Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


case1183479397.pdf (7.99 MB)

ETD Abstract Container

Abstract Header

THE ROLE OF IKKBETA IN INTERFERON-GAMMA-DEPENDENT SIGNALING

Shultz, David Benjamin
http://rave.ohiolink.edu/etdc/view?acc_num=case1183479397

Abstract Details

2007, Doctor of Philosophy, Case Western Reserve University, Pathology.
Activation of NFkB requires the inhibitor of NFkB (IkB) kinase (IKK) complex, which comprises two functional kinases, IKKalpha and IKKbeta, and the scaffolding protein IKKgamma. We previously identified several interferon (IFN)-gamma-stimulated genes (ISGs) that are not induced in mouse embryonic fibroblast cells (MEFs) doubly -null for the expression of IKKalpha and IKKbeta, and we show here that IFN-gamma-induced transcription of IKK-dependent ISGs requires IKKbeta but not IKKalpha. Through microarray studies, we identified IKKbeta-dependent ISGs in both MEFs and RAW 264.7 macrophages. Many have both kB and ISRE elements, the latter of which bind IRF proteins, in their promoters. Although the IFN-gamma-induced expression of the IKKbeta-dependent gene ip-10 is sensitive to the super-repressor of NFkB and requires the p65 subunit of NFkB, IFN-gamma does not activate NFkB. Thus, a distinct subset of IRF-activated IFN-gamma-dependent genes requires some components of a normal NFkB activation pathway but not actual activation of NFkB in response to IFN-gamma. IFN-gamma activates IRF1 to bind the ISRE of ip-10. In IKKbeta-null cells, IRF1 activation and binding to DNA are slightly weaker and the ability of IRF1 to transactivate a synthetic promoter composed of tandem copies of the ip-10 ISRE element is impaired. IFN-gamma and IL-1 strongly synergize to induce ip-10. However, except at 1 h, the binding of IRF1 to the ip-10 ISRE in response to IFN-gamma is not enhanced by IL-1, and NFkB activation in response to IL-1 is not affected by IFN-gamma . IRF1-null cells show impaired ip-10 induction in response to IFN-gamma compared to wild-type cells. However, synergy between IFN-gamma and IL-1 is unaffected. The results presented provide new evidence of how NFkB components function in the induction of a specific subset of ISGs, and they provide mechanistic information about how IRF1 and NFkB cooperate to activate these promoters.
George Stark (Advisor)
104 p.
Biology, Molecular
Interferon-gamma; NFkB; IRF1; p65

Recommended Citations

Citations

  • Shultz, D. B. (2007). THE ROLE OF IKKBETA IN INTERFERON-GAMMA-DEPENDENT SIGNALING [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1183479397

    APA Style (7th edition)

  • Shultz, David. THE ROLE OF IKKBETA IN INTERFERON-GAMMA-DEPENDENT SIGNALING. 2007. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1183479397.

    MLA Style (8th edition)

  • Shultz, David. "THE ROLE OF IKKBETA IN INTERFERON-GAMMA-DEPENDENT SIGNALING." Doctoral dissertation, Case Western Reserve University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1183479397

    Chicago Manual of Style (17th edition)

case1183479397
699
© 2007, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.