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Regulation of Cell Functions
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
A number of genes showing variable degrees of homology to the classic cyclin/PCNA gene have been detected in mammalian and nonmammalian cells. These genes encode members of the cyclin family of proteins, which include cyclins A, B, C, Dl, D3, and E. At least some of these cyclin types (cyclins A and E) may satisfy the criteria for a labile protein involved in the control of the restriction point (R point) of the cell cycle.289 Two distinct cyclins, A and B, exhibit differential variation during the cycle of human cells.290 The two types of cyclin have a different location in the cell, with cyclin A being predominantly found in the nucleus and cyclin B in the cytoplasm.291 Moreover, cyclin A and cyclin B undergo cell cycle-dependent transport from the cytoplasm to the nucleus, suggesting different functions for the two proteins. Human cyclin A mRNA and protein levels vary during the cell cycle and increase and decrease in advance of cyclin B levels.292 Cyclin A is required for the onset of DNA replication in mammalian fibroblasts as well as during S phase in normal epithelial cells.293,294 Cyclin B forms a functional complex with the 34-kDa cdc2 kinase (p34cdc2), whereas cyclin A may act in association with a protein kinase of 33 kDa, the cdk2 kinase (p33cdc2).295 The cdk2/cyclin A complexes may have a unique role in cell cycle regulation.
CDK Inhibitors in Leukemia and Lymphoma
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Of the large number of CDK complexes identified, CDKs 1, 2, 4, and 6 and cyclins A (A1 and A2), B (B1 and B2), D (D1, D2, and D3), and E (E1 and E2) are directly involved in the cell cycle machinery. Generally, cyclins D-CDK4 and D-CDK6 phosphorylate or inactivate the retinoblastoma protein (pRb, a major member of the “pocket protein” family) and release transcriptional factors E2Fs (activated) from an inactive pRb-E2F complex. E2F binds to its heterodimeric partner DP-1 and induces the expression of genes that is responsible for S-phase entry and progression, including cyclin E. In addition, cyclin E-CDK2 also facilitates G1→S transition by further phosphorylating pRb, complete activation of which requires phosphorylation by both cyclin D-CDK4/6 (hypophosphorylation) and cyclin E-CDK2 (hyperphosphorylation) (4). Cyclin D-CDK4, but not cyclin E-CDK2, also phosphorylates p130 and p107 (additional members of the “pocket protein” family), which may interact with certain E2Fs (e.g., E2F1 and 4) and mimic the function of pRb in RB null tumor cells. In the S phase, cyclin A-CDK2 phosphorylates various substrates, which allows DNA replication and also inactivates G1 transcriptional factors (i.e., E2Fs). Cyclin A-CDK1/CDC2 and cyclin B-CDK1/CDC2 govern G2→M transition. The cyclin B-CDK1 complex also regulates the transition of cells into anaphase and through mitosis. In addition, certain CDK complexes, e.g., cyclin A-CDK2 in the S phase and cyclin B1-CDK1 in the G2/M phase, are associated with the DNA replication competent (RC) complex, which may be directly involved in regulation of DNA replication (5). Lastly, cyclin H-CDK7 (also known as CAK) activates CDKs 1, 2, 4, and 6 via phosphorylation at specific threonine residues, events required for full activation of these CDKs.
Ruthenium Anticancer Drugs
Published in Astrid Sigel, Helmut Sigel, Metal Ions in Biological Systems, 2004
Enzo Alessio, Giovanni Mestroni, Alberta Bergamo, Gianni Sava
Many Ru-dmso complexes can stop cell proliferation at the pre-mitotic G2-M phase. The percent of cells present in G2-M phase increases proportionally to the concentration of the ruthenium complex and to the length of cell exposure which ultimately determine the amount of compound that enters tumor cells (Figure 2) [63]. The dependence of the cell cycle effects on ruthenium uptake by tumor cells has been confirmed using a series of different ruthenium complexes and of treatment schedules. The molecular changes accompanying the distribution of cells among cell cycle phases have been investigated for some dinuclear Ru-dmso compounds [37]. The choice to test the dimeric complex 8Pyz was made principally because it is as active as NAMI-A in blocking cells in G2-M phase and more active then NAMI-A in inhibiting the gelatinase MMP-9 and the matrigel invasion and it is active on MCa mammary carcinoma in vivo. In the model of in vitro treated KB carcinoma cells 8Pyz shows the ability to increase the steady-state level of cyclin B, a protein that, together with the Cdkl kinase, regulates the progression of cells from the G2 to the M phase [64]. This effect has a well defined time course: it is detectable 24 hr after the end of an hour treatment and it is completely reverted after 48 hr. At the same time no change of Cdkl, as well as of other cell cycle regulating proteins (Cdk2, p27, PCNA) is detectable. In a different model of transformed endothelial cells (ECV304), NAMI-A treatment caused a decrease of steady-state levels of Cdkl and of PCNA, in accordance to the inhibition of cell proliferation in these cell types [2]. Therefore cell cycle alterations may be indicative of effects of ruthenium complexes with the regulation of cell proliferation.
Application of the Mannich reaction in the structural modification of natural products
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Miao-Xia Pu, Hong-Yan Guo, Zhe-Shan Quan, Xiaoting Li, Qing-Kun Shen
Flavopiridol is a semi-synthetic flavonoid derivative of rohitukine that has a strong inhibitory effect on a variety of tumour cells and is currently undergoing phase II clinical trials as an anti-tumour agent. Baicalein and quercetin are also flavonoids derivatives that can induce cell cycle arrest and apoptosis in cancer cells; however, flavopiridol and baicalein have poor inhibitory activity on CDKs. Zhang et al.36 studied the chemical structure of flavopiridol and introduced a nitrogen-containing D ring in the baicalein and quercetin structures to increase their CDK inhibitory activity. Sixteen flavopiridol, baicalein, and quercetin analogues were synthesised through the Mannich reaction and evaluated for their inhibitory activity against CDK1/cyclin B (Table 1). Among them, compounds 24 and 25 (Figure 2) exhibited the strongest CDK1/Cyclin B inhibitory activity and had IC50 values of 0.27 and 0.28 µM, respectively, which is comparable to that of the positive control drug flavopiridol (IC50 = 0.33 µM). Therefore, compounds 24 and 25 warrants further study.
Expanding roles of cell cycle checkpoint inhibitors in radiation oncology
Published in International Journal of Radiation Biology, 2023
Sissel Hauge, Adrian Eek Mariampillai, Gro Elise Rødland, Lilli T. E. Bay, Helga B. Landsverk, Randi G. Syljuåsen
The transition from one cell cycle phase to the next is driven by the activation of Cyclin-dependent kinases (CDKs). According to the classical view, progression through G1 phase is controlled by Cyclin D–CDK4 and Cyclin D–CDK6 activities, and entry into S phase is driven by Cyclin E–CDK2 activity. Cyclin A–CDK2 and Cyclin A–CDK1 are then responsible for further progression through S phase and toward mitosis, and Cyclin B–CDK1 pushes the cell into mitosis (Hochegger et al. 2008). The WEE1, CHK1 and ATR kinases act as negative regulators of CDK1 and CDK2 activity (Figure 1). WEE1 is active in interphase and is inhibited when cells enter mitosis, and it works by directly mediating the inhibitory phosphorylation on tyrosine 15 (Y15) of CDK1 and CDK2 (Parker and Piwnica-Worms 1992; Watanabe et al. 1995, 2004; Katayama et al. 2005). CHK1 suppresses CDK1 and CDK2 activity by promoting degradation of the CDC25A phosphatase that removes the Y15 inhibitory phosphorylation (Zhao et al. 2002; Sørensen et al. 2003). As CHK1 is activated by ATR, ATR thus suppresses CDK1 and CDK2 activity through CHK1-mediated degradation of CDC25A (Sørensen et al. 2004).
Cell cycle dysregulation on prenatal and postnatal arsenic exposure in skin of Wistar rat neonates
Published in Xenobiotica, 2023
Navneet Kumar, Astha Mathur, Suresh Kumar Bunker, Placheril J. John
There was a dose dependent decrease in transcript levels of cyclin A and cyclin B1 with increasing dose groups, whereas a similar increase in transcript levels of cyclin E1 with increasing dose groups. We also observed the downregulation of transcript levels of both CDK1 and CDK2 in a dose dependent manner. The increased expression of cyclin E1 has been shown to be involved in accelerated G1 to S phase transition (Resnitzky et al. 1994). The observed increase in cyclin E1 transcript expression levels can be a sign of increasing amount of cells transitioning to S phase. The cyclin A/CDK2 complex causes the transition of the cell cycle from the S phase to the G2 phase, and cyclin A then activates CDK1 to cause the cell to enter the M phase. The cyclin B/CDK1 complex maintains CDK1 activity during mitosis (Kalous et al. 2020). Disruption in the levels of CDK/cyclin complexes can result in cell cycle arrest in S phase and G2/M phase.