keywordsShrna
dc.subject.keywordsqPCR
dc.subject.keywordsChip
dc.subject.keywordsSerum
dc.subject.keywordsSerum withdrawal
dc.subject.keywordsPdgf
dc.subject.keywordsNocodazole
dc.subject.keywordsRO-3306
dc.subject.keywordsCyclin
dc.subject.keywordsCdk. cell cycle
dc.titleThe Role of CDCA7 in Akt-mediated Myc-Dependent Apoptosis and Proliferation
dc.typeElectronic Thesis or Dissertation

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