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The complexity of NF-κB signaling in inflammation and cancer.

Hoesel B, Schmid JA - Mol. Cancer (2013)

Bottom Line: The NF-κB family of transcription factors has an essential role in inflammation and innate immunity.During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways.Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.

ABSTRACT
The NF-κB family of transcription factors has an essential role in inflammation and innate immunity. Furthermore, NF-κB is increasingly recognized as a crucial player in many steps of cancer initiation and progression. During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways. Prominent nodes of crosstalk are mediated by other transcription factors such as STAT3 and p53 or the ETS related gene ERG. These transcription factors either directly interact with NF-κB subunits or affect NF-κB target genes. Crosstalk can also occur through different kinases, such as GSK3-β, p38, or PI3K, which modulate NF-κB transcriptional activity or affect upstream signaling pathways. Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs. In this review, we provide an overview of the most relevant modes of crosstalk and cooperativity between NF-κB and other signaling molecules during inflammation and cancer.

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Crosstalk of the canonical NF-κB pathway with other signaling processes. (A) Many different kinases can phosphorylate and activate the IKKα and IKKβ subunits of the IKK complex or can enhance NF-κB transcriptional activity. Important examples are glycogen synthase kinase 3β (GSK3β), Protein Kinase B (PKB or Akt), Protein Kinase R (PKR), Protein Kinase C (PKC), Mitogen-Activated Type 3-Protein Kinase 7 (MAP3K7 or TAK1), p38 MAP Kinases or c-Jun N-terminal kinases (JNKs). (B) Various transcription factors such as p53, Ets Related Gene (ERG) or Signal Transducer and Activator of Transcription 3 (STAT3) can influence the transcriptional activity of NF-κB or directly activate transcription of NF-κB target genes. (C) microRNAs (miRNAs) can be target genes of the NF-κB signaling pathways or can affect the expression of NF-κB family members or effector molecules of the NF-κB activation pathway. (D) Prominent target genes of the NF-κB signaling pathway include anti-apoptotic genes as the Baculoviral IAP repeat-containing proteins (BIRCs or cIAPs) and the B-cell lymphoma 2 gene (Bcl-2), cytokines such as Interleukin-1 (IL-1), IL-6, IL-8 and chemokine (C-C motif) ligand 2 (CCL2), adhesion factors including the Vascular Cell Adhesion Molecule 1 (VCAM-1) and the Intercellular Cell Adhesion Molecule 1 (ICAM-1). (E) Another layer of complexity of NF-κB signaling are positive and negative feedback mechanism. Examples for positive feedback molecules are the X-linked inhibitor of apoptosis protein (XIAP) as well as TNFα or IL-1. Important negative feedback circuits are generated by the NF-κB target genes IκBα, Cylindromatosis (CYLD) or A20.
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Figure 5: Crosstalk of the canonical NF-κB pathway with other signaling processes. (A) Many different kinases can phosphorylate and activate the IKKα and IKKβ subunits of the IKK complex or can enhance NF-κB transcriptional activity. Important examples are glycogen synthase kinase 3β (GSK3β), Protein Kinase B (PKB or Akt), Protein Kinase R (PKR), Protein Kinase C (PKC), Mitogen-Activated Type 3-Protein Kinase 7 (MAP3K7 or TAK1), p38 MAP Kinases or c-Jun N-terminal kinases (JNKs). (B) Various transcription factors such as p53, Ets Related Gene (ERG) or Signal Transducer and Activator of Transcription 3 (STAT3) can influence the transcriptional activity of NF-κB or directly activate transcription of NF-κB target genes. (C) microRNAs (miRNAs) can be target genes of the NF-κB signaling pathways or can affect the expression of NF-κB family members or effector molecules of the NF-κB activation pathway. (D) Prominent target genes of the NF-κB signaling pathway include anti-apoptotic genes as the Baculoviral IAP repeat-containing proteins (BIRCs or cIAPs) and the B-cell lymphoma 2 gene (Bcl-2), cytokines such as Interleukin-1 (IL-1), IL-6, IL-8 and chemokine (C-C motif) ligand 2 (CCL2), adhesion factors including the Vascular Cell Adhesion Molecule 1 (VCAM-1) and the Intercellular Cell Adhesion Molecule 1 (ICAM-1). (E) Another layer of complexity of NF-κB signaling are positive and negative feedback mechanism. Examples for positive feedback molecules are the X-linked inhibitor of apoptosis protein (XIAP) as well as TNFα or IL-1. Important negative feedback circuits are generated by the NF-κB target genes IκBα, Cylindromatosis (CYLD) or A20.

Mentions: In a recent report it was shown that miR-15a, miR-16 and miR-223 can influence IKK1 protein expression during macrophage differentiation. Interestingly, these miRNAs did not affect IKK2 or NEMO expression suggesting that they might be modifiers of the non-canonical NF-κB signaling pathway [152]. Another study showed that miR-502e acts as tumor suppressor by modifying cell proliferation in hepatoma cell lines and hepatocellular carcinoma. The authors suggested that this function is due to the ability of targeting NIK thus directly influencing the non-canonical NF-κB pathway [153]. A depiction of the crosstalk between miRNAs and members of the NF-κB signaling pathway is summarized very well in [146] (Figure 5).


The complexity of NF-κB signaling in inflammation and cancer.

Hoesel B, Schmid JA - Mol. Cancer (2013)

Crosstalk of the canonical NF-κB pathway with other signaling processes. (A) Many different kinases can phosphorylate and activate the IKKα and IKKβ subunits of the IKK complex or can enhance NF-κB transcriptional activity. Important examples are glycogen synthase kinase 3β (GSK3β), Protein Kinase B (PKB or Akt), Protein Kinase R (PKR), Protein Kinase C (PKC), Mitogen-Activated Type 3-Protein Kinase 7 (MAP3K7 or TAK1), p38 MAP Kinases or c-Jun N-terminal kinases (JNKs). (B) Various transcription factors such as p53, Ets Related Gene (ERG) or Signal Transducer and Activator of Transcription 3 (STAT3) can influence the transcriptional activity of NF-κB or directly activate transcription of NF-κB target genes. (C) microRNAs (miRNAs) can be target genes of the NF-κB signaling pathways or can affect the expression of NF-κB family members or effector molecules of the NF-κB activation pathway. (D) Prominent target genes of the NF-κB signaling pathway include anti-apoptotic genes as the Baculoviral IAP repeat-containing proteins (BIRCs or cIAPs) and the B-cell lymphoma 2 gene (Bcl-2), cytokines such as Interleukin-1 (IL-1), IL-6, IL-8 and chemokine (C-C motif) ligand 2 (CCL2), adhesion factors including the Vascular Cell Adhesion Molecule 1 (VCAM-1) and the Intercellular Cell Adhesion Molecule 1 (ICAM-1). (E) Another layer of complexity of NF-κB signaling are positive and negative feedback mechanism. Examples for positive feedback molecules are the X-linked inhibitor of apoptosis protein (XIAP) as well as TNFα or IL-1. Important negative feedback circuits are generated by the NF-κB target genes IκBα, Cylindromatosis (CYLD) or A20.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3750319&req=5

Figure 5: Crosstalk of the canonical NF-κB pathway with other signaling processes. (A) Many different kinases can phosphorylate and activate the IKKα and IKKβ subunits of the IKK complex or can enhance NF-κB transcriptional activity. Important examples are glycogen synthase kinase 3β (GSK3β), Protein Kinase B (PKB or Akt), Protein Kinase R (PKR), Protein Kinase C (PKC), Mitogen-Activated Type 3-Protein Kinase 7 (MAP3K7 or TAK1), p38 MAP Kinases or c-Jun N-terminal kinases (JNKs). (B) Various transcription factors such as p53, Ets Related Gene (ERG) or Signal Transducer and Activator of Transcription 3 (STAT3) can influence the transcriptional activity of NF-κB or directly activate transcription of NF-κB target genes. (C) microRNAs (miRNAs) can be target genes of the NF-κB signaling pathways or can affect the expression of NF-κB family members or effector molecules of the NF-κB activation pathway. (D) Prominent target genes of the NF-κB signaling pathway include anti-apoptotic genes as the Baculoviral IAP repeat-containing proteins (BIRCs or cIAPs) and the B-cell lymphoma 2 gene (Bcl-2), cytokines such as Interleukin-1 (IL-1), IL-6, IL-8 and chemokine (C-C motif) ligand 2 (CCL2), adhesion factors including the Vascular Cell Adhesion Molecule 1 (VCAM-1) and the Intercellular Cell Adhesion Molecule 1 (ICAM-1). (E) Another layer of complexity of NF-κB signaling are positive and negative feedback mechanism. Examples for positive feedback molecules are the X-linked inhibitor of apoptosis protein (XIAP) as well as TNFα or IL-1. Important negative feedback circuits are generated by the NF-κB target genes IκBα, Cylindromatosis (CYLD) or A20.
Mentions: In a recent report it was shown that miR-15a, miR-16 and miR-223 can influence IKK1 protein expression during macrophage differentiation. Interestingly, these miRNAs did not affect IKK2 or NEMO expression suggesting that they might be modifiers of the non-canonical NF-κB signaling pathway [152]. Another study showed that miR-502e acts as tumor suppressor by modifying cell proliferation in hepatoma cell lines and hepatocellular carcinoma. The authors suggested that this function is due to the ability of targeting NIK thus directly influencing the non-canonical NF-κB pathway [153]. A depiction of the crosstalk between miRNAs and members of the NF-κB signaling pathway is summarized very well in [146] (Figure 5).

Bottom Line: The NF-κB family of transcription factors has an essential role in inflammation and innate immunity.During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways.Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.

ABSTRACT
The NF-κB family of transcription factors has an essential role in inflammation and innate immunity. Furthermore, NF-κB is increasingly recognized as a crucial player in many steps of cancer initiation and progression. During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways. Prominent nodes of crosstalk are mediated by other transcription factors such as STAT3 and p53 or the ETS related gene ERG. These transcription factors either directly interact with NF-κB subunits or affect NF-κB target genes. Crosstalk can also occur through different kinases, such as GSK3-β, p38, or PI3K, which modulate NF-κB transcriptional activity or affect upstream signaling pathways. Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs. In this review, we provide an overview of the most relevant modes of crosstalk and cooperativity between NF-κB and other signaling molecules during inflammation and cancer.

Show MeSH
Related in: MedlinePlus