Eradication of pathogenic β-catenin by Skp1/Cullin/F box ubiquitination machinery

Su, Yeping; Ishikawa, Satoshi; Kojima, Masayasu; Liu, Bo

doi:10.1073/pnas.2133261100

Cited by 55 publications

(41 citation statements)

References 38 publications

(42 reference statements)

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“…For instance, Hypoxia-inducible factor-1a (HIF-1a) is a well-documented substrate of pVHL-associated SCF ubiquitin ligase complex (Lisztwan et al 1999), although most recent studies on the impact of MLN4924 on angiogenesis showed that NEDDylation inhibition could efficiently inhibit tumor vascularization process by inducing RhoA accumulation . Also, components in the tumorigenic Wnt signaling pathway, including the Dishevelled protein that integrates extra-cellular stimulus to activate Wnt pathway and b-catenin a key transcriptional factor activation of which will promote cell proliferation and invasion, are also wellestablished as substrates of CRLs (Angers et al 2006;Gao and Chen 2010;Su et al 2003). Currently, there is no study evaluating the impact of the stabilization of these oncogenic proteins upon MLN4924 treatment.…”

Section: Discussionmentioning

confidence: 99%

Targeting cullin-RING ligases for cancer treatment: rationales, advances and therapeutic implications

Shu-ju

2015

Cytotechnology

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New therapeutic intervention strategies for the treatment of human malignancies are always desired. Approval of bortezomib as a front-line treatment for multiple myeloma highlighted the significance of ubiquitin-proteasome system (UPS) as a promising therapeutic target. However, due to the broad impact of proteasome inhibition, deleterious side effects have been reported with bortezomib treatment. Cullin RING ligases (CRLs)-mediated ubiquitin conjugation process is responsible for the ubiquitin conjugation of 20 % cellular proteins that are designated for degradation through the UPS, most of them are critical proteins involved in cell cycle progression, signaling transduction and apoptosis. Studies have depicted the upstream NEDDylation pathway that controls the CRL activity by regulating the conjugation of an ubiquitin-like-protein NEDD8 to the cullin protein in the complex. A specific pharmaceutical inhibitor of NEDD8 activating enzyme (NAE; E1) MLN4924 was recently developed and has been promoted to Phase I clinical trials for the treatment of several human malignancies. This article summarizes the most recent understanding about the process of NEDD8 conjugation, its relevance for cancer therapy and molecular mechanisms responsible for the potent anti-tumor activity of MLN4924.

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Section: Discussionmentioning

confidence: 99%

Targeting cullin-RING ligases for cancer treatment: rationales, advances and therapeutic implications

Shu-ju

2015

Cytotechnology

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“…However, given that the abundance of many oncoproteins is regulated by the ubiquitin-proteasome system, a strategy targeted at the protein level is a potential alternative. Indeed, engineered E3 enzymes have been shown to eliminate oncoproteins; h-TrCP, the substrate recognition component of an SCF complex-type E3, was thus fused either with human papilloma virus E7 to eliminate members of the pRB family of proteins (18,19), with E-cadherin, APC, or Tcf-4 to eliminate mutant h-catenin (20)(21)(22), or with p21 to eliminate cyclin A-Cdk2 (23). In addition, a chimeric compound, protein-targeting chimeric molecule 1 (Protac-1), recruits methionine aminopeptidase-2 (MetAP-2) to h-TrCP (24).…”

Section: Introductionmentioning

confidence: 99%

Targeted Destruction of c-Myc by an Engineered Ubiquitin Ligase Suppresses Cell Transformation and Tumor Formation

et al. 2005

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Given that expression of c-Myc is up-regulated in many human malignancies, targeted inactivation of this oncoprotein is a potentially effective strategy for cancer treatment. The ubiquitinproteasome pathway of protein degradation is highly specific and can be engineered to achieve the elimination of undesirable proteins such as oncogene products. We have now generated a fusion protein (designated Max-U) that is composed both of Max, which forms a heterodimer with c-Myc, and of CHIP, which is a U box-type ubiquitin ligase (E3).

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“…Results obtained with the ODC͞AZ system and other previously reported approaches for inducing proteasome-dependent degradation of specific proteins (2,3,(5)(6)(7)(8) should be interpreted with understanding that the particular protein ligand chosen may have multiple cellular targets, including unknown or unanticipated protein targets in addition to known interacting proteins intended for targeted degradation. Thus, phenotypes created by these targeted protein-degradation methods could potentially reflect the loss of expression of several interacting proteins.…”

Section: Discussionmentioning

confidence: 97%

“…1). Accordingly, expression systems have been described in which whole proteins or fragments constituting functional proteininteraction domains or peptide ligands are expressed as chimeric fusion proteins together with modified versions of ubiquitin (2,3), ubiquitin ligases (e.g., HECT-domain-containing proteins) (4), or adapter proteins that associate with ubiquitin ligase complexes (e.g., F-box proteins of Skp1͞cullin͞F-box protein complexes) (5)(6)(7)(8), with the intention of inducing polyubiquitination of cellular proteins that bind these chimeric proteins, thus creating holes in pathways that reveal cellular phenotypes.…”

mentioning

confidence: 99%

Method for targeting protein destruction by using a ubiquitin-independent, proteasome-mediated degradation pathway

Matsuzawa

Cuddy

Fukushima

et al. 2005

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

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With the euchromatic portion of several mammalian genomes now sequenced, emphasis has turned to ascertaining the functions of gene products. A method for targeting destruction of selected proteins in mammalian cells is described, based on the ubiquitinindependent mechanism by which ornithine decarboxylase (ODC) is degraded by the 26S proteasome in collaboration with antizyme (AZ). We show that expressing whole proteins, protein domains, or peptide ligands fused to the N terminus of ODC promotes proteasome-dependent degradation of these chimeric fusion proteins and their interacting cellular target proteins. Moreover, the degradation of the interacting (targeted) protein depends on coexpression of AZ in about half of cases, providing an inducible switch for triggering the degradation process. By using 12 pairs of interacting proteins for testing, direct comparisons with several alternative strategies for achieving targeted protein destruction based on the concept of induced ubiquitination revealed advantages of the ODC͞AZ system, which does not require posttranslational attachment of ubiquitin to target proteins. As proof of concept, the ODC͞AZ system was used to ablate expression of specific endogenous proteins (e.g., TRAF6; Rb), and was shown to create the expected lesions in cellular pathways that require these proteins. Altogether, these findings reveal a strategy for achieving targeted destruction of cellular proteins, thus providing an additional tool for revealing the cellular phenotypes of gene products.antizyme ͉ ornithine decarboxylase ͉ proteasome ͉ protein degradation F unctions are known for fewer than half the genes identified in mammalian genomes to date, indicating a need for gene functionalization technologies that can reveal the phenotypes of genes and their encoded proteins in various cellular contexts. Methods targeting gene-expression pathways at the level of mRNA, such as antisense oligonucleotides and small interfering RNA, offer exquisite specificity for gene silencing through Watson-Crick-type hybridization of synthetic or vector-derived nucleotide sequences to target mRNAs. These gene-silencing methods, however, sometimes prove ineffective, either because the targeted mRNAs encode long-lived stable proteins or because of functional redundancy among members of multigene families. These deficiencies have prompted attempts to inducibly target degradation of the protein products of genes by tapping into components of the eukaryotic ubiquitination machinery, which induces proteasome-dependent degradation of ubiquitin-modified proteins (reviewed in ref. 1). Accordingly, expression systems have been described in which whole proteins or fragments constituting functional proteininteraction domains or peptide ligands are expressed as chimeric fusion proteins together with modified versions of ubiquitin (2, 3), ubiquitin ligases (e.g., HECT-domain-containing proteins) (4), or adapter proteins that associate with ubiquitin ligase complexes (e.g., F-box proteins of Skp1͞cullin͞F-box protein complexes...

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Eradication of pathogenic β-catenin by Skp1/Cullin/F box ubiquitination machinery

Cited by 55 publications

References 38 publications

Targeting cullin-RING ligases for cancer treatment: rationales, advances and therapeutic implications

Targeting cullin-RING ligases for cancer treatment: rationales, advances and therapeutic implications

Targeted Destruction of c-Myc by an Engineered Ubiquitin Ligase Suppresses Cell Transformation and Tumor Formation

Method for targeting protein destruction by using a ubiquitin-independent, proteasome-mediated degradation pathway

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