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J Biol Chem, Vol. 275, Issue 13, 9882-9889, March 31, 2000
From the Albert Einstein College of Medicine, Department of
Microbiology and Immunology, Bronx, New York 10461
FIP3, isolated as a type 2 adenovirus
E3-14.7-kDa interacting protein, is an essential component of the
multimeric I
Regulation of the NF-
B Activation Pathway by Isolated Domains
of FIP3/IKK
, a Component of the IB-
Kinase Complex*
,
B-
kinase (IKK) complex and has been shown to
interact with various components (Fas receptor-interacting protein,
NF-B-inducing kinase, IKK
) of the NF-B activation pathway.
FIP3 has also been shown to repress basal and tumor necrosis factor
(TNF) -induced NF-B activity as well as to induce cell death when
overexpressed. The adenovirus E3-14.7-kDa protein (E3-14.7K) is an
inhibitor of TNF-induced cell death. In the current study, we
generated deletion mutants to map the domains of FIP3, which are
responsible for its various functions. The NF-B inhibitory activity
and the E3-14.7K binding domains were mapped at the carboxyl half of
the FIP3 protein. We also found that the carboxyl-terminal half of FIP3
blocked TNF-induced IB- phosphorylation and subsequent
degradation, which suggests that the stabilization of the cytoplasmic
inhibitor of NF-B underlies the FIP3 inhibition of NF-B activity.
The amino-terminal 119 amino acids were responsible for the FIP3-IKK and FIP3-IKK interaction, and the middle of the protein (amino acids
201-300) appeared to be both the FIP3 self-association domain as well
as the FIP3-Fas receptor-interacting protein interaction domain. Thus,
FIP3 might serve as a scaffold protein to organize the various
components of the IB- kinase complex. Whereas the full-length
protein is required for efficient cell death, the amino-terminal 200 amino acids are sufficient to cause rounding and detachment of the
cells from the monolayer.
*
This work was supported by the National Institutes of Health
Grant RO1 CA72963 (to M. S. H. and J. Y.), National
Institutes of Health Cancer Center Core Grant CA13330 (to M. S. H.), and the Forchheimer Foundation (to M. S. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The data in this paper will be submitted in partial fulfillment of
the requirements for the degree of Doctor of Philosophy in the Sue
Golding Graduate Division of Medical Sciences, Albert Einstein College
of Medicine, Yeshiva University.
§
To whom correspondence should be addressed. Tel.: 718-430-2230;
Fax: 718-430-8702; E-mail: horwitz@aecom.yu.edu.
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