Alteration in Cell Cycle Control Factors and the Induction of Oxygen-Regulated Proteins by Hypoxic Stress
John J. Lemasters, Constance Oliver in Cell Biology of Trauma, 2020
The trivial explanation for this effect, namely, that pRB phosphorylation state in hypoxic cells simply reflects the reduced energy charge of the cells, does not appear to be the complete story. Cyclin A belongs to a family of proteins known as cyclins, the primary function of which appears to be modulation of the activities of specific kinases and cell cycle regulatory factors through a direct interaction.45,47,51,52 Cyclin A and its interactions appear to be important for S phase progression. This protein is rapidly synthesized during S phase and subsequently rapidly degraded as a prerequisite to M phase progression. Cyclin A is targeted for proteolysis through an ATP-dependent phosphorylation.53 If the loss of energy charge in hypoxic cells was strictly responsible for pRB hypophosphorylation, then it would be anticipated that cyclin A could not be degraded. In contrast, the data show that cyclin A is rapidly lost from hypoxic cells and is not resynthesized until the cells are reoxygenated (Figures 3 and 4). These data suggest that hypoxia may impair cell cycle progression by specifically affecting control through key cell cycle regulatory factors. It is also of interest that alterations in the phosphorylation state of pRB and the turnover of cyclin A in hypoxic cells appear to be uncoupled from the requirement that cells overtly progress through the cell cycle in response to these changes.
Regulation of Airway Smooth Muscle Proliferation by β2-Adrenoceptor Agonists
Alastair G. Stewart in AIRWAY WALL REMODELLING in ASTHMA, 2020
The cyclins are a family of proteins which are synthesised at different rates according to the stage in the cell cycle. The key G1 cyclins are cyclins D and E.151 Cyclin D1 was first identified as a product expressed in G1 by mouse macrophage cell line (BAC1.2F5A).152 Cyclins D2 and D3 were identified by using cyclin D1 cDNA as a probe to screen cDNA libraries.152,153 After mitogenic stimulation, cyclin D1 expression is apparent during the G0/G1 transition and reaches maximal levels prior to G1/S transition.152 The oscillation of the levels of expression of cyclin D during the cell cycle is moderate in comparison with other cyclins,151 but its elevation late in G1 is compatible with a role in the passage of cells through the restriction point. A decrease in cyclin D1 accumulation and/or its extrusion from the nucleus may be a prerequisite for the entry of cells into S phase.154
Small-Molecule Targeted Therapies
David E. Thurston, Ilona Pysz in 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.
Genomics in non-adenoid cystic group of salivary gland cancers: one or more druggable entities?
Published in Expert Opinion on Investigational Drugs, 2019
Stefano Cavalieri, Francesca Platini, Cristiana Bergamini, Carlo Resteghini, Donata Galbiati, Paolo Bossi, Federica Perrone, Elena Tamborini, Pasquale Quattrone, Lisa Licitra, Laura Deborah Locati, Salvatore Alfieri
Cyclins are proteins involved in cell cycle control. Specific cyclin-dependent kinase inhibitors (CDK-I) have a major role in cancer therapy. In detail, in ER-positive breast cancer, CDK-Is (palbociclib and abemaciclib) associated with hormone therapy significantly improved outcome in the recurrent/metastatic setting [50,51], also in terms of overall survival [52]. Genomic alterations of the cyclins/cyclin-dependent kinase (CDK) pathway (CCND1, CDK4/6 or CDKN2A/B aberrations) were found in approximately one third of non-ACC, particularly in acinic cell carcinoma (71%), undifferentiated carcinoma (67%), adenocarcinoma NOS (35%), myoepithelial carcinoma (33%) and mucoepidermoid carcinoma (20%) [7]. With regards to prevalence of CDKN2A and CDKN2B mutations in salivary gland malignancies, mucoepidermoid carcinoma was the most frequently mutated histotype, where these two mutations were respectively observed in 45% and 32% of cases [8]. Therefore, the role of CDK-Is should be investigated for treatment in those mutated patients with advanced disease.
Benzo(a)pyrene affects proliferation with reference to metabolic genes and ROS/HIF-1α/HO-1 signaling in A549 and MCF-7 cancer cells
Published in Drug and Chemical Toxicology, 2022
Meili Gao, Aqun Zheng, Lan Chen, Fan Dang, Xiaojing Liu, Jianghong Gao
The proliferation of cancer cells is associated with the proportion of cells that enter the cell cycle. Our results were similar to those of previous reports, which showed that BaP exposure caused S phase arrest, with enlarged cell sizes in A549 cells (Wang et al. 2009) and lengthened the S phase interval, resulting in G2/M accumulation in MCF-7 cells (Jeffy et al.2000). The results of the present study indicated the induction of cell cycle progression in the examined cancer cell lines. Cell cycle progression is regulated by interactions between cyclins and CDKs. The cyclin A–CDK2 interaction activates DNA synthesis and promotes DNA replication and is essential for the G1⁄S phase transition and progression through the S phase (Copeland et al. 2015). Mitosis is triggered by the activation of CDK1/cyclin B, also known as M-phase promoting factor (Ma et al.2016). A previous study reported that BaP exposure increased the expression levels of cyclin D1, CDK4, and CDK2, but no change in cyclin A expression was reported in A549 cells (Wang et al.2009). Our findings provided evidence for CDK1-cyclin B involvement in the regulation of the BaP-mediated effects on cell cycle progression in A549 cells. We also demonstrated that cyclin A-CDK2 and CDK1-cyclin B are strongly involved in the regulation of the BaP-mediated effects on the cell cycle progression of MCF-7 cells. To the best of our knowledge, the findings of increased CDK1 and cyclin B expression induced by BaP in A549 and MCF-7 cell lines have not been previously reported in the literature.
Bone marrow derived mesenchymal stem cells transplantation rescues premature ovarian insufficiency induced by chemotherapy
Published in Gynecological Endocrinology, 2018
Riqiang Bao, Ping Xu, Yishu Wang, Jing Wang, Li Xiao, Gang Li, Chunping Zhang
In fact, the growth of normal follicles is characterized by ovarian cell proliferation, especially granulosa cells. These ovarian cells work together to synthesize estrogen and regulate normal reproductive function [39]. Overapoptosis of ovarian cells induced by chemotherapy drugs caused a declined serum estrogen level. However, the recovery of estrogen level should be associated with the increase of ovarian cell proliferation. To date, almost all studies focused on the anti-apoptosis function and underneath mechanism of MSCs in POF treatment. Encouraging results from our study revealed that BM-MSCs increased the CyclinD2 expression and decreased p21 expression. CyclinD2 is critical in promoting cell cycle progress. CyclinD2 deficiency in ovarian granulosa cells influenced the proliferation and caused infertile of females [40]. p21, known as cyclin-dependent kinase inhibitor 1A (CDKN1A), exerts its function through binding to cyclins and cyclin-dependent kinases (CDKs) directly, which lead cell arrest at G1/S and G2/M transitions [41]. Cell cycle progression is precisely regulated by cyclins and several CDKs. Based on our results, we inferred that BM-MSCs transplantation regulated CyclinD2 and p21 expression and increased residual ovarian cell proliferation and restored ovarian function.
Related Knowledge Centers
- Active Site
- Enzyme
- Maturation Promoting Factor
- Microtubule
- Phosphorylation
- Cell Cycle
- Protein Family
- Cyclin-Dependent Kinase
- Kinase
- Cyclin-Dependent Kinase 1