Cullin-based ubiquitin ligases: Cul3–BTB complexes join the family

Pintard, Lionel; Willems, Andrew; Peter, Matthias

doi:10.1038/sj.emboj.7600186

Cited by 354 publications

(262 citation statements)

References 45 publications

Supporting

Mentioning

256

Contrasting

Unclassified

Order By: Relevance

“…1), which is predicted to interact with Cul3 (29)(30)(31). However, mutations in the BTB domain of human Keap1 at the predicted interface between BTB and Cul3 did not disrupt the Keap1-Cul3 interaction, but led to downregulation of Neh2 ubiquitination as well as up-regulation of Keap1 ubiquitination (21).…”

Section: Discussionmentioning

confidence: 99%

Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2

Eggler

Pezzuto

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

421

377

View full text Add to dashboard Cite

The risks of cancer and other degenerative diseases caused by reactive oxygen species and electrophiles can be reduced by the up-regulation of detoxifying enzymes. A major mechanism whereby these protective enzymes are induced occurs through activation of the antioxidant response element (ARE) by the oxidative-stress sensor protein Kelch-like ECH-associated protein 1 (Keap1) and the transcription factor NF-E2-related factor 2 (Nrf2). Under basal conditions, Keap1 sequesters Nrf2 in the cytoplasm by binding to its Neh2 domain. Chemical inducers such as sulforaphane are known to react with Keap1 cysteine residues, thereby promoting Nrf2 nuclear accumulation and hence ARE activation. A widely accepted model for Nrf2 nuclear accumulation is that modification of Keap1 cysteines leads directly to dissociation of the Keap1-Nrf2 complex. This model is based on studies with mouse proteins and has served as the experimental basis and hypothesis for numerous investigations. Through a combination of chemical, mass spectrometry, and isothermal titration calorimetry methods, we have tested the direct-dissociation model using a series of ARE inducers: sulforaphane, isoliquiritigenin, 15-deoxy-⌬12,14-prostaglandin-J2, menadione, 1-Cl-2,4-dinitrobenzene, and biotinylated iodoacetamide. Surprisingly, these data suggest that the direct disruption model for Keap1-Nrf2 is incorrect. The relative reactivity of human Keap1 cysteines was determined. In addition to the same five cysteines identified for mouse Keap1, two highly reactive and previously unobserved cysteines were identified. Based on these results, a model is proposed that should aid in the understanding of Keap1-Nrf2 signaling mechanisms.antioxidant response element ͉ sulforaphane ͉ 15-deoxy-⌬12,14-prostaglandin J2 ͉ oxidative stress ͉ ubiquitination

show abstract

Section: Discussionmentioning

confidence: 99%

Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2

Eggler

Pezzuto

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

421

377

View full text Add to dashboard Cite

show abstract

“…Once bound to the F-box, the SCF substrate will be brought closer to the Cul1/Hrt1 catalytic core of this ubiquitin-ligase by Skp1. Finally, Cul1/Hrt1 will recruit the E2 enzyme, Cdc34, and will induce substrate ubiquitination (Pintard et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The anaphase-promoting complex: a key factor in the regulation of cell cycle

et al. 2005

View full text Add to dashboard Cite

Events controlling cell division are governed by the degradation of different regulatory proteins by the ubiquitin-dependent pathway. In this pathway, the attachment of a polyubiquitin chain to a substrate by an ubiquitin-ligase targets this substrate for degradation by the 26S proteasome. Two different ubiquitin ligases play an important role in the cell cycle: the SCF (Skp1/Cullin/ F-box) and the anaphase-promoting complex (APC). In this review, we describe the present knowledge about the APC. We pay particular attention to the latest results concerning APC structure, APC regulation and substrate recognition, and we discuss the implication of these findings in the understanding the APC function.

show abstract

“…The latter may involve a number of different E3 ubiquitin ligases. One large family of E3 ubiquitin ligases consists of multisubunit protein complexes organized by the Cullin family of scaffolding proteins (27). Our study provides evidence for a role of Cul3-based E3 ubiquitin ligases in the regulation of Glis3 protein stability and a possible connection among the actions of Cul3, SUFU, and Glis3.…”

Section: Discussionmentioning

confidence: 65%

“…Our study provides evidence for a role of Cul3-based E3 ubiquitin ligases in the regulation of Glis3 protein stability and a possible connection among the actions of Cul3, SUFU, and Glis3. Cul3 typically promotes ubiquitin-dependent proteolytic degradation by binding to the BTB domain of adaptor proteins that target specific protein substrates (27); therefore, it is likely that association between Cul3 and Glis3 is mediated by a similar mechanism. We demonstrated that Cul3 is part of a Glis3 protein complex and is able to promote the polyubiquitination of Glis3.…”

Section: Discussionmentioning

confidence: 99%

“…Glis3 Degradation Is Mediated by Cul3-The polyubiquitination and subsequent degradation of Glis3 by the proteasome system may involve several E3 ubiquitin ligases, including Cullin-based E3 ubiquitin ligases (27). To determine whether the E3 ubiquitin ligase scaffolding protein Cullin 3 (Cul3) (28 -30) was able to promote the ubiquitination of Glis3, FLAG-tagged Glis3 was immunoprecipitated with HA-tagged ubiquitin in the presence or absence of co-expression with exogenous Cul3.…”

Section: The Region Of Glis3 Between Amino Acids 296 and 354 Is Highlmentioning

confidence: 99%

See 1 more Smart Citation

Modulation of the Transactivation Function and Stability of Krüppel-like Zinc Finger Protein Gli-similar 3 (Glis3) by Suppressor of Fused

ZeRuth

Yang

Jetten

2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Glis3 is a member of the Glis subfamily of Krüppel-like zinc finger transcription factors. Recently, Glis3 has been linked to both type I and type II diabetes and shown to positively regulate insulin gene expression. In this study, we have identified a region within the N terminus of Glis3 that shares high levels of homology with the Cubitus interruptus (Ci)/Gli family of proteins. We demonstrated that Glis3 interacts with Suppressor of Fused (SUFU), which involves a VYGHF motif located within this conserved region. We further showed that SUFU is able to inhibit the activation of the insulin promoter by Glis3 but not the activation by a Glis3 mutant deficient in its ability to bind SUFU, suggesting that the inhibitory effect is dependent on the interaction between the two proteins. Exogenous SUFU did not affect the nuclear localization of Glis3; however, Glis3 promoted the nuclear accumulation of SUFU. Additionally, we demonstrated that SUFU stabilizes Glis3 in part by antagonizing the Glis3 association with a Cullin 3-based E3 ubiquitin ligase that promotes the ubiquitination and degradation of Glis3. This is the first reported instance of Glis3 interacting with SUFU and suggests a novel role for SUFU in the modulation of Glis3 signaling. Given the critical role of Glis3 in pancreatic ␤-cell generation and maintenance, the elevated Glis3 expression in several cancers, and the established role of SUFU as a tumor suppressor, these data provide further insight into Glis3 regulation and its function in development and disease.

show abstract

Cullin-based ubiquitin ligases: Cul3–BTB complexes join the family

Cited by 354 publications

References 45 publications

Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2

Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2

The anaphase-promoting complex: a key factor in the regulation of cell cycle

Modulation of the Transactivation Function and Stability of Krüppel-like Zinc Finger Protein Gli-similar 3 (Glis3) by Suppressor of Fused

Contact Info

Product

Resources

About