PCNA-dependent accumulation of CDKN1A into nuclear foci after ionizing irradiation

Wiese, Claudia; Rudolph, J. H.; Jakob, Burkhard; Fink, Daniela; Tobias, Frank; Blattner, Christine; Taucher-Scholz, G.

doi:10.1016/j.dnarep.2012.02.006

Cited by 17 publications

(10 citation statements)

References 50 publications

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“…For example, p21 prevents retinoblastoma protein (pRb) from undergoing phosphorylation 81 and increases the E2F-associated phosphor-protein (EAPP) level to maintain gene regulation by E2F transcription factors in a repressed status and to induce cell cycle arrest 82. P21 also interacts with proliferating cell nuclear antigen (PCNA), which is linked to DNA metabolism and repair in response to radiation damage 83. As p21 is widely accepted as a positive factor for differentiation or cellular senescence, we used it as one of the important differentiation indicators in the study.…”

Section: Discussionmentioning

confidence: 99%

Chlorogenic acid effectively treats cancers through induction of cancer cell differentiation

Huang¹,

Wang²,

Xue³

et al. 2019

Theranostics

126

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Rationale: Inducing cancer differentiation is a promising approach to treat cancer. Here, we identified chlorogenic acid (CA), a potential differentiation inducer, for cancer therapy, and elucidated the molecular mechanisms underlying its differentiation-inducing effects on cancer cells.Methods: Cancer cell differentiation was investigated by measuring malignant behavior, including growth rate, invasion/migration, morphological change, maturation, and ATP production. Gene expression was analyzed by microarray analysis, qRT-PCR, and protein measurement, and molecular biology techniques were employed for mechanistic studies. LC/MS analysis was the method of choice for chemical detection. Finally, the anticancer effect of CA was evaluated both in vitro and in vivo.Results: Cancer cells treated with CA showed reduced proliferation rate, migration/invasion ability, and mitochondrial ATP production. Treating cancer cells with CA resulted in elevated SUMO1 expression through acting on its 3'UTR and stabilizing the mRNA. The increased SUMO1 caused c-Myc sumoylation, miR-17 family downregulation, and p21 upregulation leading to G0/G1 arrest and maturation phenotype. CA altered the expression of differentiation-related genes in cancer cells but not in normal cells. It inhibited hepatoma and lung cancer growth in tumor-bearing mice and prevented new tumor development in naïve mice. In glioma cells, CA increased expression of specific differentiation biomarkers Tuj1 and GFAP inducing differentiation and reducing sphere formation. The therapeutic efficacy of CA in glioma cells was comparable to that of temozolomide. CA was detectable both in the blood and brain when administered intraperitoneally in animals. Most importantly, CA was safe even at very high doses.Conclusion: CA might be a safe and effective differentiation-inducer for cancer therapy. “Educating” cancer cells to differentiate, rather than killing them, could be a novel therapeutic strategy for cancer.

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Section: Discussionmentioning

confidence: 99%

Chlorogenic acid effectively treats cancers through induction of cancer cell differentiation

Huang¹,

Wang²,

Xue³

et al. 2019

Theranostics

126

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“…Mock irradiated cells at the microprobe correspond to non-irradiated cells on the same dish. X-ray irradiation was conducted as described previously (27). …”

Section: Methodsmentioning

confidence: 99%

Clustered DNA damage induces pan-nuclear H2AX phosphorylation mediated by ATM and DNA–PK

Meyer

Voss

Tobias

et al. 2013

Nucleic Acids Research

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DNA double-strand breaks (DSB) are considered as the most deleterious DNA lesions, and their repair is further complicated by increasing damage complexity. However, the molecular effects of clustered lesions are yet not fully understood. As the locally restricted phosphorylation of H2AX to form γH2AX is a key step in facilitating efficient DSB repair, we investigated this process after localized induction of clustered damage by ionizing radiation. We show that in addition to foci at damaged sites, H2AX is also phosphorylated in undamaged chromatin over the whole-cell nucleus in human and rodent cells, but this is not related to apoptosis. This pan-nuclear γH2AX is mediated by the kinases ataxia telangiectasia mutated and DNA-dependent protein kinase (DNA–PK) that also phosphorylate H2AX at DSBs. The pan-nuclear response is dependent on the amount of DNA damage and is transient even under conditions of impaired DSB repair. Using fluorescence recovery after photobleaching (FRAP), we found that MDC1, but not 53BP1, binds to the nuclear-wide γH2AX. Consequently, the accumulation of MDC1 at DSBs is reduced. Altogether, we show that a transient dose-dependent activation of the kinases occurring on complex DNA lesions leads to their nuclear-wide distribution and H2AX phosphorylation, yet without eliciting a full pan-nuclear DNA damage response.

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“…Furthermore, p21CIP1 mRNA expression was also found to be slightly upregulated by quercetin in human primary hepatocytes (∼1.3‐fold at 250 μM compared to 2.1‐fold in the microarray) and in HepaRG cells (at 10 and 50 μM). P21CIP1 (or CDKN1A (cyclin‐dependent kinase inhibitor)) is a known cyclin‐dependent kinase inhibitor, binding to and inhibiting the activity of Cyclin/Cdk2‐, Cdk1‐, and Cdk4/6‐complexes . Hence, p21CIP1 acts as a regulator of cell cycle progression .…”

Section: Resultsmentioning

confidence: 99%

Dose‐dependent induction of signaling pathways by the flavonoid quercetin in human primary hepatocytes: A transcriptomic study

Waizenegger

Lenze

Luckert

et al. 2015

Molecular Nutrition Food Res

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PCNA-dependent accumulation of CDKN1A into nuclear foci after ionizing irradiation

Cited by 17 publications

References 50 publications

Chlorogenic acid effectively treats cancers through induction of cancer cell differentiation

Chlorogenic acid effectively treats cancers through induction of cancer cell differentiation

Clustered DNA damage induces pan-nuclear H2AX phosphorylation mediated by ATM and DNA–PK

Dose‐dependent induction of signaling pathways by the flavonoid quercetin in human primary hepatocytes: A transcriptomic study

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