COPS2 Antagonizes OCT4 to Accelerate the G2/M Transition of Mouse Embryonic Stem Cells

Ding, Nan; Zhang, Weiyu; Chen, Lingyi

doi:10.1016/j.stemcr.2018.06.013

Cited by 12 publications

(9 citation statements)

References 38 publications

(50 reference statements)

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“…Thus, it is uncertain whether the level of cyclin B is upregulated/downregulated in G2/M phase-arrested cells. However, several studies showed that the downregulation of CDK1/cyclin B complex/activity is associated with cell cycle arrest at G2/M phase (24)(25)(26). Consistent with these studies, bufotalin decreased the level of CDK1, which could downregulate the level of CDK1/cyclin B complex, leading to cell cycle arrest at G2/M phase in bufotalin-treated A375 cells in the present study.…”

Section: Discussionsupporting

confidence: 90%

Bufotalin induces cell cycle arrest and cell apoptosis in human malignant melanoma A375 cells

Pan

Chen

et al. 2019

Oncol Rep

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Venenum bufonis has been used as an antitumor drug in China for many years. Bufotalin, as an active component of Venenum bufonis, has been proven to exhibit antitumor effects in cancer types. In the present study, the effect of bufotalin on the human melanoma skin cancer cell line A375 was analyzed using MTT and colony formation assays. Bufotalin significantly inhibited the proliferation and colony formation of A375 cells. Further studies demonstrated that bufotalin significantly upregulated the protein levels of ATM serine/threonine kinase and Chk2, downregulated CDC25C protein expression, and subsequently inhibited CDK1 expression, leading to cell cycle arrest at the G2/M phase of the A375 cells. Furthermore, bufotalin significantly increased BAX expression levels, decreased BCL-2 expression, and then upregulated apoptosis-related proteins, caspase-3/-9, followed by A375 cell apoptosis. Taken together, these results show that bufotalin induces cell cycle arrest at the G2/M phase and cell apoptosis, resulting in the inhibition of A375 cell proliferation, thereby suggesting that bufotalin may be utilized in melanoma treatment.

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Section: Discussionsupporting

confidence: 90%

Bufotalin induces cell cycle arrest and cell apoptosis in human malignant melanoma A375 cells

Pan

Chen

et al. 2019

Oncol Rep

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“…A whole-genome RNA interference screening revealed that COPS1, COPS2, and COPS4 are required for maintaining the expression of the OCT4-GFP reporter in human ESCs, implicating a role of the CSN in pluripotency maintenance (23). However, by knocking down individual CSN subunits, we found that only Cops2, but not any other CSN subunits, is essential for the self-renewal and G2/M transition of mouse ESCs (24,25). Moreover, Cops5 and Cops8 null embryos die after embryonic day 7.5, while no Cops2 null mice survive to embryonic day 7.5 (26)(27)(28).…”

Section: Significancementioning

confidence: 72%

“…Cops5 Regulates Cellular Metabolism through Mtch2. To understand the molecular mechanism of Cops5 in regulating cellular metabolism, we looked into the list of Cops5-interacting proteins identified by coimmunoprecipitation (co-IP) and mass spectrometric analysis (25). We focused on the 49 proteins interacting with Cops5, but not with Cops2 (Dataset S1), because the regulation of cellular metabolism by Cops5 is independent of the CSN.…”

Section: Resultsmentioning

confidence: 99%

Cops5 safeguards genomic stability of embryonic stem cells through regulating cellular metabolism and DNA repair

Gao

Cui

Zhang

et al. 2020

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

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The highly conserved COP9 signalosome (CSN), composed of 8 subunits (Cops1 to Cops8), has been implicated in pluripotency maintenance of human embryonic stem cells (ESCs). Yet, the mechanism for the CSN to regulate pluripotency remains elusive. We previously showed that Cops2, independent of the CSN, is essential for the pluripotency maintenance of mouse ESCs. In this study, we set out to investigate how Cops5 and Cops8 regulate ESC differentiation and tried to establish Cops5 and Cops8 knockout (KO) ESC lines by CRISPR/Cas9. To our surprise, no Cops5 KO ESC clones were identified out of 127 clones, while three Cops8 KO ESC lines were established out of 70 clones. We then constructed an inducible Cops5 KO ESC line. Cops5 KO leads to decreased expression of the pluripotency marker Nanog, proliferation defect, G2/M cell-cycle arrest, and apoptosis of ESCs. Further analysis revealed dual roles of Cops5 in maintaining genomic stability of ESCs. On one hand, Cops5 suppresses the autophagic degradation of Mtch2 to direct cellular metabolism toward glycolysis and minimize reactive oxygen species (ROS) production, thereby reducing endogenous DNA damage. On the other hand, Cops5 is required for high DNA damage repair (DDR) activities in ESCs. Without Cops5, elevated ROS and reduced DDR activities lead to DNA damage accumulation in ESCs. Subsequently, p53 is activated to trigger G2/M arrest and apoptosis. Altogether, our studies reveal an essential role of Cops5 in maintaining genome integrity and self-renewal of ESCs by regulating cellular metabolism and DDR pathways.

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“…Nevertheless, we cannot rule out binding of miR-26b-5p to other parts of the transcripts lacking the canonical seed sequences. COPS2 and NOL12 were shown to accelerate cell cycle and promote cell proliferation in several types of tumors [44][45][46]. MRPL15 is a member of human mitochondrial ribosomal proteins (MRPs), which provide energy in the form of ATP for cell growth [47].…”

Section: Discussionmentioning

confidence: 99%

The miR-26b-5p/KPNA2 Axis Is an Important Regulator of Burkitt Lymphoma Cell Growth

Niu

Kazimierska

Nolte

et al. 2020

Cancers

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The expression of several microRNAs (miRNAs) is known to be changed in Burkitt lymphoma (BL), compared to its normal counterparts. Although for some miRNAs, a role in BL was demonstrated, for most of them, their function is unclear. In this study, we aimed to identify miRNAs that control BL cell growth. Two BL cell lines were infected with lentiviral pools containing either 58 miRNA inhibitors or 44 miRNA overexpression constructs. Eighteen constructs showed significant changes in abundance over time, indicating that they affected BL growth. The screening results were validated by individual green fluorescent protein (GFP) growth competition assays for fifteen of the eighteen constructs. For functional follow-up studies, we focused on miR-26b-5p, whose overexpression inhibited BL cell growth. Argonaute 2 RNA immunoprecipitation (Ago2-IP) in two BL cell lines revealed 47 potential target genes of miR-26b-5p. Overlapping the list of putative targets with genes showing a growth repression phenotype in a genome-wide CRISPR/Cas9 knockout screen, revealed eight genes. The top-5 candidates included EZH2, COPS2, KPNA2, MRPL15, and NOL12. EZH2 is a known target of miR-26b-5p, with oncogenic properties in BL. The relevance of the latter four targets was confirmed using sgRNAs targeting these genes in individual GFP growth competition assays. Luciferase reporter assay confirmed binding of miR-26b-5p to the predicted target site for KPNA2, but not to the other genes. In summary, we identified 18 miRNAs that affected BL cell growth in a loss- or gain-of-function screening. A tumor suppressor role was confirmed for miR-26b-5p, and this effect could at least in part be attributed to KPNA2, a known regulator of OCT4, c-jun, and MYC.

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COPS2 Antagonizes OCT4 to Accelerate the G2/M Transition of Mouse Embryonic Stem Cells

Cited by 12 publications

References 38 publications

Bufotalin induces cell cycle arrest and cell apoptosis in human malignant melanoma A375 cells

Bufotalin induces cell cycle arrest and cell apoptosis in human malignant melanoma A375 cells

Cops5 safeguards genomic stability of embryonic stem cells through regulating cellular metabolism and DNA repair

The miR-26b-5p/KPNA2 Axis Is an Important Regulator of Burkitt Lymphoma Cell Growth

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