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Cell Autonomous and Non-Autonomous Functions of IKKβ and NF-κB during the Pathogenesis of Gastrointestinal Tumors.

Fang HY, Greten FR - Cancers (Basel) (2011)

Bottom Line: Activation of the transcription factor nuclear factor-κB (NF-κB) and its effector pathways has been proposed to be the missing link between these two processes.NF-κB is persistently activated in several types of tumors.Therefore, specific NF-κB inhibition in combination with cytotoxic drugs and/or irradiation represents a very promising strategy for cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, Munich 81675, Germany. florian.greten@lrz.tum.de.

ABSTRACT
Genetic studies describing a link between cancer and inflammation have increased recently. Activation of the transcription factor nuclear factor-κB (NF-κB) and its effector pathways has been proposed to be the missing link between these two processes. NF-κB is persistently activated in several types of tumors. However, NF-κB has a distinct role in cancer cells and in inflammatory cells. While in tumor cells NF-κB controls cell survival, in inflammatory cells NF-κB activates genes that encode pro-inflammatory cytokines which further act in a paracrine manner within the tumor microenvironment to contribute to tumorigenesis. Inactivation of NF-κB can also reduce chemoresistance and radioresistance of cancer cells. Therefore, specific NF-κB inhibition in combination with cytotoxic drugs and/or irradiation represents a very promising strategy for cancer therapy.

No MeSH data available.


Related in: MedlinePlus

The two NF-κB activation pathways. The classical NF-κB pathway (left-hand side) results in translocation of primarily p50/p65 dimers in an IKKβ/IKKγ dependent manner. The alternative pathway for NF-κB (right-hand side) results in nuclear translocation of p52-RelB dimers and is strictly dependent on IKKα homodimers.
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f1-cancers-03-02214: The two NF-κB activation pathways. The classical NF-κB pathway (left-hand side) results in translocation of primarily p50/p65 dimers in an IKKβ/IKKγ dependent manner. The alternative pathway for NF-κB (right-hand side) results in nuclear translocation of p52-RelB dimers and is strictly dependent on IKKα homodimers.

Mentions: In unchallenged cells NF-κB dimers are bound to inhibitory IκB proteins retaining them in the cytoplasm. Two major pathways lead to translocation of NF-κB dimers from the cytoplasm to the nucleus: the canonical pathway and the alternative pathway (Figure 1). The canonical NF-κB pathway is triggered by pro-inflammatory cytokines or pathogen-associated molecular patterns (PAMPs) that engage different receptors belonging to the TNF receptor (TNFR), IL-1 receptor (IL-1R) or Toll-like receptor (TLR) superfamilies. Via various adaptor molecules signaling impinges on the IκB kinase (IKK) complex, which acts as the central regulator of NF-κB activation. The IKK complex is comprised of two catalytical subunits IKKα (IKK1 or CHUK) and IKKβ (IKK2) as well as the regulatory subunit IKKγ (NEMO). In case of the canonical pathway, the activated IKK complex phosphorylates IκBs in an IKKβ/IKKγ dependent manner. These phosphorylated IκBs are now subject to poly-ubiquitination and consecutive proteasomal degradation, thus liberating p50/p65 heterodimers that can now translocate to the nucleus to initiate transcription of genes that are involved in cell survival, immunity and inflammation, cell proliferation and cell migration. Furthermore, activated p50/65 dimers activate genes encoding chemokines, cytokine and adhesion molecules that are important for innate immune response to invading microorganisms and are required for migration of inflammatory and phagocytic cells to tissues where NF-κB has been activated in response to infection or injury [2,3]. NF-κB dimers also assure the re-synthesis of IκB proteins that serve as negative feedback inhibitors. In contrast, the alternative NF-κB pathway is triggered by different TNF superfamily members such as BAFF, lymphotoxin-β or CD40L. These agonists induce processing of p100 to p52 via activation of IKKα, resulting in the nuclear translocation of p52-RelB. The alternative pathway has been suggested to play a central role in development and maintenance of secondary lymphoid organs. The canonical NF-κB pathway may also be indirectly linked to the alternative NF-κB pathway and may influence the amplitude and duration of its activation [2,4-6]. Increased p100 processing also contributes to the malignant phenotype of certain T- and B-cell lymphomas.


Cell Autonomous and Non-Autonomous Functions of IKKβ and NF-κB during the Pathogenesis of Gastrointestinal Tumors.

Fang HY, Greten FR - Cancers (Basel) (2011)

The two NF-κB activation pathways. The classical NF-κB pathway (left-hand side) results in translocation of primarily p50/p65 dimers in an IKKβ/IKKγ dependent manner. The alternative pathway for NF-κB (right-hand side) results in nuclear translocation of p52-RelB dimers and is strictly dependent on IKKα homodimers.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757413&req=5

f1-cancers-03-02214: The two NF-κB activation pathways. The classical NF-κB pathway (left-hand side) results in translocation of primarily p50/p65 dimers in an IKKβ/IKKγ dependent manner. The alternative pathway for NF-κB (right-hand side) results in nuclear translocation of p52-RelB dimers and is strictly dependent on IKKα homodimers.
Mentions: In unchallenged cells NF-κB dimers are bound to inhibitory IκB proteins retaining them in the cytoplasm. Two major pathways lead to translocation of NF-κB dimers from the cytoplasm to the nucleus: the canonical pathway and the alternative pathway (Figure 1). The canonical NF-κB pathway is triggered by pro-inflammatory cytokines or pathogen-associated molecular patterns (PAMPs) that engage different receptors belonging to the TNF receptor (TNFR), IL-1 receptor (IL-1R) or Toll-like receptor (TLR) superfamilies. Via various adaptor molecules signaling impinges on the IκB kinase (IKK) complex, which acts as the central regulator of NF-κB activation. The IKK complex is comprised of two catalytical subunits IKKα (IKK1 or CHUK) and IKKβ (IKK2) as well as the regulatory subunit IKKγ (NEMO). In case of the canonical pathway, the activated IKK complex phosphorylates IκBs in an IKKβ/IKKγ dependent manner. These phosphorylated IκBs are now subject to poly-ubiquitination and consecutive proteasomal degradation, thus liberating p50/p65 heterodimers that can now translocate to the nucleus to initiate transcription of genes that are involved in cell survival, immunity and inflammation, cell proliferation and cell migration. Furthermore, activated p50/65 dimers activate genes encoding chemokines, cytokine and adhesion molecules that are important for innate immune response to invading microorganisms and are required for migration of inflammatory and phagocytic cells to tissues where NF-κB has been activated in response to infection or injury [2,3]. NF-κB dimers also assure the re-synthesis of IκB proteins that serve as negative feedback inhibitors. In contrast, the alternative NF-κB pathway is triggered by different TNF superfamily members such as BAFF, lymphotoxin-β or CD40L. These agonists induce processing of p100 to p52 via activation of IKKα, resulting in the nuclear translocation of p52-RelB. The alternative pathway has been suggested to play a central role in development and maintenance of secondary lymphoid organs. The canonical NF-κB pathway may also be indirectly linked to the alternative NF-κB pathway and may influence the amplitude and duration of its activation [2,4-6]. Increased p100 processing also contributes to the malignant phenotype of certain T- and B-cell lymphomas.

Bottom Line: Activation of the transcription factor nuclear factor-κB (NF-κB) and its effector pathways has been proposed to be the missing link between these two processes.NF-κB is persistently activated in several types of tumors.Therefore, specific NF-κB inhibition in combination with cytotoxic drugs and/or irradiation represents a very promising strategy for cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, Munich 81675, Germany. florian.greten@lrz.tum.de.

ABSTRACT
Genetic studies describing a link between cancer and inflammation have increased recently. Activation of the transcription factor nuclear factor-κB (NF-κB) and its effector pathways has been proposed to be the missing link between these two processes. NF-κB is persistently activated in several types of tumors. However, NF-κB has a distinct role in cancer cells and in inflammatory cells. While in tumor cells NF-κB controls cell survival, in inflammatory cells NF-κB activates genes that encode pro-inflammatory cytokines which further act in a paracrine manner within the tumor microenvironment to contribute to tumorigenesis. Inactivation of NF-κB can also reduce chemoresistance and radioresistance of cancer cells. Therefore, specific NF-κB inhibition in combination with cytotoxic drugs and/or irradiation represents a very promising strategy for cancer therapy.

No MeSH data available.


Related in: MedlinePlus