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Radiobiology of Tumours
Published in W. P. M. Mayles, A. E. Nahum, J.-C. Rosenwald, Handbook of Radiotherapy Physics, 2021
Gordon Steel, Catharine West, Alan Nahum
Evidence suggests a role for DNA repair processes and cell-cycle checkpoint processes in the response of cells to low doses of ionising radiation (Martin et al. 2014). One model describing the hypersensitivity low-dose phenomenon postulates that the major forms of ataxia-telangiectasia mutated (ATM) gene products are cytoplasmic dimers and that ionising radiation induces ATM protein monomerisation (Bodgi and Foray 2016). The ATM monomers diffuse into the nucleus to facilitate double-strand break (DSB) repair. Bodgi and Foray (2016) gave a molecular interpretation of the LQ model by considering the yield of recognised but unrepaired (α-type) DSBs and the non-recognised (β-type) DSBs. Cell tolerance to unrepaired DSBs was interpreted as due to not all DSBs being lethal.
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Careful regulation of the cell cycle is crucial for cells, and dysregulation can result in several disease types including cancer. In particular, progression from G1 to S is a key checkpoint in protecting a cell from abnormal replication. Key to progression through this restriction point is the interaction between a subgroup of serine/threonine kinases known as the cyclin-dependent kinases (CDKs) with another group of proteins known as the cyclins. During the transformation of healthy cells to cancer cells, the complex signaling pathways of the cell-cycle checkpoint processes can become corrupted (e.g., by the mutation or over-expression of certain kinases) to promote cell division, a well-known characteristic of most cancer cells. Thus, targeting over-expressed or mutated control proteins is a valuable approach to cancer therapy.
Non-Melanoma Skin Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Irene De Francesco, Sean Whittaker, Stephen L. Morris
However, the correlation between the tumor biology and the clinical diversity observed in patients is currently unknown. Additional events include inactivation of the tumor suppressor gene p53, which controls the G1 cell cycle checkpoint and thus regulates DNA repair or induces apoptosis of irretrievably damaged cells. Mutations of the p53 gene have been detected in almost all human tumors, and in skin tumors, these have been shown to be UV related. The mutation of a single p53 allele leads to the production of mutant p53 protein, which will inactivate wild-type p53, allowing cells that have DNA damage to proliferate. One study demonstrated that phenotypically normal UV-exposed human epidermal cells contain islands of keratinocytes that show mutant p53 on immunostaining.72 Such islands suggest that these cells are clonally expanded and therefore selectively out-grow those keratinocytes without mutation for p53.73 Indeed, 30% of sporadic BCCs show UV-type mutations of the p53 gene.73 Polymorphisms in the gene for glutathione reductase, which is important in the detoxification of active oxygen species, have been linked to BCCs, as have polymorphisms in the cytochrome P450 genes, which are important in metabolizing environmental carcinogens.74
Effects of MFG-E8 expression on the biological characteristics of ovarian cancer cells via the AKT/mTOR/S6K signalling pathway
Published in Journal of Obstetrics and Gynaecology, 2023
Na Li, Yazhuo Wang, Lin Liu, Pei Wang, Xiaohua Wu
In addition to traditional cyclin-dependent protein kinases, cell checkpoint genes, such as ataxia-telangiectasia gene (ATM), cell cycle checkpoint kinase 2 (Chk2), p53 gene, Rb gene and P21cip1 are others cell cycle regulators that play an unneglectable role in inhibiting cell division (Jerzak et al. 2018, Manu et al. 2019, Mustofa et al. 2020, Liebl and Hofmann 2021, Engeland 2022). In our previous study, we evaluated the expression of MFG-E8 in ovarian cancer tissues (Li et al. 2020). In this study, we found that the high expression of MFG-E8 in ovarian cancer tissues could promote cell proliferation. Thus, we evaluated the role of MFG-E8 silence in the expression of CDK4 and cyclin D1 proteins. However, the relationship between MFG-E8 expression and cell checkpoint genes above needs to be confirmed in further investigation.
Mitochondrial DNA copy number in cumulus granulosa cells as a predictor for embryo morphokinetics and chromosome status
Published in Systems Biology in Reproductive Medicine, 2023
Pitra Rahmawati, Budi Wiweko, Arief Boediono
Evaluation of embryo morphokinetics does not only provide real-time observation of embryo development, but also records the duration and synchrony of the cellular division (Milewski et al. 2015). A division process is determined by the embryo metabolic state and the availability of energy in the form of ATP (Mishra and Chan 2014). Evidence on the dynamics between mitochondrial morphology and function with the progress of a cell cycle has been reported. In G1/S, mitochondria fuse to form a connected network, and thereafter undergo fusion again in G2/M (Westermann 2010). A cell cycle checkpoint protein exists at both the G1/S and G2/M phase to serve as regulators for the cell division. Sufficient ATP must available for the genome integrity maintenance and DNA replication (Ma 2017). The pool of energy in the form of ATP is produced by the mitochondria in the oocyte because sperm mitochondria undergo autophagy during fertilization (Ménézo 2006; Colaco and Sakkas 2018). Thus, when oocyte mitochondria are impaired, the ATP pool is reduced, constraining cellular growth at the G0 phase. Subsequently, the duration of several moprhokinetic parameters could become higher (tPN, tPNf, t2, t3, t4, t5, t6, t7, t8, tC, tM and tB) due to the delayed embryonic development.
Identification of novel non-toxic and anti-angiogenic α-fluorinated chalcones as potent colchicine binding site inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Moran Sun, Minghua Yuan, Yingying Kang, Jinling Qin, Yixin Zhang, Yongtao Duan, Longfei Wang, Yongfang Yao
Cdc2 kinase, a member of Ser/Thr protein family, is considered as a driving force of G2/M transition. Activation of Cdc2 catalysed the phosphorylation of a variety of substrate proteins, thus promoting cell transition from G2 phase to M phase18. Cyclin B1 plays a vital role to control cell transition from G2 to M phase19. P21 also effectively regulates cell cycle progress by increasing the intracellular G2/M phase ratio. Therefore, the expression of cell cycle checkpoint protein was investigated. Figure 4(E,F) showed that chalcone 4c decrease the phosphorylation levels of Cdc2 in a concentration-dependent manner. We further observed that 4c caused a decrease in Cyclin B1 and increased the expression of tumour suppressor protein P21, which confirmed a G/M phase arrest by 4c. These results were consistent with flow cytometry analysis and microtubule immunofluorescence assay, which confirmed the mechanism of the cell cycle blocking effect at the cellular biochemical level.