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FORMAL DESCRIPTION OF NF-κB PATHWAY,
ITS ROLE IN INFLAMMATION, INHIBITION
OF APOPTOSIS, CARCINOGENESIS, AND WAYS
OF INACTIVATION FOR PREDICTION
OF NEW TARGETS FOR ANTI-INFLAMMATORY
AND ANTI-CANCER TREATMENT
Sharipov R.N.*1, 2, 3, Kolpakova A.F.4
1
Institute of Cytology and Genetics, SB RAS, Novosibirsk, 630090, Russia; 2 Design Technological
Institute of Digital Techniques, SB RAS, Novosibirsk, Russia; 3 Institute of Systems Biology OOO,
Novosibirsk, Russia; 4 State Research Institute for Medical Problems of the North, SB RAMS,
Krasnoyarsk, Russia
Key words:
NF-κB, transcription factor, apoptosis, cell survival, inflammation, cancer, Biopath
SUMMARY
Motivation: Hyperactivation of transcription factor NF-κB plays important part in
development of number of human pathologies: autoimmune diseases, many types of
inflammation, and various viral infections. Progress in cancer research allowed to reveal
importance of NF-κB in induction of anticancer drug resistance and cell proliferation.
Formal description of NF-κB pathways and related issues will help to predict new targets
for NF-κB inactivation and design better drugs and therapeutic strategies.
Results: NF-κB pathway, mechanisms of its activation, regulation of dependent genes,
crosstalks with other regulatory pathways, participation in development of human
diseases, as well as known mechanisms of drug actions were described formally using
literature annotation and BioUML workbench. All data are stored and classified in
Biopath database.
Availability: http://biopath.biouml.org.
INTRODUCTION
Since discovery of NF-κB in 1986 it has been attracting attention because of its
unusual regulation, diversity of activating stimuli, regulated genes and biological effects,
striking evolutionary conservatism of structure and functions among its family members
(Ghosh et al., 1998). NF-κB hyperactivation was observed associated with block of
apoptosis and increased cell proliferation in many cases of cancer in breast, thymus,
colon, non-Hodgekin lymphomas, T- and B-cell leukemia, and various types of melanoma
(Wu, Kral, 2005). Hyperactivation of NF-κB also plays important role in inflammation,
autoimmune diseases and various viral infections (Baldwin, 2001).
A number of drugs and substances were developed to inhibit NF-κB pathway.
However in many cases their specificity is not sufficient that causes side effects (Baldwin,
2001). Complete inhibition of NF-κB pathway could result in unexpected side effects due
to its importance for cell survival. Formal description of NF-κB pathways and related
issues will help to predict new targets for NF-κB inactivation and design better drugs and
therapeutic strategies for treatment of cancer, inflammation and autoimmune diseases.
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METHODS
Data about NF-κB pathway and related issues were obtained by literature annotation
and from following biological databases: TRANSPATH, TRANSFAC, InterPro, KEGG,
OMIM
and
Gene
Ontology.
BioUML
technology
(Kolpakov,
2004;
http://www.biouml.org) was used for formal description of NF- κB pathway and related
issues. Three BioUML diagram types were used for formal description: semantic
networks, gene networks, and pathways. All diagrams and description diagram elements
(genes, proteins, substances, concepts, reactions and semantic relationships) were stored
in Biopath database. BeanExplorer Enterprise Edition (http://www.beanexplorer.com)
was used for web interface developing for Internet access to Biopath database (Fig. 1).
Figure 1. Points of NF-κB pathway – targets for NF-κB inhibitors (DGR0136).
Web interface of Biopath database.
RESULTS
Data obtained from more than 300 articles were analysed and represented in the form
of 66 diagrams with descriptions (the most important diagrams are listed in Table 1).
These diagrams can be classified into following groups:
• structure of NF-κB pathway (7 diagrams);
• stimuli and mechanisms of NF-κB activation (35 DGRs);
• role of NF-κB in inflammation, cancer and other human diseases (13 DGRs);
• regulation of apoptosis (7 DGRs);
• mechanisms and targets of NF-κB inactivation by NF-κB inhibitors (4 DGRs; Fig. 1).
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Part 3.2
Table 1. List of the most important diagrams about NF-κB
Structure of NF-κB pathway
Diagram ID
Name of diagram
DGR0010
Rel/NF-κB family
DGR0003
IκB family
DGR0027
Proteins, regulated by NF-κB
DGR0012
NF-κB interactions with transcription co-activators in nucleus
DGR0135
p100- and p105-processing
DGR0219
NF-κB and cell cycle regulation
Stimuli and mechanisms of NF-κB activation
DGR0026
Stimuli, that activate NF-κB
DGR0051
NF-κB activation pathways
DGR0118
TNF-α-induced NF-κB activating pathway
DGR0119
IL-1β-induced NF-κB activating pathway
DGR0120
LPS(lipopolysaccharide)-TLR4(Toll-like receptor 4)-dependent NF-κB
activating pathway
DGR0134
dsRNA-TLR3(Toll-like receptor 3)-dependent NF-κB-activating pathway
DGR0122
p38 mitogen-activated protein kinase pathway
DGR0109
Immune cell activation as response to bacterial infection
DGR0106
LPS-induced effects in mammal cells
DGR0110
TNF-α and IL-1β effects in VSMCs(vascular smooth muscle cells)
DGR0033
Cell-type specific role of ROS in NF-κB activation by IL-1
DGR0045
Activation of the IκB kinase (IKK)
DGR0013
Activation of NF-κB by non-IKK and other stimuli
DGR0102
Akt (PKB) regulation of NF-κB
DGR0128
Metals and metals-induced ROS influence on NF-κB signaling
Role of NF-κB in inflammation, cancer and other human diseases
DGR0047
Diseases associated with NF-κB activation
DGR0104
NF-κB in the initiation of chronic inflammation
DGR0105
NF-κB and the perpetuation of chronic inflammation
DGR0050
Acute lung injury and NF-κB
DGR0052
Development of multiple organ dysfunction syndrome in human lung
DGR0049
NF-κB involvement in asthma development
DGR0113
RSV(respiratory syncytial virus)- and TNF-α-induced differential
activation of p65 and p50 in human airway epithelium
DGR0048
Role of NF-κB in oncogenesis
DGR0132
Rearrangements of NF-κB and IκB-α genes loci in oncogenesis
DGR0220
NF-κB: a possible link between obesity and breast cancer
DGR0221
Role of NF-κB in chemoresistance
Regulation of apoptosis
DGR0131
NF-κB in regulation of apoptosis
DGR0234
Cell death pathways
DGR0235
The Extrinsic Cell Death Pathway: Fas
DGR0238
Multiple Roads to Cell Death from E2F-1
Known mechanisms and targets of NF-κB inactivation, and NF-κB inhibitors
DGR0136
Critical points of NF-κB pathway - targets for interventions
DGR_NF-kB_inhibs
NF-κB inhibitors
DGR0021
Effects of glucocorticoids on NF-κB
DISCUSSION
Proinflammatory stimuli (e.g., cell damage, UV radiation, reactive oxygen species
(ROS), cytokines) activate NF-κB through signal transduction pathways and induce
overexpression of a set of genes encoding cytokines (e.g., IL-1, IL-2, IL-8), interferons
(IFNβ, IFNγ) and enzymes producing mediators of inflammation (e.g., inducible NO
synthase (iNOS), cyclooxygense-2 (COX-2), and 5-lipooxygenase (5-LOX)). Highly
increased levels of active NF-κB were found in asthma, different types of arthritis and
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lung inflammations in human (Ghosh et al., 1998). A general scheme of NF-κB activation
by proinflammatory stimuli is represented on Fig. 1.
NF-κB also regulates expression of genes encoding inhibitors of apoptosis cIAPs,
Bfl/A1 and Bcl-XL. These proteins function through inhibition of activity of proapoptotic
proteins (e.g., caspases, tBid), stabilization of mitochondrial membrane and promotion of
cell survival. Expression of gene of p53 protein – important apoptosis inductor – is also
regulated by NF-κB. In certain conditions NF-κB was shown to induce apoptosis
mediated by p53. Complete detailed scheme of NF-κB-mediated regulation of apoptosis is
not known. Every year brings reports about new proteins that involved in regulation of
NF-κB pathway. Complexity of NF-κB regulating pathway can be characterized by the
fact that in certain conditions well-known apoptosis-inducing factor TNF-α is able to
induce cell survival mediated by this transcription factor. It was suggested that induction
of cell survival by TNF-α was mediated by TRAF2 protein interacting with deathinducing signal complex (DISC) and leading to NF-κB activation. Expression of TRAF2
gene is also under control of NF-κB (Wu, Kral, 2005).
NF-κB participates in human carcinogenesis through blocking of apoptosis and
induction of cell survival and cell proliferation. Elevated levels of NF-κB were revealed
in many types of cancer (e.g., breast, colon, prostate). This fact was explained partly by
observed in cells amplifications of NF-κB family genes or deletion of nucleotide
sequences encoding sites for interactions with intracellular inhibitor of NF-κB (IκB). In
addition, NF-κB was shown to inhibit action of anti-cancer drugs – inductors of apoptosis
– in tumor cells and cause chemotherapy resistance (Wu, Kral, 2005).
Different types of NF-κB inhibitors are used extensively for treatment of inflammation
and as supportive drugs against chemotherapy resistance and target different steps of NFκB pathway (Fig. 1). Many of them are non-specific (antioxidants) or possess significant
side effects (glucocorticoids) (Baldwin, 2001). Comprehensive data about NF-κB
pathway united in one database will help in design of specific and effective NF-κB
inhibitors without side effects.
The NF-κB data collected in Biopath is used by our colleagues from Institute of
Biomedical Chemistry (Moscow) for prediction of chemical substances – effective
inhibitors of NF-κB pathways – by use of PASS (Prediction of Biological Activity
Spectra for Substances) system (Poroikov, Filimonov, 2005).
ACKNOWLEDGEMENTS
This work was supported by INTAS grant No. 03-51-5218 and RFBR grant No. 0404-49826-а.
REFERENCES
Baldwin A.S.Jr. (2001) Series introduction: the transcription factor NF-kappaB and human diseases. J.
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Ghosh S. et al. (1998) NF-kappaB and Rel proteins: evolutionarily conserved mediators of immune
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Poroikov V., Filimonov D. (2005) PASS: Prediction of Biological Activity Spectra for Substances. In
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Wu J.T., Kral J.G. (2005) The NF-kappaB/IkappaB signaling system: a molecular target in breast cancer
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