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The role of hypoxia in inflammatory disease (review).

Biddlestone J, Bandarra D, Rocha S - Int. J. Mol. Med. (2015)

Bottom Line: Mammals have developed evolutionarily conserved programs of transcriptional response to hypoxia and inflammation.Several common disease processes are characterised by aberrant transcriptional programs in response to environmental stress.In this review, we discuss the current understanding of the role of the hypoxia-responsive (hypoxia-inducible factor) and inflammatory (nuclear factor-κB) transcription factor families and their crosstalk in rheumatoid arthritis, inflammatory bowel disease and colorectal cancer, with relevance for future therapies for the management of these conditions.

View Article: PubMed Central - PubMed

Affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.

ABSTRACT
Mammals have developed evolutionarily conserved programs of transcriptional response to hypoxia and inflammation. These stimuli commonly occur together in vivo and there is significant crosstalk between the transcription factors that are classically understood to respond to either hypoxia or inflammation. This crosstalk can be used to modulate the overall response to environmental stress. Several common disease processes are characterised by aberrant transcriptional programs in response to environmental stress. In this review, we discuss the current understanding of the role of the hypoxia-responsive (hypoxia-inducible factor) and inflammatory (nuclear factor-κB) transcription factor families and their crosstalk in rheumatoid arthritis, inflammatory bowel disease and colorectal cancer, with relevance for future therapies for the management of these conditions.

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(A) Schematic diagram of NF-κB subunits. p50 and p52 are not shown, and they are derived from p105 and p100, respectively. Boxes represent different protein domains. (B) NF-κB canonical pathway. The presence of a stimuli results in the activation of the IKK complex, which mediates the phosphorylation of IκB protein, which signals it for proteasomal degradation. This results in NF-κB dimer release and translocation into the nucleus. NF-κB, nuclear factor-κB; IKK, inhibitor of κB kinase; RHD, Rel homology domain; TAD, C-terminal transactivation domain; LZ, leucine zipper motif; NLS, nuclear localisation signal; ANK, ankyrin-repeat motifs; DD, death domain.
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f2-ijmm-35-04-0859: (A) Schematic diagram of NF-κB subunits. p50 and p52 are not shown, and they are derived from p105 and p100, respectively. Boxes represent different protein domains. (B) NF-κB canonical pathway. The presence of a stimuli results in the activation of the IKK complex, which mediates the phosphorylation of IκB protein, which signals it for proteasomal degradation. This results in NF-κB dimer release and translocation into the nucleus. NF-κB, nuclear factor-κB; IKK, inhibitor of κB kinase; RHD, Rel homology domain; TAD, C-terminal transactivation domain; LZ, leucine zipper motif; NLS, nuclear localisation signal; ANK, ankyrin-repeat motifs; DD, death domain.

Mentions: NF-κB is considered the main pro-inflammatory family of transcription factors (42–44). In mammalians, it is characterised as a family of five Rel-domain proteins; RelA, RelB, cRel, p100/p52 and p105/p50 (Fig. 2A). Interestingly, it has been shown that almost all combinations of homo- or hetero-dimers between the five NF-κB subunits are possible (45). This is important, not only because it gives an extra layer of complexity to the NF-κB system, but also because it gives specificity according to cellular context, stimuli or DNA sequences that are bound to the subunits (44,46). All the NF-κB subunits are characterised by a conserved 300-amino acid domain, the Rel homology domain (RHD), which is located in the N-terminus of the protein (Fig. 2A), and is responsible for dimerisation, and DNA binding. While RelA, RelB and cRel contain a C-terminal transactivation domain (TAD) (Fig. 2A), p105 and p100 contain Ankyrin-repeats motifs in their C-terminus (ANK) (Fig. 2A), responsible for the dimerisation with other subunits, and subsequent sequestration/inactivation in the cytoplasm (Fig. 2B).


The role of hypoxia in inflammatory disease (review).

Biddlestone J, Bandarra D, Rocha S - Int. J. Mol. Med. (2015)

(A) Schematic diagram of NF-κB subunits. p50 and p52 are not shown, and they are derived from p105 and p100, respectively. Boxes represent different protein domains. (B) NF-κB canonical pathway. The presence of a stimuli results in the activation of the IKK complex, which mediates the phosphorylation of IκB protein, which signals it for proteasomal degradation. This results in NF-κB dimer release and translocation into the nucleus. NF-κB, nuclear factor-κB; IKK, inhibitor of κB kinase; RHD, Rel homology domain; TAD, C-terminal transactivation domain; LZ, leucine zipper motif; NLS, nuclear localisation signal; ANK, ankyrin-repeat motifs; DD, death domain.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356629&req=5

f2-ijmm-35-04-0859: (A) Schematic diagram of NF-κB subunits. p50 and p52 are not shown, and they are derived from p105 and p100, respectively. Boxes represent different protein domains. (B) NF-κB canonical pathway. The presence of a stimuli results in the activation of the IKK complex, which mediates the phosphorylation of IκB protein, which signals it for proteasomal degradation. This results in NF-κB dimer release and translocation into the nucleus. NF-κB, nuclear factor-κB; IKK, inhibitor of κB kinase; RHD, Rel homology domain; TAD, C-terminal transactivation domain; LZ, leucine zipper motif; NLS, nuclear localisation signal; ANK, ankyrin-repeat motifs; DD, death domain.
Mentions: NF-κB is considered the main pro-inflammatory family of transcription factors (42–44). In mammalians, it is characterised as a family of five Rel-domain proteins; RelA, RelB, cRel, p100/p52 and p105/p50 (Fig. 2A). Interestingly, it has been shown that almost all combinations of homo- or hetero-dimers between the five NF-κB subunits are possible (45). This is important, not only because it gives an extra layer of complexity to the NF-κB system, but also because it gives specificity according to cellular context, stimuli or DNA sequences that are bound to the subunits (44,46). All the NF-κB subunits are characterised by a conserved 300-amino acid domain, the Rel homology domain (RHD), which is located in the N-terminus of the protein (Fig. 2A), and is responsible for dimerisation, and DNA binding. While RelA, RelB and cRel contain a C-terminal transactivation domain (TAD) (Fig. 2A), p105 and p100 contain Ankyrin-repeats motifs in their C-terminus (ANK) (Fig. 2A), responsible for the dimerisation with other subunits, and subsequent sequestration/inactivation in the cytoplasm (Fig. 2B).

Bottom Line: Mammals have developed evolutionarily conserved programs of transcriptional response to hypoxia and inflammation.Several common disease processes are characterised by aberrant transcriptional programs in response to environmental stress.In this review, we discuss the current understanding of the role of the hypoxia-responsive (hypoxia-inducible factor) and inflammatory (nuclear factor-κB) transcription factor families and their crosstalk in rheumatoid arthritis, inflammatory bowel disease and colorectal cancer, with relevance for future therapies for the management of these conditions.

View Article: PubMed Central - PubMed

Affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.

ABSTRACT
Mammals have developed evolutionarily conserved programs of transcriptional response to hypoxia and inflammation. These stimuli commonly occur together in vivo and there is significant crosstalk between the transcription factors that are classically understood to respond to either hypoxia or inflammation. This crosstalk can be used to modulate the overall response to environmental stress. Several common disease processes are characterised by aberrant transcriptional programs in response to environmental stress. In this review, we discuss the current understanding of the role of the hypoxia-responsive (hypoxia-inducible factor) and inflammatory (nuclear factor-κB) transcription factor families and their crosstalk in rheumatoid arthritis, inflammatory bowel disease and colorectal cancer, with relevance for future therapies for the management of these conditions.

Show MeSH
Related in: MedlinePlus