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Post-translational regulation of ccaat/enhancer binding progrein δ(C/EBPδ)by ubiquitin family proteins

Zhou, Shanggen

Abstract Details

2007, Doctor of Philosophy, Ohio State University, Ohio State Biochemistry Program.
CCAAT/enhancer binding proteins (C/EBPs) are a family of highly conserved bZIP type transcription factors function in cell differentiation, proliferation, inflammation, intermediary metabolism and apoptosis. C/EBPδ plays an important role in cellular response to serum withdrawal induced growth arrest of mammary epithelial cells. The goal of this dissertation was to gain better understanding on post-translational regulation of C/EBPδ by ubiquitin family proteins. We found that while the leucine zipper domain facilitates C/EBPδ ubiquitination by providing recognition sequence for ubiquitinating enzymes, it stabilizes C/EBPδ protein by forming functional homo-dimers. We further demonstrated that proteasome mediated C/EBPδ protein degradation is ubiquitin independent. Increased C/EBPδ ubiquitination is associated with cellular response to hydrogen peroxide (H2O2) induced oxidative stress in G0 growth arrested mammary epithelial cells; however, C/EBPd protein stability is not influenced. Ubiquitination of C/EBPδ is associated with repression of C/EBPδ transcriptional activity. C/EBPδ lysine 120 (K120) is a target for SUMO conjugation. SUMO over-expression does not affect C/EBPδ transcriptional activity. Over-expression of PIAS proteins, a class of SUMO ligases, however, repressed C/EBPδ transcriptional activity with PIASy being the most potent inhibitor. PIASy mediated repression of C/EBPδ transcriptional activity does not involve HDAC recruitment or enhanced C/EBPδ sumoylation. PIASy inhibited transcriptional activity of the sumoylation defective C/EBPδ K120R mutant as efficiently as wild type C/EBPδ. Protein-protein interaction experiments demonstrated that the N-terminal nuclear matrix association domain (SAP) of PIASy interacts with the N-terminal transactivation domain (TAD) of C/EBPδ, and this interaction is required for PIASy to inhibit C/EBPδ transcriptional activity. Protein subnuclear localization studies using confocal microscopy demonstrated that PIASy sequesters C/EBPδ from transcriptionally active nuclear foci to transcriptionally inactive nuclear periphery, a mechanism that does not involve PIASy SUMO ligase activity or C/EBPδ sumoylation. C/EBPδ plays a protective role in cellular response to oxidative stress. C/EBPδ does not alter reactive oxygen species production or elimination in the cells, but may be involved in inhibition of NF-κB activity and maintenance of cellular growth arrest condition.
James DeWille (Advisor)

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Citations

  • Zhou, S. (2007). Post-translational regulation of ccaat/enhancer binding progrein δ(C/EBPδ)by ubiquitin family proteins [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1195227986

    APA Style (7th edition)

  • Zhou, Shanggen. Post-translational regulation of ccaat/enhancer binding progrein δ(C/EBPδ)by ubiquitin family proteins. 2007. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1195227986.

    MLA Style (8th edition)

  • Zhou, Shanggen. "Post-translational regulation of ccaat/enhancer binding progrein δ(C/EBPδ)by ubiquitin family proteins." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1195227986

    Chicago Manual of Style (17th edition)