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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
In order to divide successfully, a cell must copy its DNA so that each daughter cell receives its full set of chromosomes. This is achieved by a tightly regulated mitosis following the cell cycle pathway (Figure 2.6). Passage through the cell cycle is controlled by cyclin proteins, in a cascade of phosphorylation events. Each cyclin acts as a catalytic subunit in partnership with a cyclin-dependent kinase (CDK). Upon cyclin binding, CDKs phosphorylate target proteins that are required for cell-cycle progression. CDK-specific inhibitors (CDKIs) bind cyclin–CDK complexes to regulate their activity and can themselves be regulated by other proteins. During mitosis, one member of each chromosome pair becomes attached to a centriole. Centrioles move to opposite ends of the cell, taking the chromosomes with them. In order to prevent inappropriate proliferation of cells, mitosis is tightly controlled, with various checkpoints to ensure that every part of the mitotic process is completed correctly before the next stage begins. Because uncontrolled proliferation is a hallmark of cancer, the cell cycle provides an obvious target for therapy. CDKIs often act as tumour suppressors and are potentially useful anticancer agents.
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The cyclins form the regulatory subunits, and CDKs the catalytic subunits, of an activated heterodimer complex. Thus, the cyclins have no catalytic activity of their own, and the CDKs are inactive until associated with a partner cyclin. When bound by an appropriate cyclin, CDKs perform a phosphorylation reaction that activates or inactivates target proteins to facilitate entry into the next phase of the cell cycle. The various downstream proteins are targeted by different cyclin-CDK combinations. It follows that CDKs are constitutively expressed in cells, whereas cyclins are synthesized during different stages of the cell cycle in response to specific molecular signals. Thus, the CDK proteins have been the most sought-after targets for drug discovery purposes due to their constitutive expression during all the cell-cycle phases.
The Fight Against Cancer
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
A number of restraining proteins are in place to regulate the effects of cyclins and have an inhibitory effect by blocking the activity of CDKs. The amount of restraining protein present is controlled by P53, which is important for monitoring the health of the cell and the integrity of DNA. Several cancers are associated with overactive cyclins or CDKs. This occurs when these molecules are produced in excess, or the genes that code for inhibitory proteins are malfunctioning. Indeed, half of all human tumours lack a properly functioning P53 protein, consequently the levels of restraining protein are low; in other words, there is insufficient production of CDK inhibiters and so the cell cycle proceeds unregulated.
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
The G1/S phase transition of the cell cycle is controlled by cyclin-dependent protein kinases. The kinase-cyclin complex, which modulates the kinase activity, regulates cell cycle progression by targeted phosphorylation. The activity of these complexes peaks during the G1/S transition of the cell cycle and promotes cell mitosis (Lee et al.2019). Cyclin D mainly regulates the G1/S cell cycle transition, and its expression is closely related to the abnormal proliferation of tumours (Blain 2008). Besides, MFG-E8 could promote the proliferation of human pulmonary artery smooth muscle cells via p-Akt/cyclin D1 pathway (Wang et al.2021). Our present study showed consistent changes in cell proliferation and expression of cyclin D1 and CDK4 after MFG-E8 silence. Previous studies have focussed on the role of MFG-E8 in artery smooth muscle cells (VSMC) (Wang et al.2012, 2021), however, our study confirmed that MFG-E8 is involved in cell cycle regulation, which could help us better understand the mechanism of MFG-E8 in tumours.
Development of newly synthesised quinazolinone-based CDK2 inhibitors with potent efficacy against melanoma
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Eman R. Mohammed, Ghada F. Elmasry
Cyclin-dependent kinase 2 (CDK2) is a key regulator of the cell cycle transition and progression. CDK2 performs a critical role in controlling various events of the cell division cycle, such as DNA repair, gene transcription, G1-S transition, and modulation of G2 progression6–8. Additionally, the altered expression of cyclins whose association with CDKs is essential for their catalytic activity can drive aberrant proliferation in cancer. In the same vein, the overexpression of CDK2 regulatory subunits cyclin A and/or E is a key oncogenic process in many types of cancers9,10. Owing to the crucial role of CDK2 in cell cycle regulation, transcription activity, and tumours epigenetic modifications, CDK2 inhibition may confer a therapeutic benefit against certain cancers viz breast cancer11, colo-rectal cancer12,13, glioblastoma14–16, and melanoma17,18.
High Glucose Induced Upregulation of Cyclin a Associating with a Short Survival of Patients with Cholangiocarcinoma: A Potential Target for Treatment of Patients with Diabetes Mellitus
Published in Nutrition and Cancer, 2022
Charupong Saengboonmee, Marutpong Detarya, Sakkarn Sangkhamanon, Kanlayanee Sawanyawisuth, Wunchana Seubwai, Sopit Wongkham
In this study, flavopiridol, a pan-CDKs inhibitor, significantly suppressed growth of CCA cells in a dose and time dependent manner. The antiproliferative effect of flavopiridol on CCA cells at the G2/M phase has been reported (23). The major effect of flavopiridol on S and G2/M phases of cells has also been reported in other cancer types (45–47). A combination of using a pan-CDKs inhibitor and siCyclin A treatment had a pronounced effect on growth of CCA cells in contrast to those treated with the pan-CDKs inhibitor alone. This might be due to the major effect of flavopiridol on the G2/M phase, in which cyclin A and CDK2 are the key drivers of this phase in the cell cycle and inhibit both cyclin and its partner CDK that could effectively block a compensatory effect from alternate binding. Noteworthy, CDK2, a CDK partner of cyclin A, also showed a significant upregulation in HG cells of both cell lines. Moreover, suppression of cyclin A expression enhanced cytotoxicity of a pan-CDKs inhibitor on CCA cells. These results might reiterate some key roles of cyclin A and its CDK partner in the cell cycle progression of CCA cells cultured under high glucose conditions. This finding agrees with many reports that a high expression of cyclin A had a positive association with sensitivity to this chemotherapeutic drug in several cancers, nevertheless, with an unclarified mechanism (30–33). The direct involvement of cyclin A in enhancing drug sensitivity should be further investigated.