To control or to be controlled? Dual roles of CDK2 in DNA damage and DNA damage response

Liu, Qi; Gao, Jinlan; Zhao, Chenyang; Guo, Yingying; Wang, Yunlong; Shen, Fei; Xing, Xuesha; Luo, Yang

doi:10.1016/j.dnarep.2019.102702

Cited by 32 publications

(18 citation statements)

References 130 publications

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“…However, other genes associated with the cell cycle, such as cdk2 , were strongly UR. Cdk2 activation leads to DNA replication in the cell, and it is also involved in DNA damage and the DNA repair response [ 47 ]. Some ciliates probably suffered DNA damage because of attack from the turbot immune system, thus explaining the increase in cdk2 expression.…”

Section: Discussionmentioning

confidence: 99%

Interactions between the Parasite Philasterides dicentrarchi and the Immune System of the Turbot Scophthalmus maximus. A Transcriptomic Analysis

Valle

Leiro

Pereiro

et al. 2020

Biology

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The present study analyses the interactions between Philasterides dicentrarchi (a ciliate parasite that causes high mortalities in cultured flatfish) and the peritoneal cells of the turbot Scophthalmus maximus during an experimental infection. The transcriptomic response was evaluated in the parasites and in the fish peritoneal cells, at 1, 2 and 4 h post-infection (hpi) in turbot injected intraperitoneally (ip) with 107 ciliates and at 12 and 48 hpi in turbot injected ip with 105 ciliates. Numerous genes were differentially expressed (DE) in P. dicentrarchi, relative to their expression in control ciliates (0 hpi): 407 (369 were up-regulated) at 1 hpi, 769 (415 were up-regulated) at 2 hpi and 507 (119 were up-regulated) at 4 hpi. Gene ontology (GO) analysis of the DE genes showed that the most representative categories of biological processes affected at 1, 2 and 4 hpi were biosynthetic processes, catabolic processes, biogenesis, proteolysis and transmembrane transport. Twelve genes of the ABC transporter family and eight genes of the leishmanolysin family were DE at 1, 2 and 4 hpi. Most of these genes were strongly up-regulated (UR), suggesting that they are involved in P. dicentrarchi infection. A third group of UR genes included several genes related to ribosome biogenesis, DNA transcription and RNA translation. However, expression of tubulins and tubulin associated proteins, such as kinesins or dyneins, which play key roles in ciliate division and movement, was down-regulated (DR). Similarly, genes that coded for lysosomal proteins or that participate in the cell cycle mitotic control, glycolysis, the Krebs cycle and/or in the electron transport chain were also DR. The transcriptomic analysis also revealed that in contrast to many parasites, which passively evade the host immune system, P. dicentrarchi strongly stimulated turbot peritoneal cells. Many genes related to inflammation were DE in peritoneal cells at 1, 2 and 4 hpi. However, the response was much lower at 12 hpi and almost disappeared completely at 48 hpi in fish that were able to kill P. dicentrarchi during the first few hpi. The genes that were DE at 1, 2 and 4 hpi were mainly related to the apoptotic process, the immune response, the Fc-epsilon receptor signalling pathway, the innate immune response, cell adhesion, cell surface receptors, the NF-kappaB signalling pathway and the MAPK cascade. Expression of toll-like receptors 2, 5 and 13 and of several components of NF-κB, MAPK and JAK/STAT signalling pathways was UR in the turbot peritoneal cells. Genes expressing chemokines and chemokine receptors, genes involved in prostaglandin and leukotriene synthesis, prostaglandins, leukotriene receptors, proinflammatory cytokines and genes involved in apoptosis were strongly UR during the first four hours of infection. However, expression of anti-inflammatory cytokines such as Il-10 and lipoxygenases with anti-inflammatory activity (i.e., arachidonate 15-lipoxygenase) were only UR at 12 and/or 48 hpi, indicating an anti-inflammatory state in these groups of fish. In conclusion, the present study shows the regulation of several genes in P. dicentrarchi during the early stages of infection, some of which probably play important roles in this process. The infection induced a potent acute inflammatory response, and many inflammatory genes were regulated in peritoneal cells, showing that the turbot uses all the protective mechanisms it has available to prevent the entry of the parasite.

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Section: Discussionmentioning

confidence: 99%

Interactions between the Parasite Philasterides dicentrarchi and the Immune System of the Turbot Scophthalmus maximus. A Transcriptomic Analysis

Valle

Leiro

Pereiro

et al. 2020

Biology

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“…Interestingly, kinomic analysis of the combination treatments demonstrates the greatest suppression of CDK and MAPK/ERK pathways. The involvement of these pathways in DNA repair is previously reported ( Golding et al, 2007 , 2009 ; Sharma et al, 2007 ; Khalil et al, 2011 ; Dean et al, 2012 ; Zalmas et al, 2013 ; Wang et al, 2018 ; Liu et al, 2020 ). Upon DNA damage, CDK2 activates the DNA damage response, and CDK2 knockout or deficiency increases sensitivity to radiation ( Liu et al, 2020 ).…”

Section: Discussionmentioning

confidence: 80%

Combining PARP and DNA-PK Inhibitors With Irradiation Inhibits HPV-Negative Head and Neck Cancer Squamous Carcinoma Growth

et al. 2020

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Novel targeted agents to inhibit DNA repair pathways to sensitize tumors to irradiation (IR) are being investigated as an alternative to chemoradiation for locally advanced human papilloma virus negative (HPV-negative) head and neck squamous cell carcinoma (HNSCC). Two well-characterized targets that, when inhibited, exhibit potent IR sensitization are PARP1 and DNA-PKcs. However, their cooperation in sensitizing HPV-negative HNSCC to IR remains to be explored given that PARP1 and DNA-Pk CS bind to unresected stalled DNA replication forks and cooperate to recruit XRCC1 to facilitate double-strand break repair. Here, we show that the combination of the DNA-PK inhibitor NU7441 and the PARP inhibitor olaparib significantly decrease proliferation (61–78%) compared to no reduction with either agent alone ( p < 0.001) in both SCC1 and SCC6 cell lines. Adding IR to the combination further decreased cell proliferation (91–92%, p < 0.001) in SCC1 and SCC6. Similar results were observed using long-term colony formation assays [dose enhancement ratio (DER) 2.3–3.2 at 4Gy, p < 0.05]. Reduced cell survival was attributed to increased apoptosis and G2/M cell cycle arrest. Kinomic analysis using tyrosine (PTK) and serine/threonine (STK) arrays reveals that combination treatment results in the most potent inhibition of kinases involved in the CDK and ERK pathways compared to either agent alone. In vivo , a significant delay of tumor growth was observed in UM-SCC1 xenografts receiving IR with olaparib and/or NU7441, which was similar to the cisplatin-IR group. Both regimens were less toxic than cisplatin-IR as assessed by loss of mouse body weight. Taken together, these results demonstrate that the combination of NU7441 and olaparib with IR enhances HPV-negative HNSCC inhibition in both cell culture and in mice, suggesting a potential innovative combination for effectively treating patients with HPV-negative HNSCC.

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“…Cyclin E, Cyclin D1, Cyclin A and Cyclin B1 occur in G1, late G1 or early S, and the S or G2 phases, respectively [28]. Cyclins function by binding CDKs, which play an important role in cell cycle progression of cancer [29]. CDK inhibitor plays the role of 'cell cycle brake' which combines the complex of Cyclin and CDK and inhibits their cell cycle accelerator function [30].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-122-5p inhibits cell proliferation, migration and invasion by targeting CCNG1 in pancreatic ductal adenocarcinoma

Dai

Zhang

et al. 2020

Cancer Cell Int

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Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal human malignancy, and previous researches support the contribution of microRNA (miRNA) to cancer progression. MiR-122-5p is reported to participate in the regulation of various cancers, while the function of miR-122-5p in PDAC remains unclear. In this study, we investigated the precise mechanism of miR-122-5p involved in PDAC pathogenesis. Methods: The expression levels of miR-122-5p were detected in human PDAC tissues and cell lines by miRNA RT-PCR. The effects of miR-122-5p on cell proliferation were explored by MTT assays, colony formation assays and flow cytometry assays. The ability of migration and invasion was determined by transwell assays. Dual Luciferase reporter assay was performed to validate the direct interaction between miR-122-5p and its target gene. The related molecules of cell cycle, apoptosis and epithelial-mesenchymal transition (EMT) were examined with qRT-PCR and western blot. In addition, xenograft mouse models were applied to explore the effects of miR-122-5p in vivo. Results: MiR-122-5p was underexpressed, while CCNG1 was highly expressed in PDAC tissues and cells. MiR-122-5p was negatively correlated with TNM stage, tumor size and lymph node metastasis in PDAC patients. Overexpression of miR-122-5p suppressed the proliferation, migration and invasion in vitro and inhibited tumorigenesis in vivo. Furthermore, CCNG1 was a direct target of miR-122-5p. Upregulated CCNG1 could partially reverse the effects caused by miR-122-5p. Moreover, miR-122-5p inhibited EMT through downregulation of CCNG1. Conclusion: Overexpression of miR-122-5p could inhibit cell proliferation, migration, invasion, and EMT by downregulating CCNG1 in PDAC, suggesting a potential therapeutic target for PDAC.

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To control or to be controlled? Dual roles of CDK2 in DNA damage and DNA damage response

Cited by 32 publications

References 130 publications

Interactions between the Parasite Philasterides dicentrarchi and the Immune System of the Turbot Scophthalmus maximus. A Transcriptomic Analysis

Interactions between the Parasite Philasterides dicentrarchi and the Immune System of the Turbot Scophthalmus maximus. A Transcriptomic Analysis

Combining PARP and DNA-PK Inhibitors With Irradiation Inhibits HPV-Negative Head and Neck Cancer Squamous Carcinoma Growth

MicroRNA-122-5p inhibits cell proliferation, migration and invasion by targeting CCNG1 in pancreatic ductal adenocarcinoma

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