Transcript Lecture 12 - Lectures For UG-5

Cell Signaling
Lecture 12
NFkB
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NFkB (nuclear factor kappa beta) is a transcription
factor that plays important roles in the immune system.
NFkB regulates the expression of cytokines, inducible
nitric oxide synthase (iNOS)-the enzyme that produces
nitric oxide which is toxic to bacterial cells.
inhibitors of apoptosis protein that prevent cell death
and effector enzymes in response to ligation of many
receptors involved in immunity including T-cell receptors
(TCRs), B-cell receptors (BCRs) and members of the
Toll-like receptor/IL-1 receptor super family.
NFkB also plays a role in the development and the
activity of a number of tissues including the central
nervous system, liver cells etc.
Moreover, pathological dysregulation of NFkB is linked to
inflammatory and autoimmune diseases as well as cancer.
NFkB family
In mammals, the NFkB family is composed of five related
transcription factors: p50, p52, RelA (p65), c-Rel and RelB.
 These transcription factors are related through an N-terminal,
300 amino acid, DNA binding/dimerization domain, called the Rel
homology domain (RHD), through which they can form
homodimers and heterodimers that bind to 9-10 base pair DNA
sites, known as kB sites, in the promoters and enhancer regions
of genes, thereby modulating gene expression.
 RelA, c-Rel and RelB contain C-terminal transcriptional
activation domains (TADs), which enable them to activate target
gene expression. In contrast, p50 and p52 do not contain Cterminal TADs; therefore, p50 and p52 homodimers repress
transcription unless they are bound to a protein containing a
TAD, such as RelA, c-Rel or RelB or Bcl-3 (a related
transcriptional co-activator)..
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NFkB’s transcriptional activity is silenced
by interactions with inhibitory IkB
proteins present in the cytoplasm.
 There are currently seven identified IkB
family members - IkBa, IkBb, Bcl-3, IkBe,
IkBg and the precursor
proteins p100and p105
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NFkB signaling pathway
There are two signaling pathways leading to the activation
of NFkB known as the canonical pathway (or classical) and
the non-canonical pathway (or alternative pathway).
 The common regulatory step in both of these cascades is
activation of an IkB kinase (IKK) complex consisting of
catalytic kinase subunits (IKKa and/or IKKb) and the
regulatory non-enzymatic scaffold protein NEMO (NFkappa B essential modulator also known as IKKg).
 Activation of NFkBdimers is due to IKK-mediated
phosphorylation-induced proteasomal degradation of the
IkB inhibitor enabling the active NFkBtranscription factor
subunits to translocate to the nucleus and induce target
gene expression.
 NFkB activation leads to the expression of the IkBa gene,
which consequently sequesters NFkB subunits and
terminates transcriptional activity unless a persistent
activation signal is present.
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Conical/classical
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In the canonical signaling pathway, binding of
ligand to a cell surface receptor such as a
member of the the Toll-like receptor
superfamily leads to the recruitment of
adaptors (such as TRAF) to the cytoplasmic
domain of the receptor.
These adaptors in turn recruit the IKK
complex which leads to phosphorylation and
degradation of the IkB inhibitor.
The canonical pathway
activatesNFkB dimers comprising of RelA, cRel, RelB and p50.
Canonical and non-canonical NF-κB signaling pathways. Canonical pathway is triggered by
numerous signals, including those mediated by innate and adaptive immune receptors. It
involves activation of IKK complex by Tak1, IKK-mediated IκBα phosphorylation, and
subsequent degradation, resulting in rapid and transient nuclear translocation of the
prototypical NF-κB heterodimer RelA/p50. Non-canonical NF-κB pathway relies on
phosphorylation-induced p100 processing, which is triggered by signaling from a subset of
TNFR members. This pathway is dependent on NIK and IKKα, but not on the trimeric IKK
complex, and mediates the persistent activation of RelB/p52 complex.
Non-conical
The non-canonical pathway is responsible for the activation of
p100/RelB complexes and occurs during the development of
lymphoid organs responsible for the generation of B and T
lymphocytes.
 Only a small number of stimuli are known to activate NFkB via
this pathway and these factors include lymphotoxin B and B cell
activating factor (BAFF).
 This pathway utilizes an IKK complex that comprises two IKKa
subunits, but not NEMO. In the non-canonical pathway, ligand
induced activation results in the activation of NFkB-inducing
kinase (NIK), which phosphorylates and activates the IKKa
complex, which in turn phosphorylates p100 leading to the
processing and liberation of the p52/RelB active heterodimer. In
contrast to p100, p105 undergoes constitutive cleavage to
producep50, whether p105 can undergo inducible processing
remains a contentious issue.
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Role of NFkB in diseases
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Asthma is a chronic inflammatory disorder. The pathogenesis of asthma involves
the persistent expression of pro-inflammatory cytokines, chemokines and other
such inflammatory mediators. Many of these genes contain the kB site
for NFkB within their promoters, suggesting that NFkB plays a vital role in
asthma. Indeed, increased NFkB activity has been observed in the airways of
asthmatic patients.
NFkB is also implicated in inflammatory bowel disease such as Crohn’s disease
and ulcerative colitis.
NFkBactivation is evident in biopsies from such patients and treatment of
patients with steroids decreases NFkB activity in biopsies as well as reducing
the clinical symptoms of disease. Furthermore, NFkB is involved in the
pathophysiology of the autoimmune disorder rheumatoid arthritis
(RA). NFkB itself is upregulated in RA and cytokines such as TNFa that
activate NFkB are elevated in the synovial fluid of patients with RA.
In addition to the roles that NFkB plays in inflammatory diseases, constitutive
activation of the NFkB pathway is involved in some forms of cancer such as
leukemia, lymphoma, colon cancer and ovarian cancer.
Mutations that can lead to such tumors include those that inactivate IkB
proteins as well as amplifications and rearrangements of genes encoding
the NFkBtranscription factor subunits. However, more commonly it is thought
that changes in the upstream pathways that lead to NFkBactivation become
deregulated in cancer.
Assignment topics
G1: Herdgehog Signaling pathway in
breast cancer development
 G2:RTK/RasMAP signaling pathway
 G3: Notch signaling pathway
 G4: PI3K/AKT pathway
 G5: EGFR and Ras Signaling pathway
 G6: Ras/Raf/MEK/ERK
 G7: NFkB signaling pathway
 G8: JAK/STAT signaling pathway
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Assignment should include
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What is breast cancer?
Types of breast cancer
Stages of breast cancer
Epidemeology of this cancer world wide, South East Asia and
Pakistan. Write in tabulated form
Introduce and explain your signaling pathway with schematic
diagram or cycle.
What happens in breast cancer when this pathway gets
disrupted and how? Include diagram or cycle
Potential treatments for making the pathway normal.
References with every information is required otherwise you
will lose marks
Pages 10.
DEADline: 15 May
Table of statistics
Countr
y
No. of
Ethnicit Gender
patients y
/%age of
populati
on
affected
Age (if
given)
Type of
breast
cancer
Type of Referen
mutatio ces
ns
For the American and European data, you should give the reference of a paper or
data by US cancer research or UK cancer research
For South East Asian and Pakistan data, include references from WHO, Shoukat
Khannam or research papers.