| 2009 |
CUL4B contains a nuclear localization signal (NLS) in its N-terminus (amino acids 37-40, KKRK) that binds importin α1, α3, and α5. Unlike CUL4A and other cullins which carry NLS in their C-termini, this N-terminal NLS is unique to CUL4B. NLS-deleted CUL4B localizes to the cytoplasm and fails to promote cell proliferation. CUL4B promotes ubiquitination and degradation of cyclin E, and RNAi silencing leads to overaccumulation of cyclin E, prolonged S phase, and inhibited cell proliferation. |
RNAi silencing, NLS deletion mutants, importin binding assays, subcellular fractionation, cell cycle analysis |
The Journal of biological chemistry |
High |
19801544
|
| 2007 |
CUL4B is a scaffold protein that organizes a cullin-RING (E3) ubiquitin ligase complex. A nonsense mutation (p.R388X) truncates the C-terminal catalytic domain and causes nonsense-mediated mRNA decay, demonstrating that the C-terminal domain is essential for ligase function. |
Mutation analysis, mRNA expression in patient leukocytes, X-chromosome inactivation analysis |
American journal of human genetics |
Medium |
17273978
|
| 2013 |
CUL4B promotes DNA replication licensing by positively regulating CDC6 (a replication licensing factor) through a CDK2-dependent mechanism: CUL4B represses miR-372 and miR-373, which target CDK2, thereby elevating CDK2 levels; CDK2 then phosphorylates CDC6, protecting it from APC(CDH1)-mediated degradation, which in turn promotes loading of MCM2 onto chromatin. |
RNAi knockdown, chromatin fractionation for MCM2 loading, miRNA overexpression/inhibition, immunoblotting |
The Journal of cell biology |
High |
23479742
|
| 2013 |
CUL4B ubiquitin ligase targets Jab1/CSN5 (a component of the COP9 signalosome) for polyubiquitination and proteasomal degradation. The DDB1-CUL4B-ROC1 complex is required for this degradation, which is independent of CUL4A. Loss of CUL4B leads to Jab1 accumulation and abnormal upregulation of BMP signaling. |
RNAi, in vitro and in vivo ubiquitination assays, Co-IP, Cul4b-deficient mouse embryonic fibroblasts |
Biochimica et biophysica acta |
High |
23357576
|
| 2013 |
CUL4B promotes ubiquitination and degradation of TSC2 and cyclin E in neocortical neurons. XLID mutants (R388X, R572C, V745A) fail to promote ubiquitination/degradation of TSC2 or cyclin E. By targeting TSC2 for degradation, wild-type CUL4B positively regulates mTOR signaling (increased p-mTOR, p-p70S6K, p-4E-BP1); CUL4B knockdown or XLID mutants fail to activate mTOR. |
Adenovirus-mediated expression in neocortical neurons, shRNA knockdown, immunoblotting for ubiquitination and mTOR pathway substrates |
Biochimica et biophysica acta |
High |
23348097
|
| 2015 |
CUL4B activates Wnt/β-catenin signaling in HCC by epigenetically silencing Wnt pathway antagonists (DKK1, PPP2R2B). CRL4B promotes recruitment/retention of PRC2 at promoters of Wnt antagonists, and CUL4B knockdown decreases PRC2 components and H3K27me3 at these promoters. CUL4B also protects β-catenin from GSK3-mediated degradation through this mechanism. |
RNAi knockdown, ChIP for PRC2/H3K27me3, rescue experiments with simultaneous knockdown of PPP2R2B, xenograft models |
The Journal of pathology |
High |
25430888
|
| 2015 |
CRL4B is required for proteasomal degradation of HUWE1 in response to DNA damage. CUL4B is activated in a NEDD8-dependent manner and ubiquitinates HUWE1 in vitro and in vivo. CUL4B depletion stabilizes HUWE1, which accelerates MCL-1 degradation and increases apoptosis; these phenotypes are rescued by simultaneous HUWE1 depletion. |
In vitro ubiquitination assay, RNAi, epistasis (double knockdown rescue), immunoblotting |
Nucleic acids research |
High |
25883150
|
| 2012 |
CUL4B is essential for embryonic development; Cul4b null mouse embryos die before E9.5 with severe developmental arrest. Cyclin E (a CRL4B substrate) accumulates in Cul4b null embryos. Epiblast-specific deletion of Cul4b prevents lethality, demonstrating that CUL4B's essential function is in extra-embryonic tissues rather than the embryo proper. |
Cul4b knockout mouse generation, conditional epiblast-specific deletion (Sox2-Cre), immunoblotting for cyclin E |
Cell research |
High |
22453236 22606329
|
| 2016 |
CUL4B negatively regulates PPARγ by promoting its polyubiquitination and proteasomal degradation. Depletion of CUL4B leads to upregulation of PPARγ-regulated genes and facilitates adipogenesis. Adipocyte-specific Cul4b KO mice show increased adipogenesis and fat accumulation but improved insulin sensitivity and glucose tolerance. |
Adipocyte-specific conditional KO mouse, PPARγ ubiquitination assay, high-fat diet metabolic phenotyping |
Diabetes |
High |
27899484
|
| 2016 |
CUL4B performs both cell-autonomous and non-cell-autonomous functions in spermatogenesis. In germ cells, CUL4B directly polyubiquitinates and degrades INSL6 (identified by mass spectrometry); loss of germ cell CUL4B impairs sperm motility due to reduced mitochondrial activity and glycolysis, and defective flagellar axoneme/outer dense fiber arrangement. In somatic cells, CUL4B maintains the spermatogonial stem cell niche. |
Germ cell-specific conditional KO, global KO, mass spectrometry substrate identification, polyubiquitination assay, sperm ATP measurement, electron microscopy of flagella |
The Journal of biological chemistry |
High |
26846852
|
| 2015 |
CUL4B represses GFAP expression in neural progenitor cells by epigenetically silencing PTGDS. Loss of Cul4b increases PTGDS expression, elevating prostaglandin D2, which promotes astrocyte (GFAP+) generation. CUL4B/PRC2 complex targets and represses Ptgds; pharmacological inhibition of PTGDS or shRNA knockdown attenuates the increased GFAP+ cells from Cul4b-null NPCs. |
Nervous system-specific Cul4b KO mice, in vitro NPC culture, ChIP for CUL4B/PRC2 at Ptgds, pharmacological PTGDS inhibition, shRNA knockdown |
Human molecular genetics |
High |
26025376
|
| 2015 |
CUL4B unexpectedly functions as a negative regulator of myeloid-derived suppressor cells (MDSCs). Hematopoietic-specific CUL4B ablation (Tek-Cre) increases MDSC accumulation via downregulation of the AKT/β-catenin pathway. CUL4B represses phosphatases PP2A and PHLPP1/2 (which dephosphorylate/inactivate AKT) to sustain AKT pathway activation. |
Hematopoietic-specific conditional KO (Tek-Cre), MDSC quantification, AKT pathway analysis, multiple tumor models |
Cancer research |
High |
26450912
|
| 2019 |
CUL4B negatively regulates TLR-triggered inflammatory responses in macrophages by epigenetically repressing transcription of Pten, thereby maintaining the anti-inflammatory PI3K-AKT-GSK3β pathway. Deletion of CUL4B in macrophages upregulates PTEN, leading to increased GSK3β activity and excessive proinflammatory cytokine production. |
Myeloid cell-specific Cul4b KO mice, LPS/pathogen challenge, GSK3β inhibitor rescue, ChIP/epigenetic analysis of Pten promoter |
Cellular & molecular immunology |
High |
31729464
|
| 2017 |
CUL4B epigenetically represses miR-194 by catalyzing monoubiquitination of H2AK119 and coordinating with PRC2 to promote H3K27me3 at the miR-194 gene cluster. miR-194 in turn targets the 3'-UTR of CUL4B, creating a double-negative feedback loop. CUL4B also represses miR-194 downstream of p53. |
ChIP for H2AK119ub and H3K27me3 at miR-194 locus, 3'-UTR luciferase reporter assay, RNAi, xenograft tumor formation |
Molecular oncology |
High |
28164432
|
| 2021 |
CUL4B renders breast cancer cells tamoxifen-resistant through a miR-32-5p/ER-α36 axis. CRL4B epigenetically represses miR-32-5p transcription by catalyzing H2AK119 monoubiquitination and coordinating with PRC2 and HDAC complexes to promote H3K27me3 at the miR-32-5p promoter, leading to upregulation of ER-α36. |
ChIP for H2AK119ub and H3K27me3 at miR-32-5p promoter, dominant-negative CUL4B mutant, pharmacological inhibition of CRL4B/PRC2/HDAC, in vitro and in vivo tamoxifen sensitivity assays |
The Journal of pathology |
High |
33638154
|
| 2014 |
CUL4B suppresses stress-induced cellular senescence by promoting p53 ubiquitination and proteasomal degradation in normal human fibroblasts exposed to oxidative stress (H2O2), thereby dampening a p53-ROS positive feedback loop that drives senescence. CUL4B is downregulated in stress-induced (but not replicative) senescent cells. |
Ectopic CUL4B expression, RNAi, H2O2 treatment, p53 ubiquitination assay, ROS measurement, senescence β-galactosidase assay |
Free radical biology & medicine |
High |
25464270
|
| 2021 |
CUL4B promotes HBV replication by interacting with the viral protein HBx and inhibiting HBx ubiquitination and proteasomal degradation, thereby stabilizing HBx. This interaction was demonstrated by immunoprecipitation and immunofluorescence co-localization. |
Co-immunoprecipitation, immunofluorescence co-staining, cycloheximide chase assay, in vivo ubiquitination assay, Cul4b transgenic and conditional KO mice with hydrodynamic HBV model |
Cancer biology & medicine |
High |
33969670
|
| 2021 |
TCDD-activated AHR is partially degraded via CUL4B-mediated ubiquitination; loss of CUL4B partially prevents AHR degradation after TCDD exposure. TiPARP additionally promotes AHR nuclear export preceding degradation; knockdown of TiPARP in CUL4B-null cells completely abolishes AHR degradation, indicating CUL4B and TiPARP cooperate to restrain AHR activity. |
Cul4b-null MEF cell line, TiPARP knockdown in null cells, TCDD treatment, AHR protein level and transcriptional activity measurement |
The Journal of biological chemistry |
High |
34146543
|
| 2023 |
The unique N-terminal extension of CUL4B is heavily phosphorylated during mitosis. Phosphorylation triggers chromatin exclusion of CUL4B while promoting binding to actin regulators and to two previously unrecognized CUL4B-specific DCAFs, LIS1 and WDR1, which interact with DDB1 in a phosphorylation-dependent manner. CUL4B phosphorylation is required for efficient mitosis progression (spindle positioning, cortical tension). The XLID mutation CUL4B-P50L perturbs this phosphorylation pattern. CUL4B is required for developing stable ventricular structures in human forebrain organoids. |
Phosphoproteomic analysis, Co-immunoprecipitation of LIS1/WDR1 with DDB1, mutagenesis of phosphorylation sites, live imaging for spindle positioning/cortical tension, human forebrain organoid model |
The EMBO journal |
High |
37365982
|
| 2023 |
CUL4B and DCAF7 form an E3 ligase complex that promotes MEN1 protein degradation by binding MEN1 and catalyzing its ubiquitination. Neddylation pathway activation is required upstream; neddylation inhibitor MLN4924 induces MEN1 accumulation. DCAF7 downregulation reverses everolimus resistance in PanNET cells in a MEN1-dependent manner. |
Co-IP, RNAi knockdown, neddylation inhibitor (MLN4924), in vitro ubiquitination, DCAF7/MEN1 double knockdown epistasis |
Cancer research |
High |
36939378
|
| 2023 |
CUL4B directly binds to the promoter of Cxcl2 and epigenetically represses its transcription. In KRAS-mutant lung tumors, CUL4B deletion increases CXCL2 expression, which promotes CXCR2-dependent MDSC recruitment to the tumor microenvironment. |
ChIP for CUL4B at Cxcl2 promoter, CUL4B KO/KD in autochthonous and transplantable KRAS-mutant tumor models, MDSC quantification, MDSC targeting experiments |
Oncogene |
High |
37653114
|
| 2024 |
CUL4B mutations (XLID patient-derived) cause premature cell cycle exit and precocious neuronal differentiation of neural progenitor cells, as well as increased synapse formation and enhanced neuronal excitability. Mechanistically, CRL4B complex represses transcription of PPP2R2B and PPP2R2C (PP2A regulatory subunit isoforms) by catalyzing H2AK119 monoubiquitination at their promoters. CUL4B mutations upregulate PP2A activity, inhibiting AKT and ERK, causing premature cell cycle exit; rescue achieved by AKT/ERK activation or PP2A inhibition. |
Patient iPSC-derived 2D neuronal cultures and cerebral organoids, ChIP for H2AK119ub, PP2A activity assay, AKT/ERK inhibition/activation, pharmacological PP2A inhibition rescue |
Cell death & disease |
High |
38331954
|
| 2021 |
CUL4B is required for CD4+ T cell proliferation and survival following TCR stimulation. In T cells, CUL4B preferentially associates with the substrate receptor DCAF1; Cul4b and DCAF1 interact with proteins involved in DNA damage sensing/repair. Cul4b-deficient CD4+ T cells accumulate DNA damage and fail to phosphorylate SMC1A (a downstream DNA damage response event), leading to proliferative failure. |
Cul4b conditional KO T cells, Co-immunoprecipitation (CUL4B-DCAF1 interaction), mass spectrometry of associated proteins, DNA damage assays, SMC1A phosphorylation analysis |
PLoS biology |
High |
33524014
|
| 2023 |
c-Myc increases Cul4b protein levels following T cell activation. Cul4b-deficient CD8+ T cells accumulate DNA damage and p21/Cyclin E2, leading to replication stress and proliferative catastrophe. c-Myc supports CD8+ T cell expansion by maintaining genome stability via Cul4b. |
Cul4b conditional KO CD8+ T cells, in vivo LCMV infection model, p21/Cyclin E2 immunoblotting, DNA damage assays |
Nature communications |
High |
37925424
|
| 2015 |
CUL4B variants interact with WDR62, a protein mutated in microcephaly patients with malformations of cortical development, suggesting a functional complex. |
Co-immunoprecipitation of CUL4B with WDR62 |
Human mutation |
Low |
25385192
|
| 2019 |
CUL4B epigenetically represses IL-6 transcription in myeloid cells via the CRL4B complex. In CUL4B-deficient MDSCs, elevated IL-6 activates IL-6/STAT3 signaling in tumor cells, rendering them stem cell-like properties. |
Hematopoietic/myeloid-specific Cul4b KO mice, IL-6 blocking, STAT3 inhibitor, ChIP/epigenetic analysis at IL-6 promoter |
Oncogene |
High |
31235785
|
| 2012 |
CUL4B is required for neural progenitor cell mitosis progression. Downregulation of CUL4B arrests NPCs and NT-2 cells in G2/M phase. Three isoforms of CUL4B exist in brain tissue; the larger isoforms (CUL4B-1, -2) are predominantly unneddylated due to their N-terminal extension, while the smaller isoform (CUL4B-3, lacking the N-terminus) is neddylated. Unneddylated CUL4B accumulates during mitosis and inhibits β-catenin degradation in neural stem cell niches. |
Immunostaining, RNAi knockdown in NPCs/NT-2 cells, cell cycle analysis, neddylation state analysis, brain tissue immunostaining |
BMC neuroscience |
Medium |
22992378
|
| 2023 |
CUL4B-DDB1-COP1 forms a functional E3 ubiquitin ligase complex responsible for targeting the histone demethylase UTX (KDM6A) for ubiquitination and proteasomal degradation in colorectal cancer cells. Cop1 deficiency in mouse intestinal tissue results in UTX accumulation and restricts tumorigenesis. |
Co-immunoprecipitation demonstrating CUL4B-DDB1-COP1 complex, immunoblot for UTX degradation, conditional Cop1 KO mouse, spontaneous AOM/DSS CRC model with GSK126 rescue |
Experimental hematology & oncology |
High |
37679762
|
| 2023 |
CUL4B promotes osteogenesis and inhibits adipogenesis of mesenchymal stem cells by epigenetically repressing KLF4 (an adipogenic factor) and C/EBPδ transcription. The CUL4B complex directly binds to Klf4 and Cebpd promoters and represses their transcription. MSC-specific Cul4b KO mice show impaired skeletal development, low bone mass, and increased marrow adipose accumulation. |
MSC-specific conditional Cul4b KO mice, ChIP for CUL4B complex at Klf4/Cebpd promoters, in vitro osteogenic/adipogenic differentiation assays, ovariectomy model |
Bone research |
High |
37268647
|
| 2019 |
CUL4B-RING E3 ligase complex represses transcription of miR-372/373 via H2AK119 monoubiquitination at the miR-372/373 gene cluster, leading to upregulation of PIK3CA and activation of AKT signaling, promoting bladder cancer metastasis and stemness. |
ChIP for H2AK119ub at miR-372/373 locus, 3'-UTR reporter assay for PIK3CA targeting, RNAi, invasion/motility assays |
Oncogene |
High |
32127645
|
| 2024 |
Prior to radiation exposure, CUL4B inhibits ubiquitination of PSME3, leading to PSME3 accumulation that negatively regulates p53-mediated apoptosis. After radiation, CUL4B dissociates from PSME3 and translocates to γH2AX foci in the nucleus, where it impedes DNA damage repair by inhibiting BRCA1 phosphorylation and RAD51, augmenting p53-mediated apoptosis. |
In vivo and in vitro intestinal models, co-IP for CUL4B-PSME3 interaction, BRCA1 phosphorylation and RAD51 immunoblotting, γH2AX co-localization by immunofluorescence |
Scientific reports |
Medium |
38689033
|
| 2024 |
CUL4B protects kidneys from acute injury by promoting polyubiquitination and proteasomal degradation of p53, thereby suppressing p53-dependent PAI-1 expression. CUL4B-deficient kidneys show exacerbated apoptosis and inflammation upon cisplatin or ischemia-reperfusion injury; inhibition of PAI-1 or p53 prevents this aggravation. |
Kidney-specific Cul4b KO mice, cisplatin and IR injury models, p53 ubiquitination assay, PAI-1 and p53 inhibition rescue experiments, transcriptome analysis |
Cell death & disease |
High |
39695153
|
| 2019 |
CUL4B in macrophages represses miR-194-5p expression; loss of CUL4B in macrophages suppresses their migration, adhesion, and renal infiltration by elevating miR-194-5p, which targets and reduces integrin α9 (ITGA9). High glucose upregulates CUL4B in macrophages in diabetic conditions. |
Myeloid-specific Cul4b KO mice with diabetic kidney disease models, miR-194-5p/ITGA9 pathway analysis, macrophage migration/adhesion assays |
Cell reports |
High |
37224018
|
| 2019 |
Small molecule TSC01682 specifically disrupts the CUL4B-DDB1 protein-protein interaction, preventing CRL4B complex assembly. TSC01682 treatment decreases CRL4B components DCAF11 and DCAF13, and increases the CRL4B substrates p21 and PTEN by inhibiting their ubiquitination, consistent with CUL4B-DDB1 interaction being required for substrate ubiquitination. |
In vitro high-throughput screening (yeast), Co-IP in osteosarcoma cells, p21/PTEN ubiquitination assay, xenograft tumor model |
American journal of cancer research |
High |
31598391
|
| 2020 |
CUL4B contributes to colorectal cancer stemness by coordinating with PRC2 to epigenetically repress miR34a expression, leading to upregulation of MYCN and NOTCH1 (miR34a targets). Inhibition of CUL4B in patient-derived tumor organoids reduces sphere formation and metastatic capacity. |
RNAi in cell lines and patient-derived organoids, ChIP for CUL4B/PRC2 at miR34a locus, sphere formation assays |
Oncogenesis |
High |
32054830
|
| 2021 |
CUL4B promotes temozolomide resistance in glioblastoma by coordinating with HDAC to co-occupy the CDKN1A (p21) promoter and epigenetically silence CDKN1A transcription, thereby attenuating TMZ-induced cellular senescence. |
ChIP demonstrating CUL4B and HDAC co-occupancy at CDKN1A promoter, senescence β-galactosidase assay, CUL4B KD/OE in GBM cells |
Frontiers in oncology |
High |
33869025
|
| 2025 |
CUL4B drives thyroid cancer dedifferentiation by promoting ubiquitination of ARID1A (a SWI/SNF complex subunit), leading to its degradation and decreased expression of the differentiation marker PAX8. |
In vivo TC models, RNA-seq, Co-IP and ubiquitination assay for CUL4B-ARID1A, immunohistochemistry, in vitro functional experiments |
Translational oncology |
High |
40203790
|
| 2021 |
THAP7-AS1 lncRNA interacts with the N-terminal 1-50 amino acid region (NLS) of CUL4B and promotes the interaction between the NLS and importin α1, thereby facilitating CUL4B nuclear import. Nuclear CUL4B then represses miR-22-3p and miR-320a by catalyzing H2AK119ub1 and coordinating EZH2-mediated H3K27me3. |
Co-IP/RIP for THAP7-AS1-CUL4B interaction, NLS domain mapping, importin α1 interaction assay, ChIP for H2AK119ub1 and H3K27me3 |
Cell death and differentiation |
Medium |
34608273
|
| 2016 |
CUL4B promotes invasion and metastasis of gastric cancer by epigenetically repressing miR-125a expression, leading to HER2 upregulation and subsequent activation of PI3K/AKT signaling. HER2 inhibitors reverse CUL4B-induced EMT. |
ChIP for epigenetic marks at miR-125a locus, HER2 inhibitor treatment, gain- and loss-of-function experiments, xenograft metastasis model |
Oncogene |
Medium |
29106389
|
| 2023 |
CUL4B directly interacts with the promoter of Csf3 (encoding G-CSF) by coordinating with PRC2, epigenetically repressing G-CSF expression. CUL4B deletion in intestinal epithelium epigenetically activates G-CSF, promoting MDSC recruitment and ApcMin/+ adenoma formation. |
ChIP for CUL4B/PRC2 at Csf3 promoter, ApcMin/+;Cul4bΔIEC mouse model, MDSC depletion rescue, organoid co-culture with MDSCs |
Neoplasia |
High |
38761506
|