The role and mechanism of CRL4 E3 ubiquitin ligase in cancer and its potential therapy implications

Sang, Youzhou; Fan, Yan; Ren, Xiubao

doi:10.18632/oncotarget.6052

Cited by 41 publications

(35 citation statements)

References 129 publications

(157 reference statements)

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“…The N-terminal region of Cullins binds with Cullin-specific adaptor protein to target diverse substrates. 29,30 Furthermore, CRLs activity is regulated by Nedd8 post-translational modification known as neddylation. Interestingly, this process can be reversed by COP9 signalosome (CSN)-mediated deneddylation, leading to inactivation of CRLs.…”

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confidence: 99%

“…Interestingly, this process can be reversed by COP9 signalosome (CSN)-mediated deneddylation, leading to inactivation of CRLs. [30][31][32] Among eight Cullins (CUL1-7 and PARC), Cullin4 (CUL4) has been well studied. Cullin4 consists of 2 members, CUL4A and CUL4B, which share extensively sequence homology and functional redundancy.…”

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confidence: 99%

“…Cullin4 consists of 2 members, CUL4A and CUL4B, which share extensively sequence homology and functional redundancy. 28,30 CUL4 is expressed aberrantly in a wide range of human tumors and involves in tumor-related changes including cell cycle, DNA damage repair, histone methylation and oncoproteins turnover. 28,30 In particular, the aberrant expression of CUL4A has been identified in breast cancer, squamous cell carcinoma, pleural mesothelioma and non-small cell lung cancer.…”

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confidence: 99%

“…28,30 CUL4 is expressed aberrantly in a wide range of human tumors and involves in tumor-related changes including cell cycle, DNA damage repair, histone methylation and oncoproteins turnover. 28,30 In particular, the aberrant expression of CUL4A has been identified in breast cancer, squamous cell carcinoma, pleural mesothelioma and non-small cell lung cancer. [33][34][35][36][37] Intriguingly, CUL4A induced EMT and promoted cancer metastasis in part via regulation of ZEB1 (zinc finger E-box-binding homebox 1) expression.…”

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confidence: 99%

“…Remarkably, CRL4 has been validated to control cell cycle through regulation of multiple proteins including cell cycle proteins (Cyclins), cyclindependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CDKIs), which are critical for cell cycle process. 30 For example, Cyclin E is a key regulator of the entry from G1 phase to S phase and its aberrant expression is observed in several types of human cancers. 43,44 Studies have discovered that CRL4 regulated the degradation of Cyclin E. 45,46 Overexpression of CRL4 decreased Cyclin E protein level, while down-regulation of CRL4 increased Cyclin E expression.…”

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confidence: 99%

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A new layer of degradation mechanism for PR-Set7/Set8 during cell cycle

et al. 2016

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Set8 is critically involved in transcription regulation, cell cycle progression and genomic stability. -dependent Set8 destruction also contributes to the tight control of cell proliferation and cell cycle progression, in response to UV irradiation. Here, we summarize our new findings regarding the crucial role of b-TRCP in CKI-mediated Set8 degradation, which could provide new evidence to support that dysregulation of a tight regulatory network of Set8 could lead to aberrant cell cycle process.

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A new layer of degradation mechanism for PR-Set7/Set8 during cell cycle

et al. 2016

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Activation of TNF‐α/NF‐κB axis enhances CRL4B^DCAF¹¹ E3 ligase activity and regulates cell cycle progression in human osteosarcoma cells

et al. 2018

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Cullin 4B, a member of the Cullins, which serve as scaffolds to facilitate the assembly of E3 ligase complexes, is aberrantly expressed in many cancers, including osteosarcoma. Recently, we observed that CUL4B forms the CRL4BDCAF 11 E3 ligase, which specifically ubiquitinates and degrades the cyclin‐dependent kinase (CDK) inhibitor p21Cip1 in human osteosarcoma cells. However, the underlying mechanisms regarding the aberrant expression of CUL4B and the upstream members of this signaling pathway are mostly unknown. In this study, we demonstrate that nuclear factor kappaB (NF‐κB) is a direct modulator of CUL4B expression. The CUL4B promoter is responsive to several NF‐κB subunits, including RelA, RelB, and c‐Rel, but not to p50 or p52. Additional studies reveal that the tumor necrosis factor alpha (TNF‐α)/NF‐κB axis pathway is activated in human osteosarcoma cells. This activation causes both CUL4B and NF‐κB subunits to become abundant in the nucleus of human osteosarcoma cells. The down‐regulation of individual genes, including TNFR1, RelA, RelB, c‐Rel, and CUL4B, or pairs of them, including TNFR1 + RelA,TNFR1 + RelB,TNFR1 + c‐Rel, and RelA+CUL4B, has similar effects on cell growth inhibition, colony formation, cell invasion, and in vivo tumor formation, whereas the overexpression of CUL4B in these knockdown cells significantly reverses their phenotypes. The inhibition of the TNF‐α/NF‐κB pathway greatly attenuates CRL4BDCAF 11 E3 ligase activity and causes the accumulation of p21Cip1, thereby leading to cell cycle arrest at the S phase. Taken together, our results support a model in which the activation of the TNF‐α/NF‐κB axis contributes to an increase in CRL4BDCAF 11 activity and a decrease in p21Cip1 protein levels, thereby controlling cell cycle progression in human osteosarcoma cells.

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The roles of E3 ubiquitin ligases in cancer progression and targeted therapy

Sampson

Wang

Otkur

et al. 2023

Clinical & Translational Med

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Ubiquitination is one of the most important post‐translational modifications which plays a significant role in conserving the homeostasis of cellular proteins. In the ubiquitination process, ubiquitin is conjugated to target protein substrates for degradation, translocation or activation, dysregulation of which is linked to several diseases including various types of cancers. E3 ubiquitin ligases are regarded as the most influential ubiquitin enzyme owing to their ability to select, bind and recruit target substrates for ubiquitination. In particular, E3 ligases are pivotal in the cancer hallmarks pathways where they serve as tumour promoters or suppressors. The specificity of E3 ligases coupled with their implication in cancer hallmarks engendered the development of compounds that specifically target E3 ligases for cancer therapy. In this review, we highlight the role of E3 ligases in cancer hallmarks such as sustained proliferation via cell cycle progression, immune evasion and tumour promoting inflammation, and in the evasion of apoptosis. In addition, we summarise the application and the role of small compounds that target E3 ligases for cancer treatment along with the significance of targeting E3 ligases as potential cancer therapy.

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The role and mechanism of CRL4 E3 ubiquitin ligase in cancer and its potential therapy implications

Cited by 41 publications

References 129 publications

A new layer of degradation mechanism for PR-Set7/Set8 during cell cycle

A new layer of degradation mechanism for PR-Set7/Set8 during cell cycle

Activation of TNF‐α/NF‐κB axis enhances CRL4B^DCAF¹¹ E3 ligase activity and regulates cell cycle progression in human osteosarcoma cells

The roles of E3 ubiquitin ligases in cancer progression and targeted therapy

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The role and mechanism of CRL4 E3 ubiquitin ligase in cancer and its potential therapy implications

Cited by 41 publications

References 129 publications

A new layer of degradation mechanism for PR-Set7/Set8 during cell cycle

A new layer of degradation mechanism for PR-Set7/Set8 during cell cycle

Activation of TNF‐α/NF‐κB axis enhances CRL4BDCAF11 E3 ligase activity and regulates cell cycle progression in human osteosarcoma cells

The roles of E3 ubiquitin ligases in cancer progression and targeted therapy

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Activation of TNF‐α/NF‐κB axis enhances CRL4B^DCAF¹¹ E3 ligase activity and regulates cell cycle progression in human osteosarcoma cells