The Fbw7 Tumor Suppressor Regulates Nuclear Factor E2-related Factor 1 Transcription Factor Turnover through Proteasome-mediated Proteolysis

Biswas, Madhurima; Phan, Diane; Watanabe, Momoko; Chan, Jefferson Y.

doi:10.1074/jbc.m111.253807

Cited by 60 publications

(69 citation statements)

References 33 publications

(31 reference statements)

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“…Depletion of FBW7 significantly inhibits the NF-κB activation and cell survival. Moreover, FBW7 has also been demonstrated as an efficient E3 ubiquitin ligase for tumor suppressor NF1 and Nrf1 [30,52]. In our study, we reported that FBW7 is required for the growth of teratoma via targeting the KLF2 for degradation and inhibiting the angiogenesis.…”

Section: Discussionmentioning

confidence: 55%

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

Wang

Liu

et al. 2013

Cell Res

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F-box and WD repeat domain-containing 7 (FBW7), the substrate-binding subunit of E3 ubiquitin ligase SCF FBW7 (a complex of SKP1, cullin-1 and FBW7), plays important roles in various physiological and pathological processes. Although FBW7 is required for vascular development, its function in the endothelium remains to be investigated. In this study, we show that FBW7 is an important regulator of endothelial functions, including angiogenesis, leukocyte adhesion and the endothelial barrier integrity. Using RNA interference, we found that the depletion of FBW7 markedly impairs angiogenesis in vitro and in vivo. We identified the zinc finger transcription factor Krüppel-like factor 2 (KLF2) as a physiological target of FBW7 in endothelial cells. Knockdown of FBW7 expression resulted in the accumulation of endogenous KLF2 protein in endothelial cells. FBW7-mediated KLF2 destruction was shown to depend on the phosphorylation of KLF2 via glycogen synthase kinase-3 (GSK3) at two conserved phosphodegrons. Mutating these phosphodegron motifs abolished the FBW7-mediated degradation and ubiquitination of KLF2. The siRNAmediated knockdown of FBW7 showed that KLF2 is an essential target of FBW7 in the regulation of endothelial functions. Moreover, FBW7-mediated KLF2 degradation was shown to be critical for angiogenesis in teratomas and in zebrafish development. Taken together, our study suggests a role for FBW7 in the processes of endothelial cell migration, angiogenesis, inflammation and barrier integrity, and provides novel insights into the regulation of KLF2 stability in vivo.

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Section: Discussionmentioning

confidence: 55%

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

Wang

Liu

et al. 2013

Cell Res

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“…We have previously shown Nrf1a is a short-lived protein degraded through the ubiquitin-proteasome pathway [61]. We show that overexpression of HCF1 and OGT, as well as PUGNAc treatment decreases steady-state ubiquitination of Nrf1a.…”

Section: Discussionmentioning

confidence: 70%

Nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) is regulated by O-GlcNAc transferase

Han

Valdez

et al. 2017

Free Radical Biology and Medicine

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A B S T R A C TThe Nrf1 (Nuclear factor E2-related factor 1) transcription factor performs a critical role in regulating cellular homeostasis. Using a proteomic approach, we identified Host Cell Factor-1 (HCF1), a co-regulator of transcription, and O-GlcNAc transferase (OGT), the enzyme that mediates protein O-GlcNAcylation, as cellular partners of Nrf1a, an isoform of Nrf1. Nrf1a directly interacts with HCF1 through the HCF1 binding motif (HBM), while interaction with OGT is mediated through HCF1. Overexpression of HCF1 and OGT leads to increased Nrf1a protein stability. Addition of O-GlcNAc decreases ubiquitination and degradation of Nrf1a. Transcriptional activation by Nrf1a is increased by OGT overexpression and treatment with PUGNAc. Together, these data suggest that OGT can act as a regulator of Nrf1a.

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“…44 On the other hand, it has also been reported that Nrf1 is a shortlived protein that is targeted by the F-box protein Fbw7, which is another substrate-specifying component of SCFtype ubiquitin ligase that mediates degradation via the ubiquitin−proteasome pathway. 45 Together, these findings indicate that Nrf1 plays a central role in upregulating the proteasome system through an ERAD-dependent feedback loop. Currently, however, the mechanism that regulates Nrf1 expression in vivo is poorly understood.…”

Section: Regulationmentioning

confidence: 82%

The Proteasome: From Basic Mechanisms to Emerging Roles

Tanaka

2013

Keio J. Med.

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The proteasome is a sophisticated, 2.5-MDa, multisubunit complex that contains a catalytic core particle (CP) and two terminal regulatory particles (RPs); the RPs associate with the termini of the central CP at opposite orientations. The CP consists of four axially stacked heptameric rings (two outer α-rings and two inner β-rings), which are made up of seven structurally related, but not identical, α and β subunits. The CP contains catalytic threonine residues (in β1, β2, and β5 with caspase-like, trypsin-like, and chymotrypsin-like activities, respectively) on the surface of the chamber formed by two abutting β-rings. The RP recognizes polyubiquitylated substrate proteins and unfolds and translocates these proteins to the interior of the CP for degradation. The RP comprises 19 different subunits, which are thought to form two subcomplexes called the lid and the base. One longstanding question is how the complex structure of the proteasome is organized with high fidelity. Recently, we proposed a novel assembly mechanism that is assisted by multiple proteasome-dedicated chaperones. In addition, we discovered two immuno-type proteasomes, the immunoproteasome and the thymoproteasome, whose catalytic subunits are replaced by homologous counterparts. These two isoforms perform specialized functions that help discriminate self from non-self in cell-mediated immunity (i.e., they function as enzymes that process intracellular antigens for cytotoxic T lymphocyte responses and thymic positive selection). Moreover, emerging evidence suggests that the proteasome is crucially involved in the pathophysiology of various intractable diseases that are increasing in today's aging society.

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The Fbw7 Tumor Suppressor Regulates Nuclear Factor E2-related Factor 1 Transcription Factor Turnover through Proteasome-mediated Proteolysis

Cited by 60 publications

References 33 publications

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

Nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) is regulated by O-GlcNAc transferase

The Proteasome: From Basic Mechanisms to Emerging Roles

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