CUL4A ubiquitin ligase: a promising drug target for cancer and other human diseases

Sharma, Puneet; Nag, Alo

doi:10.1098/rsob.130217

Cited by 70 publications

(94 citation statements)

References 153 publications

(229 reference statements)

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“…1 Downregulation of Aiolos contributes to the cytotoxic effects of an effective anti-malignant plasma cell (multiple myeloma, MM) agent, lenalidomide. 12,13 Lenalidomide targets Cereblon (CRBN), a component of the CULLIN 4 (CUL4)-containing E3 ligase complex (CRL4) that mediates the turnover of proteins, 14 thereby resulting in the proteolysis of Ikaros family proteins and apoptosis of MM cells. 12,13 The target genes of Aiolos responsible for maintaining MM cell survival have yet to be characterized.…”

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confidence: 99%

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

Hung

Chen

et al. 2016

Cell Death Differ

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The transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1) has crucial roles in the control of plasma cell differentiation and in maintaining survival of plasma cells. However, how Blimp-1 ensures the survival of plasma cell malignancy, multiple myeloma (MM), has remained elusive. Here we identified Aiolos, an anti-apoptotic transcription factor of MM cells, as a Blimp-1-interacting protein by mass spectrometry. ChIP coupled with DNA microarray was used to profile the global binding of Aiolos and Blimp-1 to endogenous targets in MM cells, which revealed their co-binding to a large number of genes, including apoptosis-related genes. Accordingly, Blimp-1 and Aiolos regulate similar transcriptomes in MM cells. Analysis of the binding motifs for Blimp-1 and Aiolos uncovered a partial motif that was similar across sites for both proteins. Aiolos promotes the binding of Blimp-1 to target genes and thereby enhances Blimp-1-dependent transcriptional repression. Furthermore, treatment with an anti-MM agent, lenalidomide, caused ubiquitination and proteasomal degradation of Blimp-1, leading to the de-repression of a new Blimp-1 direct target, CULLIN 4A (CUL4A), and reduced Aiolos levels. Accordingly, lenalidomide-induced cell death was partially rescued by reintroduction of Blimp-1 or knockdown of CUL4A. Thus, we demonstrated the functional impacts and underlying mechanisms of the interaction between Aiolos and Blimp-1 in maintaining MM cell survival. We also showed that interruption of Blimp-1/Aiolos regulatory pathways contributes to lenalidomide-mediated anti-MM activity.

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confidence: 99%

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

Hung

Chen

et al. 2016

Cell Death Differ

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“…Cul4-based E3 ligases (CRL4) are implicated in the regulation of chromatin biology including DNA damage response, histone modification, and nucleosome assembly [22][23][24] . Depletion of Cul4A results in chromatin dysfunctions in yeast and mammalian cells, and notably over expression of Cul4A has been reported in many cancer types 25 . There are several studies reporting the critical roles of CRL4s in the cell cycle, especially in S phase related degradations.…”

Section: Introductionmentioning

confidence: 99%

“…There are several studies reporting the critical roles of CRL4s in the cell cycle, especially in S phase related degradations. CRL4s have been shown to target several key players including Cdt1, p21, p27, E2f1, Set8 and Chk1 for degradation, in order to maintain proper S phase and S-G2 progression 23,[25][26][27] .…”

Section: Introductionmentioning

confidence: 99%

DDB1 and CUL4 associated factor 11 (DCAF11) mediates degradation of Stem-loop binding protein at the end of S phase

2016

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In eukaryotes, bulk histone expression occurs in the S phase of the cell cycle. This highly conserved system is crucial for genomic stability and proper gene expression. In metazoans, Stem-loop binding protein (SLBP), which binds to 3' ends of canonical histone mRNAs, is a key factor in histone biosynthesis. SLBP is mainly expressed in S phase and this is a major mechanism to limit bulk histone production to the S phase. At the end of S phase, SLBP is rapidly degraded by proteasome, depending on two phosphorylations on Thr 60 and Thr 61. Previously, we showed that SLBP fragment (aa 51-108) fused to GST, is sufficient to mimic the late S phase (S/G2) degradation of SLBP. Here, using this fusion protein as bait, we performed pull-down experiments and found that DCAF11, which is a substrate receptor of CRL4 complexes, binds to the phosphorylated SLBP fragment. We further confirmed the interaction of full-length SLBP with DCAF11 and Cul4A by co-immunoprecipitation experiments. We also showed that DCAF11 cannot bind to the Thr61/Ala mutant SLBP, which is not degraded at the end of S phase. Using ectopic expression and siRNA experiments, we demonstrated that SLBP expression is inversely correlated with DCAF11 levels, consistent with the model that DCAF11 mediates SLBP degradation. Finally, we found that ectopic expression of the S/G2 stable mutant SLBP (Thr61/Ala) is significantly more toxic to the cells, in comparison to wild type SLBP. Overall, we concluded that CRL4-DCAF11 mediates the degradation of SLBP at the end of S phase and this degradation is essential for the viability of cells.

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“…[10][11][12] In addition, CUL4A induces tumorigenesis of skin cancer by inhibition of DNA repair and accelerating S phase entry, 13 and results in inactivation of RASSF1A and promoting cell cycle progression, 14 suggesting that CUL4A may play a critical role in regulation of some biological processes. 15 Up to now, few studies report the link between CUL4A expression and OS. To confirm the function and molecular mechanisms of CUL4A in OS cells, using a tissue microarray procedure, we examined the expression of CUL4A in OS tissues by IHC assay, and constructed Lv-shCUL4A vector for investigating its effects on biological behaviors of OS cells.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of CUL4A inhibits invasion and induces apoptosis in osteosarcoma cells

Song

Zhang

Shao

2015

Int J Immunopathol Pharmacol

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Cullin4A (CUL4A) is implicated in many cellular events including cell survival and growth. However, the specific function and underlying mechanisms of CUL4A in cancer invasion have not yet been elucidated. In this work, we were focused on investigating the role of CUL4A in human osteosarcoma (OS). The expression level of CUL4A was evaluated by immunohistochemical (IHC) assay in human OS tissues. Lentivirus-mediated CUL4A shRNA (Lv-shCUL4A) constructed by us was transfected into OS cells for assessing its effects on cell proliferation and invasive potential, respectively detected by MTT and Transwell assays. It was demonstrated that the expression of CUL4A protein was markedly increased in OS tissues compared with the adjacent non-cancerous tissues (ANCT) (57.8% vs. 25.6%, P = 0.019), and was associated with the distant metastases in OS patients (P = 0.016). In vitro, silencing of CUL4A gene inhibited OS cell proliferation and invasion, and induced cell apoptosis, followed by increased expression of p27 and p53 and decreased expression of MMP-2. Therefore, these findings indicate that elevated expression of CUL4A is positively correlated with distant metastases in OS patients, and knockdown of CUL4A suppresses invasion and induces apoptosis in OS cells, suggesting that CUL4A may serve as a potential target for the treatment of OS.

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CUL4A ubiquitin ligase: a promising drug target for cancer and other human diseases

Cited by 70 publications

References 153 publications

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

DDB1 and CUL4 associated factor 11 (DCAF11) mediates degradation of Stem-loop binding protein at the end of S phase

Knockdown of CUL4A inhibits invasion and induces apoptosis in osteosarcoma cells

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