A1256655371qxPKY

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Modeling the NF-kB signaling pathway
Baltazar D. Aguda bdaguda_at_gmail.com
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How to rapidly (!) get information on NF-kB
google
nf-kb.org
http//pid.nci.nih.gov/
pathguide.org
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canonical NF-kB pathway
clickable !
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biocarta.com
NF-kB pathway signaling pathway
Nuclear factor kB (NF-kB) is a nuclear
transcription factor that regulates expression of
a large number of genes that are critical for the
regulation of apoptosis, viral replication,
tumorigenesis, inflammation, and various
autoimmune diseases. The activation of NF-kB is
thought to be part of a stress response as it is
activated by a variety of stimuli that include
growth factors, cytokines, lymphokines, UV,
pharmacological agents, and stress. In its
inactive form, NF-kB is sequestered in the
cytoplasm, bound by members of the IkB family of
inhibitor proteins, which include IkBa, IkBb,
IkBg, and IkBe. The various stimuli that activate
NF-kB cause phosphorylation of IkB, which is
followed by its ubiquitination and subsequent
degradation. This results in the exposure of the
nuclear localization signals (NLS) on NF-kB
subunits and the subsequent translocation of the
molecule to the nucleus. In the nucleus, NF-kB
binds with a consensus sequence (5'GGGACTTTCC-3')
of various genes and thus activates their
transcription. IkB proteins are phosphorylated
by IkB kinase complex consisting of at least
three proteins IKK1/IKKa, IKK2/IKKb, and
IKK3/IKKg. These enzymes phosphorylate IkB
leading to its ubiquitination and degradation.
Tumor necrosis factor (TNF) which is the
best-studied activator binds to its receptor and
recruits a protein called TNF receptor death
domain (TRADD). TRADD binds to the TNF
receptor-associated factor 2 (TRAF-2) that
recruits NF-kB-inducible kinase (NIK). Both IKK1
and IKK2 have canonical sequences that can be
phosphorylated by the MAP kinase NIK/MEKK1 and
both kinases can independently phosphorylate IkBa
or IkBb. TRAF-2 also interacts with A20, a zinc
finger protein whose expression is induced by
agents that activate NF-kB. A20 functions to
block TRAF2-mediated NF-kB activation. A20 also
inhibits TNF and IL-1 induced activation of NF-kB
suggesting that it may act as a general
inhibitor of NF-kB activation.
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canonical NF-kB pathway
(RelA-p50)
http//people.bu.edu/gilmore/nf-kb/gilmorefig2.gif
http//nf-kb.org
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Kinetic Equations (24 eqns)
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IkBat
NF-kB
NF-kB
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Most recent model has 99 differential equations !
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3-variable model of NF-kB oscillations
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G is gene target of NF-kB (N) dimer.
1/1(x/x0)h
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functional role of NF-kB oscillations?
gene expression - regulated by oscillation
frequency? - sensitive to IKK activity (link to
external signals) - sensitive to
binding/dissociation rates of NF-kB from gene
operator sites
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