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NF-κB in cancer: from innocent bystander to major culprit

Key Points

  • Nuclear factor of κB (NF-κB) is a transcriptional regulator that is made up of different protein dimers that bind a common sequence motif known as the κB site.

  • Although NF-κB target genes have been most intensely studied for their involvement in immunity and inflammation, this transcription factor also regulates cell proliferation, apoptosis and cell migration. Therefore, it is not surprising that NF-κB has been shown to be constitutively activated in several types of cancer cell.

  • NF-κB activity is tightly controlled by several regulatory proteins, and disruption of this process has been associated with various haematological malignancies, as well as epithelial tumours such as breast cancer.

  • A causal connection between inflammation and cancer has been suspected for many years. Because NF-κB becomes activated in response to inflammatory stimuli and its constitutive activation has been associated with cancer, NF-κB might also serve as the missing link between these two processes. Numerous inhibitors of NF-κB are therefore under development or have been developed.

  • Because of the widespread importance of this factor, it has been difficult to develop NF-κB inhibitors that act specifically in cancer cells. Learning more about the complicated process of NF-κB regulation should lead to better therapeutic approaches to target the factor in specific cell types.

Abstract

Nuclear factor of κB (NF-κB) is a sequence-specific transcription factor that is known to be involved in the inflammatory and innate immune responses. Although the importance of NF-κB in immunity is undisputed, recent evidence indicates that NF-κB and the signalling pathways that are involved in its activation are also important for tumour development. NF-κB should therefore receive as much attention from cancer researchers as it has already from immunologists.

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Figure 1: The IKK complex controls two distinct NF-κB activation pathways.
Figure 2: NF-κB contributes to the induction of four classes of genes.
Figure 3: Different mechanisms by which NF-κB activation can contribute to leukaemia and lymphogenesis.
Figure 4: Signalling pathways that stimulate the proliferation of mammary epithelial cells by induction of cyclin D1 gene transcription.
Figure 5: Role of NF-κB in gastric and colorectal cancers.

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Acknowledgements

M. K. is the Frank and Else Schilling American Cancer Society Research Professor. Research in his laboratory is supported by the National Institutes of Health and the State of California Cancer Research Program, and the Breast Cancer Basic Research Program. Y. C., F. R. G. and Z.-W. L. are supported by postdoctoral fellowships from the California Breast Cancer Research Program, the Deutsche Forschungsgemeinschaft and the Cancer Research Institute, respectively.

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Correspondence to Michael Karin.

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IκBɛ

IL1

IL-2

IL-6

IL-8

iNOS

LTβ

MALT1

MAPK

MMPs

NEMO

NF-κB1

Nfkb2

NF-κB2

NIK

p53

RANK

RANKL

Rel

REL

RelA

RELA

RELB

SKP1

TAX

TLRs

TNF-α

TNFR

TNFR1

VEGF

Medscape DrugInfo

aspirin

mesalamine

methotrexate

sulindac

sulphasalazine

OMIM

familial adenomatous polyposis

hereditary non-polyposis cancer

ulcerative colitis

FURTHER READING

Biology of the Mammary Gland

The Mouse Models of Human Cancers Consortium

Glossary

ANKYRIN REPEAT

A repeating sequence of 30–33 amino acids that is found in the ankyrin protein. The ankyrin repeat of IκB proteins is required for association with the nuclear localization signal of NF-κB proteins.

AUTOCRINE/PARACRINE

The effect of hormones or growth factors that act in the secretory cell itself is called autocrine, whereas the effect of those that act on adjacent cells is called paracrine.

TRANSCRIPTIONAL ANTAGONISM

The conflicting actions of multiple proteins that regulate the expression of certain genes.

GERMINAL CENTRE

A site in secondary lymphoid tissue where B cells are exposed to antigen, and are induced to either proliferate, mature or undergo cell death.

NULLIPAROUS

A female that has never borne offspring.

CAG PATHOGENICITY ISLAND

An Helicobacter pylori locus of approximately 40 kb that contains 31 genes. Several cag island genes have homology to genes that encode type IV secretion system proteins, which export proteins from bacterial cells. The terminal gene in the island, cagA, is commonly used as a marker for the entire cag locus.

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Karin, M., Cao, Y., Greten, F. et al. NF-κB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2, 301–310 (2002). https://doi.org/10.1038/nrc780

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