Knockout Mouse Models Provide Insight into the Biological Functions of CRL1 Components

Nakagawa, Tadashi; Nakayama, Keiko; Nakayama, Keiichi I.

doi:10.1007/978-981-15-1025-0_10

Cited by 5 publications

(5 citation statements)

References 157 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The F box domain of F box proteins mediates direct binding to SKP1 ( Bai et al., 1996 ). Approximately 70 F box proteins have been identified in humans, each of which specifically recognizes a distinct group of substrates, with the result that SCF complexes mediate the ubiquitylation and degradation of a large variety of proteins ( Nakagawa et al., 2020 ; Nakayama and Nakayama, 2006 ). F box proteins are categorized into three classes on the basis of their substrate interaction domains: FBXW proteins (which contain WD40 repeat domains), FBXL proteins (which contain leucine-rich repeat [LRR] domains), and FBXO proteins (whose protein interaction domains are poorly characterized) ( Jin et al., 2004 ).…”

Section: Introductionmentioning

confidence: 99%

An Amyotrophic Lateral Sclerosis-Associated Mutant of C21ORF2 Is Stabilized by NEK1-Mediated Hyperphosphorylation and the Inability to Bind FBXO3

et al. 2020

Self Cite

View full text Add to dashboard Cite

Summary C21ORF2 and NEK1 have been identified as amyotrophic lateral sclerosis (ALS)-associated genes. Both genes are also mutated in certain ciliopathies, suggesting that they might contribute to the same signaling pathways. Here we show that FBXO3, the substrate receptor of an SCF ubiquitin ligase complex, binds and ubiquitylates C21ORF2, thereby targeting it for proteasomal degradation. C21ORF2 stabilizes the kinase NEK1, with the result that loss of FBXO3 stabilizes not only C21ORF2 but also NEK1. Conversely, NEK1-mediated phosphorylation stabilizes C21ORF2 by attenuating its interaction with FBXO3. We found that the ALS-associated V58L mutant of C21ORF2 is more susceptible to phosphorylation by NEK1, with the result that it is not ubiquitylated by FBXO3 and therefore accumulates together with NEK1. Expression of C21ORF2(V58L) in motor neurons induced from mouse embryonic stem cells impaired neurite outgrowth. We suggest that inhibition of NEK1 activity is a potential therapeutic approach to ALS associated with C21ORF2 mutation.

show abstract

Section: Introductionmentioning

confidence: 99%

An Amyotrophic Lateral Sclerosis-Associated Mutant of C21ORF2 Is Stabilized by NEK1-Mediated Hyperphosphorylation and the Inability to Bind FBXO3

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Among the 27 genes, COPS6 and TRRAP have been shown to be embryonic lethal in KO mice [42,43] and to be significantly vulnerable in leukemic cells with CRISPR or shRNA KO. Similarly, CUL1, a well-known HI gene associated with -7/del7q has been recognized as a promising candidate because (i) its expression resulted ubiquitously HI in almost all -7/del7q cases, (ii) it showed an ideal negative slope in clonal size and gene expression, (iii) few cases had biallelic LOF mutations, and (iv) it was previously associated with embryonic lethality in KO mice [44].…”

Section: Discussionmentioning

confidence: 99%

Genomics of deletion 7 and 7q in myeloid neoplasm: from pathogenic culprits to potential synthetic lethal therapeutic targets

Mori,

Kubota,

Durmaz

et al. 2023

Leukemia

View full text Add to dashboard Cite

Complete or partial deletions of chromosome 7 (-7/del7q) belong to the most frequent chromosomal abnormalities in myeloid neoplasm (MN) and are associated with a poor prognosis. The disease biology of -7/del7q and the genes responsible for the leukemogenic properties have not been completely elucidated. Chromosomal deletions may create clonal vulnerabilities due to haploinsufficient (HI) genes contained in the deleted regions. Therefore, HI genes are potential targets of synthetic lethal strategies. Through the most comprehensive multimodal analysis of more than 600 -7/del7q MN samples, we elucidated the disease biology and qualified a list of most consistently deleted and HI genes. Among them, 27 potentially synthetic lethal target genes were identified with the following properties: (i) unaffected genes by hemizygous/homozygous LOF mutations; (ii) prenatal lethality in knockout mice; and (iii) vulnerability of leukemia cells by CRISPR and shRNA knockout screens. In -7/del7q cells, we also identified 26 up or down-regulated genes mapping on other chromosomes as downstream pathways or compensation mechanisms. Our findings shed light on the pathogenesis of -7/del7q MNs, while 27 potential synthetic lethal target genes and 26 differential expressed genes allow for a therapeutic window of -7/del7q.

show abstract

“…The C-terminal domain of CUL protein forms a core ligase complex in combination with a RING finger protein, either RBX1 or RBX2, while the N-terminal domain interchangeably assembles with CUL-specific substrate receptors through adaptors. For instance, CRL1, also named SKP1-CUL1-F-box (SCF), uses SKP1 as its adaptor, and F-box as substrate receptor (Skowyra et al, 1997;Nakagawa et al, 2020).…”

Section: F-box E3 Ubiquitin Ligasesmentioning

confidence: 99%

E3 ubiquitin ligases in the acute leukemic signaling pathways

Zhan

Zhang

et al. 2022

Front. Physiol.

View full text Add to dashboard Cite

Acute leukemia is a common hematologic tumor with highly genetic heterogeneity, and many factors are involved in the pathogenesis and drug-resistance mechanism. Emerging evidence proves that E3 ubiquitin ligases participate in the acute leukemic signaling pathways via regulating substrates. This review summarized the E3 ligases which can affect the leukemic signal. It is worth noting that the abnormal signal is often caused by a deficiency or a mutation of the E3 ligases. In view of this phenomenon, we envisioned perspectives associated with targeted agonists of E3 ligases and proteolysis-targeting chimera technology. Moreover, we emphasized the significance of research into the upstream factors regulating the expression of E3 ubiquitin ligases. It is expected that the understanding of the mechanism of leukemic signaling pathways with which that E3 ligases are involved will be beneficial to accelerating the process of therapeutic strategy improvement for acute leukemia.

show abstract

Knockout Mouse Models Provide Insight into the Biological Functions of CRL1 Components

Cited by 5 publications

References 157 publications

An Amyotrophic Lateral Sclerosis-Associated Mutant of C21ORF2 Is Stabilized by NEK1-Mediated Hyperphosphorylation and the Inability to Bind FBXO3

An Amyotrophic Lateral Sclerosis-Associated Mutant of C21ORF2 Is Stabilized by NEK1-Mediated Hyperphosphorylation and the Inability to Bind FBXO3

Genomics of deletion 7 and 7q in myeloid neoplasm: from pathogenic culprits to potential synthetic lethal therapeutic targets

E3 ubiquitin ligases in the acute leukemic signaling pathways

Contact Info

Product

Resources

About