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mco1243865120.pdf (1.29 MB)
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The Role of RKIP in NFκB singaling pathway
Author Info
Tang, Huihui
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=mco1243865120
Abstract Details
Year and Degree
2009, Doctor of Philosophy in Biomedical Sciences (Ph.D.), University of Toledo, College of Medicine.
Abstract
RKIP (Raf Kinase Inhibitor Protein) was first identified as an inhibitor of Raf1 kinase inthe Raf-MEK-ERK signaling pathway. It can interact with Raf1 and MEK and disrupt the interaction of Raf1 and MEK by competing with their binding. Since RKIP is a very abundant protein, it must have additional targets other than Raf-MEK-ERK pathway. Indeed, RKIP was also found to play a pivotal role in NF-κB pathway. NF-κB pathways are ubiquitous pathways that exist in many different tissues. NF-κB pathway is involved in different biological processes including inflammation and immune responses. NF-κB gets activated by phosphorylation and subsequent degradation of IκB in response to stimulation. Our studies show that RKIP interacts with multiple components of canonical NF-κB pathway in response to IL-1β stimulation. RKIP affected IκB degradation. Overexpression of RKIP inhibited IκB degradation, whereas downregulation of RKIP also inhibits IκB degradation. The inhibitory effect of IκB degradation in RKIP knockdown cells can be rescued by restoring RKIP. The effect of RKIP on IκB degradation was concentration dependent. The mode of action of RKIP on IκB degradation was consistent with the properties described for a scaffolding protein. A scaffolding protein’s main function is to bring other proteins together and allow them to interact. The signaling of the scaffolding cascade is dependent on the concentration of the scaffold protein. Both low and high concentration of scaffold protein will disrupt the interaction of the components of the scaffolding signaling cascade. Only intermediate concentration of scaffolding protein will allow for the optimal association of the different components in the signaling cascade, thus leads to the optimal signaling. One major feature of scaffolding protein is that it can interact with different components of the signaling cascade. Our studies show that RKIP interacts with TRAF6 and TAK1 of the canonical NF-κB pathway in both overexpression condition and physiological condition, and that the interaction of TAK1 and TRAF 6 was inhibited by knockdown of RKIP. Knockdown of RKIP inhibited phosphorylation of IκB, IKKβ and TAK1. Ubiquitination of TRAF6 and TAK1 were also inhibited by the knockdown of RKIP. Once IκB was degraded, p50/p65 heterodimer would be released and then translocate to the nucleus. Our studies showed that both p50 and p65 nuclear translocation was inhibited in RKIP knockdown cells. Consistently, CHIP assays showed that binding of p65 with promoter of CIAP2, Rantes and IκB genes was also decreased in RKIP knockdown cells.
Committee
Kam Yeung, Ph.D. (Committee Chair)
Z. Kevin Pan, Ph.D. (Committee Member)
Dorothea Sawicki, Ph.D. (Committee Member)
Zi-Jian Xie, Ph.D. (Committee Member)
Ivana de la Serna, Ph.D. (Committee Member)
Pages
114 p.
Subject Headings
Health
;
Molecular Biology
Keywords
RKIP
;
PEBP
;
scaffold protein
;
NFkB
;
signaling pathway
;
Ubiquitination
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Citations
Tang, H. (2009).
The Role of RKIP in NFκB singaling pathway
[Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1243865120
APA Style (7th edition)
Tang, Huihui.
The Role of RKIP in NFκB singaling pathway.
2009. University of Toledo, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=mco1243865120.
MLA Style (8th edition)
Tang, Huihui. "The Role of RKIP in NFκB singaling pathway." Doctoral dissertation, University of Toledo, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=mco1243865120
Chicago Manual of Style (17th edition)
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Document number:
mco1243865120
Download Count:
538
Copyright Info
© 2009, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.