Computational Molecular Biology 2016, Vol.6, No.1, 1-20
1
Research Article Open Access
NFkB pathway and inhibition: an overview
Ria Biswas, Angshuman Bagchi
Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, India
Corresponding author Email
Computational Molecular Biology, 2016, Vol.6, No.1 do
Received: 30 Nov, 2015
Accepted: 15 Feb, 2016
Published: 24 Feb., 2016
Copyright © 2016
Biswas and Bagchi, This is an open access article published under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Preferred citation for this article
:
Biswas R., and Bagchi A., 2016, NFkB pathway and inhibition: an overview, Computational Molecular Biology, 6(1): 1-20 (doi
)
Abstract
The nuclear factor kappa B (NFkB) modulates a broad range of cellular processes. NFkB pathway is stimulated by
various signaling cascades and is involved in various cross-talks in the cell. NFkB controls the pro-inflammatory response by the
TNFα and IL-1 signaling pathway. Inflammation is a defense mechanism of the body but when prolonged and chronic it results in
various diseases, such as cancer, neurodegeneration, ageing, obesity, etc. NFkB pathway could be regulated at various levels to
control chronic inflammation. As NFkB is involved in various cross-talks within the cell, a better understanding of the inter-linked
pathway using computational modeling may introduce us with potential new drug targets. E3 ligases unlike other components of the
pathway provide specificity, as it binds to the substrate molecule. Drugs designed to inhibit E3 ligase will ultimately choke the
proteosomal degradation pathway and inhibit the NFkB pathway. This review provides the knowledge of the detailed NFkB pathway
and its molecular mechanism. Also, we focused on computational modeling using deterministic and stochastic modeling methods in
NFkB signaling pathway. This review also focuses on E3 ligases structure, function and inhibition by small-molecules as well as
computational drug designing methods and their significance in finding new therapeutic candidates.
Keywords
Molecular Modeling; Drug Design; Cancer, Apoptosis;Mathematical Modeling
1 Introduction
Fish In 1986, Ranjan Sen and David Baltimore discovered the transcription factor which binds to the enhancer
element of immunoglobulin kappa light chain of activated B cells covering the sequence GGGACTTTCC by
using simple gel-electrophoresis-mobility-shift -assay. They named the factor NFkB as this nuclear factor bonded
selectively to k enhancers of the tumours B cells (Baltimore, 2009). Years of research has spread light into the
mechanism of action of NFkB pathway which revealed that the associated proteins of the pathway are expressed
in nearly in all cells and dictate many cellular signaling pathways. These proteins exist as dimeric transcription
factor and orchestrate various metabolic processes as well as immunological responses (Karlsen et al., 2007;
Madonna et al., 2012; Maqbool et al., 2013). NFkB family includes five members, designated as p65 (RelA),
RelB, c-Rel, NF-kB1 and NF-kB2. The NF-kB1 and NF-kB2 proteins are synthesized in pre-forms (p105 and
p100) and are later processed by proteolytic cleavage into p50 and p52. All members form homo or heterodimers
and have some common structural features like Rel homology domain (RHD), whic h helps in dimerization as well
as in DNA binding (Perkins and Gilmore, 2006). In most inactive cells the NFkB dimmers are bound to an
inhibitor known as IkB (Inhibitor of kappa B). These factors have characteristic six ankyrin repeat domain which
bind the DNA binding domains of the dimmers rendering them inactive. The ankyrin repeats of the pro p50 and
p52 are cleaved by auto-proteolytic cleavage, hence making self-inhibition. p50 and p52 unlike other members
do-not have transactivation domain hence when these dimmers bind to the kappa B region of DNA they act as
repressors of the transcriptional pathway. However, when they bind to any member having transactivation domain
they act as transcriptional activator. Bcl-3, a member of the IkB family consists of transactivating domain and
makes the p50-p52 dimmer transcriptionally active upon binding (Gilmore, 2006).
NFkB is involved in a variety of cellular processes like cell proliferation and apoptosis, neural development,
response to infection, inflammation. Malfunctioning of the NFkB results in the onset of chronic inflammatory
diseases like cancers and neurodegenerative disorders (Lawrence, 2009). The regulation of the pathway is very
essential for treating these diseases. Many upstream and downstream molecules are involved in the cascade,
