Sodium Fluoride Arrests Renal G2/M Phase Cell-Cycle Progression by Activating ATM-Chk2-P53/Cdc25C Signaling Pathway in Mice

Abstract

Background/Aims: Excessive fluoride intake can induce cytotoxicity, DNA damage and cell-cycle changes in many tissues and organs, including the kidney. However, the underlying molecular mechanisms of fluoride-induced renal cell-cycle changes are not well understood at present. In this study, we used a mouse model to investigate how sodium fluoride (NaF) induces cell-cycle changes in renal cells. Methods: Two hundred forty ICR mice were randomly assigned to four equal groups for intragastric administration of NaF (0, 12, 24 and 48 mg/kg body weight/day) for 42 days. Kidneys were taken to measure changes of the cell-cycle at 21 and 42 days of the experiment, using flow cytometry, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot methods. Results: NaF, at more than 12 mg/kg body weight, induced G2/M phase cell-cycle arrest in the renal cells, which was supported by the finding of significantly increased percentages of renal cells in the G2/M phase. We found also that G2/M phase cell-cycle arrest was accompanied by up-regulation of p-ATM, p-Chk2, p-p53, p-Cdc25C, p-CDK1, p21, and Gadd45a protein expression levels; up-regulation of ATM, Chk2, p53, p21, and Gadd45a mRNA expression levels; down-regulation of CyclinB1, mdm2, PCNA protein expression levels; and down-regulation of CyclinB1, CDK1, Cdc25C, mdm2, and PCNA mRNA expression levels. Conclusion: In this mouse model, NaF, at more than 12 mg/ kg, induced G2/M phase cell-cycle arrest by activating the ATM-Chk2-p53/Cdc25C signaling pathway, which inhibits the proliferation of renal cells and development of the kidney. Activation of the ATM-Chk2-p53/Cdc25C signaling pathway is the mechanism of NaF-induced renal G2/M phase cell-cycle arrest in this model.

Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway

“…CHK2 is a tumour suppressor gene encoding a serine/threonine kinase. It plays a very important role in the regulation of cell cycle checkpoints caused by DNA damage and participates in maintaining genome stability . MDMX, as an inhibitor of p53, could cause the ubiquitination and degradation of p53 .…”

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

“…For instance, post irradiation, ATM is activated, and ATM phosphorylates p53 and MDM2, promoting dissociation of p53 from MDM2 and inhibiting p53 translocation from the nucleus to cytoplasm; on the other hand, CHK2 is activated, which phosphorylates and stabilizes p53, and the increased level of p53 triggers the transcription of downstream genes such as p21, contributing to G1/S arrest [217][218][219] . Compared to the ATM/p53/p21 pathway, the ATM/CHK2/CDC25C pathway induces rapid signaling in response to DNA damage 220 . G1/S arrest is induced when CDC25C is degraded via ATM/CHK2 after IR-induced DNA damage [221][222][223] .…”

Cellular Senescence in the Kidney

“…18,19 Work with several experimental models of fibrotic kidney disease identified that accumulation of cells arrested at the later G2/M checkpoint (via inhibition of cdc25c/cdc2 by p53 or activation of the Chk1 and Chk2 proteins) not only results in senescence but triggers a profibrotic secretory phenotype. [20][21][22] Inhibiting this checkpoint using JNK, histone deacetylase, or p53 inhibitors results in reduced numbers of G2/M arrested cells and reduced fibrosis in a model of unilateral renal ischemia. 20 Delineating the differences and commonality between G1/S and G2/M arrested cells will be of interest in the future.…”