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  • Review Article
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NF-κB, chemokine gene transcription and tumour growth

Key Points

  • Chemokines are small, pro-inflammatory cytokines. There are four subfamilies of chemokines on the basis of their structural similarity — CXC-, CX3C-, C- and CC-chemokines. In the CXC family of chemokines, some are angiogenic (with a conserved Glu-Leu-Arg (ELR) motif at the amino terminus) and some are angiostatic (which do not have an ELR motif at the amino terminus).

  • Normally, the transcription of chemokine genes is tightly regulated. However, many chemokine genes are constitutively transcribed by tumour cells at relatively high levels.

  • Transcription of the angiogenic CXC-chemokine genes is modulated by nuclear factor-κB (NF-κB). When the inhibitor of NF-κB (IκB) is phosphorylated by IκB kinase (IKK), IκB is targeted for ubiquitylation and degradation by the proteasome, which frees NF-κB to translocate to the nucleus and activate gene transcription. The constitutive activation of IKK in tumour cells leads to the endogenous transcription of certain angiogenic and tumorigenic chemokine genes, including CXCL1 and CXCL8.

  • Melanoma tumour cells have endogenous activation of two other kinases that modulate NF-κB activity: NF-κB-inducing kinase (NIK) and AKT, a serine/threonine kinase that affects the phosphorylation and activation of RELA/p65.

  • NF-κB modulates gene expression in the context of a promoter/enhancer that comprises other positive and negative regulatory factors. Gene transcription of chemokines is the result of the combined interaction of NF-κB with factors that modulate histone acetylation or deacetylation and factors that interact with other proteins to stabilize or destabilize the transcriptional machinery.

  • Chemokine gene transcription is regulated by an enhanceosome-like structure. For CXCL1, this comprises SP1, NF-κB, the high-mobility group protein HMGIY and immediate upstream region (IUR) elements. For CXCL8, it comprises AP1, nuclear factor induced by IL-6 (NF-IL-6), NF-κB and a negative regulatory factor (NRF).

  • The inhibition of activation of NF-κB offers potential for the therapeutic intervention of tumour growth.

Abstract

The constitutive expression of angiogenic and tumorigenic chemokines by tumour cells facilitates the growth of tumours. The transcription of these angiogenic and tumorigenic chemokine genes is modulated, in part, by the nuclear factor-κB (NF-κB) family of transcription factors. In some tumours, there is constitutive activation of the kinases that modulate the activity of inhibitor of NF-κB (IκB) kinase (IKK), which leads to the constitutive activation of members of the NF-κB family. This activation of NF-κB is associated with the dysregulation of transcription of genes that encode cytokines, chemokines, adhesion factors and inhibitors of apoptosis. In this review, I discuss the factors that lie upstream of the NF-κB cascade that are activated during tumorigenesis and the role of the putative NF-κB enhanceosome in constitutive chemokine gene transcription during tumorigenesis.

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Figure 1: NF-κB is activated by plasma-membrane receptors that transduce signals to kinases such as PI3K.
Figure 2: Similarities between the proposed enhanceosomes for IL-6, CXCL8 and CXCL1.
Figure 3: Model of potential components involved in the constitutive activation of NF-κB and enhanced expression of CXCL1 and CXCL8 in melanoma.

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Acknowledgements

The work described in this review was facilitated by funding from the Department of Veterans Affairs (Senior Career Scientist Award and Merit Award) and the National Cancer Institute. The figures were contributed by C. S. Nirodi and P. Dhawan. I am also endebted to M. Boothby (Vanderbilt University School of Medicine) for critical review of this manuscript.

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DATABASES

Cancer.gov

breast cancer

colon carcinoma

head and neck cancer

leukaemia

lung cancer

lymphoma

melanoma

ovarian cancer

pancreatic cancer

prostate cancer

thyroid cancer

FlyBase

Dif

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Relish

LocusLink

AKT

AP1

Bcl3

CBP

CCL3

CCL5

CCL11

CCL19

CCL20

CCL21

CCR7

CCR10

CDP

C/EBP

CKII

c-Met

CXCL1

CXCL2

CXCL3

CXCL5

CXCL6

CXCL7

CXCL9

CXCL10

CXCL11

CXCL12

CXCL13

CXCR1

CXCR2

CXCR3

CXCR4

cyclin D

ERK1

ERK2

FasL

GM-CSF

HDAC

HDAC1

HMGIY

HRAS

IκB

Iap1

IFN-γ

IKKα

IKKβ

IKKγ

KC

IL-1

IL-4

IL-6

IL-8

IL-13

LTβ

MEKK1

MEKK3

NF-κB

NIK

p21

p27

p38 MAPK

p100

p105

PAK

PARP

PDK1

Pea15

PI3K

PKA

PLCβ

PTEN

RELA

RELB

SP1

Syk

TAK1

TGF-β

TNF

TRAF2

VEGF

XCL1

Yes-associated protein

Medscape DrugInfo

sulindac

Glossary

ENHANCEOSOME

Gene transcription is achieved by the assembly of higher-order, three-dimensional transcription factor/enhancer DNA complexes, termed enhanceosomes. Enhanceosomes activate transcription by recruiting chromatin-modifying activities and basal transcription factors to the nearby promoters.

SCID

(Severe combined immunodeficiency). Mice with this defect in their immune system do not have B or T cells and can, therefore, accept tumour cells from another species without rejection.

DIFFERENTIAL DISPLAY

This is a powerful tool for the comparison of gene expression between two or more messenger RNA populations.

MICROARRAYS

This technique allows the screening of messenger RNA extracted from cells against DNA from many thousands of genes. The DNA from each gene is positioned on a solid support in a highly ordered array.

ANOXIA

Limited oxygen supply.

FOCUS FORMATION

The ability of tumour cells to grow in an anchorage-independent manner by adhering to one another, thereby forming 'foci' of tumour cells.

NEMO

(NF-κB essential modulator). This is the regulatory component of the inhibitor of NF-κB (IκB) kinase (IKK) complex, also known as IKKγ.

TNF-RECEPTOR-ASSOCIATED FACTORS

(TRAFs). A term that originated with proteins that were found to bind to the cytoplasmic domain of the tumour-necrosis factor (TNF) receptor in a yeast two-hybrid screen.

TATA BOX

A DNA motif that binds several factors (TATA-binding proteins, TBPs; and TBP-associated factors, TAFs) that facilitate the initiation of transcription.

ELECTROPHORETIC MOBILITY-SHIFT ASSAY

A technique for detecting DNA–protein complex formation. It involves the incubation of nuclear extracts with a radiolabelled oligonucleotide probe, then separating the probe that has bound to nuclear proteins from the free radiolabelled probe by gel electrophoresis, followed by autoradiography.

DEACETYLATION

Acetylation is a post-translational modification of chromatin components, particularly histones. Histone deacetylases have been identified as components of nuclear co-repressor complexes.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

(NSAIDs). Drugs, such as aspirin, that are used to ablate the inflammatory response. These drugs can stimulate apoptosis and inhibit angiogenesis, thereby suppressing malignant transformation and tumour growth. They work, in part, by suppressing NF-κB activation.

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Richmond, A. NF-κB, chemokine gene transcription and tumour growth. Nat Rev Immunol 2, 664–674 (2002). https://doi.org/10.1038/nri887

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