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Cytoprotection "gone astray": Nrf2 and its role in cancer.

Geismann C, Arlt A, Sebens S, Schäfer H - Onco Targets Ther (2014)

Bottom Line: The deregulation of Nrf2 can result from various epigenetic and genetic alterations directly affecting Nrf2 control or from the complex interplay of Nrf2 with numerous oncogenic signaling pathways.A better understanding of these modalities is essential for the safe use of Nrf2 as an activation target for chemoprevention on the one hand and as an inhibition target in cancer therapy on the other.The present review mainly addresses the conditions that promote the oncogenic function of Nrf2 and the resulting consequences providing the rationale for using Nrf2 as a target structure in cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Gastroenterology, Department of Internal Medicine I, Universitätsklinikum Schleswig-Holstein Campus Kiel, Kiel, Germany.

ABSTRACT
Nrf2 has gained great attention with respect to its pivotal role in cell and tissue protection. Primarily defending cells against metabolic, xenobiotic and oxidative stress, Nrf2 is essential for maintaining tissue integrity. Owing to these functions, Nrf2 is regarded as a promising drug target in the chemoprevention of diseases, including cancer. However, much evidence has accumulated that the beneficial role of Nrf2 in cancer prevention essentially depends on the tight control of its activity. In fact, the deregulation of Nrf2 is a critical determinant in oncogenesis and found in many types of cancer. Therefore, amplified Nrf2 activity has profound effects on the phenotype of tumor cells, including radio/chemoresistance, apoptosis protection, invasiveness, antisenescence, autophagy deficiency, and angiogenicity. The deregulation of Nrf2 can result from various epigenetic and genetic alterations directly affecting Nrf2 control or from the complex interplay of Nrf2 with numerous oncogenic signaling pathways. Additionally, alterations of the cellular environment, eg, during inflammation, contribute to Nrf2 deregulation and its persistent activation. Therefore, the status of Nrf2 as anti- or protumorigenic is defined by many different modalities. A better understanding of these modalities is essential for the safe use of Nrf2 as an activation target for chemoprevention on the one hand and as an inhibition target in cancer therapy on the other. The present review mainly addresses the conditions that promote the oncogenic function of Nrf2 and the resulting consequences providing the rationale for using Nrf2 as a target structure in cancer therapy.

No MeSH data available.


Related in: MedlinePlus

(A and B) Principle of controlling Nrf2 by Keap1 and its activation.Notes: (A) Under homeostatic conditions, Nrf2 is kept at low levels through its Keap1-dependent targeting to Cullin3/Rbx1-mediated Lys-48 polyubiquitination and subsequent proteasomal degradation. (B) During exposure to stress activators, the interaction between Nrf2 and Keap1 is weakened, thereby impairing Nrf2 polyubiquitination. While free Nrf2 then can enter the nucleus and drive antioxidant response element (ARE)-dependent gene expression along with certain modifications (eg, Ser-40 phosphorylation, acetylation), Keap-1 can be subject to Lys-63 polyubiquitination that leads to the release of Nrf2. Ubiquitin-specific protease (USP)-15 deubiquitinase reverses Keap1 polyubiquitination.
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f1-ott-7-1497: (A and B) Principle of controlling Nrf2 by Keap1 and its activation.Notes: (A) Under homeostatic conditions, Nrf2 is kept at low levels through its Keap1-dependent targeting to Cullin3/Rbx1-mediated Lys-48 polyubiquitination and subsequent proteasomal degradation. (B) During exposure to stress activators, the interaction between Nrf2 and Keap1 is weakened, thereby impairing Nrf2 polyubiquitination. While free Nrf2 then can enter the nucleus and drive antioxidant response element (ARE)-dependent gene expression along with certain modifications (eg, Ser-40 phosphorylation, acetylation), Keap-1 can be subject to Lys-63 polyubiquitination that leads to the release of Nrf2. Ubiquitin-specific protease (USP)-15 deubiquitinase reverses Keap1 polyubiquitination.

Mentions: Together with two closely related proteins – Nrf1 and Nrf3 – as well as with NF-E2 and Bach-1, and Bach-2, Nrf2 belongs to a family of transcription factors termed CNC-bZIP proteins.34 Quite unique to Nrf2 is the Neh2 domain near to the amino-terminal end, which serves as interaction domain with the Nrf2 inhibitory protein Keap1.35 This interaction depends on the low-affinity binding of a DLG and the high-affinity binding of an ETGE motif. Under homeostatic conditions, Nrf2 is kept at low levels when bound via DLG and ETGE to a homodimer of Keap1 through the DC domain of either one of the Keap1 subunits, leading to Cullin3/Rbx1-catalyzed polyubiquitination and subsequent proteasomal degradation of Nrf2 (Figure 1A).36,37 During conditions of oxidative/electrophilic or xenobiotic stress, the Cullin3/Rbx1-dependent polyubiquitination of Nrf2 under the assistance of Keap1 is blocked, thereby leading to the accumulation of Nrf2 protein and its subsequent translocation to the nucleus (Figure 1B).36 The derepression of Nrf2 in this way depends on the dissociation of the Nrf2 polyubiquination site from Cullin3/Rbx1 without releasing Nrf2 from the protein complex (according to the hinge–latch model, in which the ETGE motif remains bound to Keap1), hence saturating Keap1 and competing with free Nrf2 that instead can enter the nucleus (Figure 2).38,39 An alternative mode of induction occurs through the release of Cullin3 from Keap1, thereby directly impeding the polyubiquitination of Nrf2.40 During Nrf2 activation, Keap1 itself can be Lys63 polyubiquitinated,41 which does not target the protein to the proteasome (in contrast to the Lys48 polyubiquitination of Nrf2), but instead seems to destabilize its Cullin3 interaction. Recently, the ubiquitin-specific protease-15 deubiquitinase was identified to deubiquitinate Keap1,42 thereby restoring Cullin3 recruitment and accordingly Nrf2 suppression. This ubiquitination/deubiquitination of Keap1 may function as an additional Nrf2-regulatory mechanism.


Cytoprotection "gone astray": Nrf2 and its role in cancer.

Geismann C, Arlt A, Sebens S, Schäfer H - Onco Targets Ther (2014)

(A and B) Principle of controlling Nrf2 by Keap1 and its activation.Notes: (A) Under homeostatic conditions, Nrf2 is kept at low levels through its Keap1-dependent targeting to Cullin3/Rbx1-mediated Lys-48 polyubiquitination and subsequent proteasomal degradation. (B) During exposure to stress activators, the interaction between Nrf2 and Keap1 is weakened, thereby impairing Nrf2 polyubiquitination. While free Nrf2 then can enter the nucleus and drive antioxidant response element (ARE)-dependent gene expression along with certain modifications (eg, Ser-40 phosphorylation, acetylation), Keap-1 can be subject to Lys-63 polyubiquitination that leads to the release of Nrf2. Ubiquitin-specific protease (USP)-15 deubiquitinase reverses Keap1 polyubiquitination.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4155833&req=5

f1-ott-7-1497: (A and B) Principle of controlling Nrf2 by Keap1 and its activation.Notes: (A) Under homeostatic conditions, Nrf2 is kept at low levels through its Keap1-dependent targeting to Cullin3/Rbx1-mediated Lys-48 polyubiquitination and subsequent proteasomal degradation. (B) During exposure to stress activators, the interaction between Nrf2 and Keap1 is weakened, thereby impairing Nrf2 polyubiquitination. While free Nrf2 then can enter the nucleus and drive antioxidant response element (ARE)-dependent gene expression along with certain modifications (eg, Ser-40 phosphorylation, acetylation), Keap-1 can be subject to Lys-63 polyubiquitination that leads to the release of Nrf2. Ubiquitin-specific protease (USP)-15 deubiquitinase reverses Keap1 polyubiquitination.
Mentions: Together with two closely related proteins – Nrf1 and Nrf3 – as well as with NF-E2 and Bach-1, and Bach-2, Nrf2 belongs to a family of transcription factors termed CNC-bZIP proteins.34 Quite unique to Nrf2 is the Neh2 domain near to the amino-terminal end, which serves as interaction domain with the Nrf2 inhibitory protein Keap1.35 This interaction depends on the low-affinity binding of a DLG and the high-affinity binding of an ETGE motif. Under homeostatic conditions, Nrf2 is kept at low levels when bound via DLG and ETGE to a homodimer of Keap1 through the DC domain of either one of the Keap1 subunits, leading to Cullin3/Rbx1-catalyzed polyubiquitination and subsequent proteasomal degradation of Nrf2 (Figure 1A).36,37 During conditions of oxidative/electrophilic or xenobiotic stress, the Cullin3/Rbx1-dependent polyubiquitination of Nrf2 under the assistance of Keap1 is blocked, thereby leading to the accumulation of Nrf2 protein and its subsequent translocation to the nucleus (Figure 1B).36 The derepression of Nrf2 in this way depends on the dissociation of the Nrf2 polyubiquination site from Cullin3/Rbx1 without releasing Nrf2 from the protein complex (according to the hinge–latch model, in which the ETGE motif remains bound to Keap1), hence saturating Keap1 and competing with free Nrf2 that instead can enter the nucleus (Figure 2).38,39 An alternative mode of induction occurs through the release of Cullin3 from Keap1, thereby directly impeding the polyubiquitination of Nrf2.40 During Nrf2 activation, Keap1 itself can be Lys63 polyubiquitinated,41 which does not target the protein to the proteasome (in contrast to the Lys48 polyubiquitination of Nrf2), but instead seems to destabilize its Cullin3 interaction. Recently, the ubiquitin-specific protease-15 deubiquitinase was identified to deubiquitinate Keap1,42 thereby restoring Cullin3 recruitment and accordingly Nrf2 suppression. This ubiquitination/deubiquitination of Keap1 may function as an additional Nrf2-regulatory mechanism.

Bottom Line: The deregulation of Nrf2 can result from various epigenetic and genetic alterations directly affecting Nrf2 control or from the complex interplay of Nrf2 with numerous oncogenic signaling pathways.A better understanding of these modalities is essential for the safe use of Nrf2 as an activation target for chemoprevention on the one hand and as an inhibition target in cancer therapy on the other.The present review mainly addresses the conditions that promote the oncogenic function of Nrf2 and the resulting consequences providing the rationale for using Nrf2 as a target structure in cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Gastroenterology, Department of Internal Medicine I, Universitätsklinikum Schleswig-Holstein Campus Kiel, Kiel, Germany.

ABSTRACT
Nrf2 has gained great attention with respect to its pivotal role in cell and tissue protection. Primarily defending cells against metabolic, xenobiotic and oxidative stress, Nrf2 is essential for maintaining tissue integrity. Owing to these functions, Nrf2 is regarded as a promising drug target in the chemoprevention of diseases, including cancer. However, much evidence has accumulated that the beneficial role of Nrf2 in cancer prevention essentially depends on the tight control of its activity. In fact, the deregulation of Nrf2 is a critical determinant in oncogenesis and found in many types of cancer. Therefore, amplified Nrf2 activity has profound effects on the phenotype of tumor cells, including radio/chemoresistance, apoptosis protection, invasiveness, antisenescence, autophagy deficiency, and angiogenicity. The deregulation of Nrf2 can result from various epigenetic and genetic alterations directly affecting Nrf2 control or from the complex interplay of Nrf2 with numerous oncogenic signaling pathways. Additionally, alterations of the cellular environment, eg, during inflammation, contribute to Nrf2 deregulation and its persistent activation. Therefore, the status of Nrf2 as anti- or protumorigenic is defined by many different modalities. A better understanding of these modalities is essential for the safe use of Nrf2 as an activation target for chemoprevention on the one hand and as an inhibition target in cancer therapy on the other. The present review mainly addresses the conditions that promote the oncogenic function of Nrf2 and the resulting consequences providing the rationale for using Nrf2 as a target structure in cancer therapy.

No MeSH data available.


Related in: MedlinePlus