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Trends in Cell Biology Sep 2021E-type cyclins, collectively called cyclin E, represent key components of the core cell cycle machinery. In mammalian cells, two E-type cyclins, E1 and E2, activate... (Review)
Review
E-type cyclins, collectively called cyclin E, represent key components of the core cell cycle machinery. In mammalian cells, two E-type cyclins, E1 and E2, activate cyclin-dependent kinase 2 (CDK2) and drive cell cycle progression by phosphorylating several cellular proteins. Abnormally elevated activity of cyclin E-CDK2 has been documented in many human tumor types. Moreover, cyclin E overexpression mediates resistance of tumor cells to various therapeutic agents. Recent work has revealed that the role of cyclin E extends well beyond cell proliferation and tumorigenesis, and it may regulate a diverse array of physiological and pathological processes. In this review, we discuss these various cyclin E functions and the potential for therapeutic targeting of cyclin E and cyclin E-CDK2 kinase.
Topics: Animals; Cell Cycle; Cell Proliferation; Cyclin E; Cyclins; Humans
PubMed: 34052101
DOI: 10.1016/j.tcb.2021.05.001 -
Open Biology Sep 2018Since their characterization as conserved modules that regulate progression through the eukaryotic cell cycle, cyclin-dependent protein kinases (CDKs) in higher... (Comparative Study)
Comparative Study Review
Since their characterization as conserved modules that regulate progression through the eukaryotic cell cycle, cyclin-dependent protein kinases (CDKs) in higher eukaryotic cells are now also emerging as significant regulators of transcription, metabolism and cell differentiation. The cyclins, though originally characterized as CDK partners, also have CDK-independent roles that include the regulation of DNA damage repair and transcriptional programmes that direct cell differentiation, apoptosis and metabolic flux. This review compares the structures of the members of the CDK and cyclin families determined by X-ray crystallography, and considers what mechanistic insights they provide to guide functional studies and distinguish CDK- and cyclin-specific activities. Aberrant CDK activity is a hallmark of a number of diseases, and structural studies can provide important insights to identify novel routes to therapy.
Topics: Animals; Binding Sites; Cell Cycle; Crystallography, X-Ray; Cyclin-Dependent Kinases; Cyclins; Humans; Models, Molecular; Multigene Family; Protein Binding; Protein Conformation
PubMed: 30185601
DOI: 10.1098/rsob.180112 -
Molecular and Cellular Biology Nov 1994Herpesvirus saimiri contains an open reading frame called eclf2 with homology to the cellular type D cyclins. We now show that the eclf2 gene product is a novel...
Herpesvirus saimiri contains an open reading frame called eclf2 with homology to the cellular type D cyclins. We now show that the eclf2 gene product is a novel virus-encoded cyclin (v-cyclin). The protein encoded by the v-cyclin gene of this oncogenic herpesvirus was found to have an apparent molecular size of 29 kDa in transformed cells. v-Cyclin protein was found to be associated with cdk6, a cellular cyclin-dependent kinase known to interact with cellular type D cyclins. cdk6/v-cyclin complexes strongly phosphorylated Rb fusion protein and histone H1 as substrates in vitro. Mutational analyses showed that highly conserved amino acids in the cyclin box of v-cyclin were important for association with cdk6 and for activation of cdk6 kinase activity. Thus, v-cyclin resembles cellular type D cyclins in primary sequence, in its association with cdk6, by its ability to activate protein kinase activity, and by the presence of functional cyclin box sequences. v-Cyclin exhibited a selective preference for association with cdk6 over other cyclin-dependent kinases and a high level of kinase activation. The properties of v-cyclin suggest a likely role in oncogenic transformation by this T-lymphotropic herpesvirus.
Topics: Amino Acid Sequence; Animals; Base Sequence; Cell Cycle; Cell Line; Conserved Sequence; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinases; Cyclins; DNA Primers; DNA, Viral; Genes, Viral; Herpesvirus 2, Saimiriine; Molecular Sequence Data; Molecular Weight; Moths; Mutation; Open Reading Frames; Phosphorylation; Protein Kinases; Protein Serine-Threonine Kinases
PubMed: 7935438
DOI: 10.1128/mcb.14.11.7235-7244.1994 -
Genes Jul 2023D-type cyclins encode G1/S cell cycle checkpoint proteins, which play a crucial role in defining cell cycle exit and progression. Precise control of cell cycle exit is... (Review)
Review
D-type cyclins encode G1/S cell cycle checkpoint proteins, which play a crucial role in defining cell cycle exit and progression. Precise control of cell cycle exit is vital during embryonic development, with defects in the pathways regulating intracellular D-type cyclins resulting in abnormal initiation of stem cell differentiation in a variety of different organ systems. Furthermore, stabilisation of D-type cyclins is observed in a wide range of disorders characterized by cellular over-proliferation, including cancers and overgrowth disorders. In this review, we will summarize and compare the roles played by each D-type cyclin during development and provide examples of how their intracellular dysregulation can be an underlying cause of disease.
Topics: Cyclins; Cyclin D3; Cell Division; Cell Cycle; Cell Proliferation
PubMed: 37510349
DOI: 10.3390/genes14071445 -
Cell Cycle (Georgetown, Tex.) Apr 2023The family protein of cyclins, as well as cyclin-dependent kinases (CDKs) cooperating with them, are broadly researched, as a matter of their dysfunction may lead to... (Review)
Review
The family protein of cyclins, as well as cyclin-dependent kinases (CDKs) cooperating with them, are broadly researched, as a matter of their dysfunction may lead to tumor transformation. Cyclins are defined as key regulators that have a controlling function of the mammalian nuclear cell divides. Cyclin Y (CCNY) is a recently characterized member of the cyclin family and was first identified from the human testis cDNA library. It is an actin-binding protein acting through decreased actin dynamics at a steady state and during glycine-induced long-term potentiation (LTP) and involves the inhibition of cofilin activation. What is more, CCNY is a positive regulatory subunit of the CDK14/PFTK1 complexes affected by the activation of the Wnt signaling pathway in the G2/M phase by recruiting CDK14/PFTK1 to the plasma membrane and promoting phosphorylation of LRP6. The expression of CCNY has been significantly mentioned within the cell migration and invasion activity both in vivo and in vitro. The aim of this review is evaluation of the expression of CCNY in the physiology processes and compare the expression of this protein in cancer cells, taking into account the impact of the level of expression on tumor progression.
Topics: Animals; Humans; Male; Testis; Cyclin-Dependent Kinases; Cell Nucleus; Cyclins; Phosphorylation; Mammals
PubMed: 36576166
DOI: 10.1080/15384101.2022.2162668 -
Life Science Alliance Sep 2022The founding member of the F-box protein family, Cyclin-F, serves as a substrate adaptor for the E3 ligase Skp1-Cul1-F-box (SCF)<sup>Cyclin-F</sup> which is...
The founding member of the F-box protein family, Cyclin-F, serves as a substrate adaptor for the E3 ligase Skp1-Cul1-F-box (SCF)<sup>Cyclin-F</sup> which is responsible for ubiquitination of proteins involved in cell cycle progression, DNA damage and mitotic fidelity. Missense mutations in <i>CCNF</i> encoding for Cyclin-F are associated with amyotrophic lateral sclerosis (ALS). However, it remains elusive whether <i>CCNF</i> mutations affect the substrate adaptor function of Cyclin-F and whether altered SCF<sup>Cyclin-F</sup>-mediated ubiquitination contributes to pathogenesis in <i>CCNF</i> mutation carriers. To address these questions, we set out to identify new SCF<sup>Cyclin-F</sup> targets in neuronal and ALS patient-derived cells. Mass spectrometry-based ubiquitinome profiling of <i>CCNF</i> knockout and mutant cell lines as well as Cyclin-F proximity and interaction proteomics converged on the HSP90 chaperone machinery as new substrate candidate. Biochemical analyses provided evidence for a Cyclin-F-dependent association and ubiquitination of HSP90AB1 and implied a regulatory role that could affect the binding of a number of HSP90 clients and co-factors. Together, our results point to a possible Cyclin-F loss-of-function-mediated chaperone dysregulation that might be relevant for ALS.
Topics: Amyotrophic Lateral Sclerosis; Cyclins; F-Box Proteins; HSP90 Heat-Shock Proteins; Humans; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 36114006
DOI: 10.26508/lsa.202101359 -
Biology of Reproduction Nov 2019Oocyte meiotic maturation is a vital and final process in oogenesis. Unlike somatic cells, the oocyte needs to undergo two continuous meiotic divisions (meiosis I and... (Review)
Review
Oocyte meiotic maturation is a vital and final process in oogenesis. Unlike somatic cells, the oocyte needs to undergo two continuous meiotic divisions (meiosis I and meiosis II) to become a haploid gamete. Notably, oocyte meiotic progression includes two rounds of unique meiotic arrest and resumption. The first arrest occurs at the G2 (germinal vesicle) stage and meiosis resumption is stimulated by a gonadotropin surge; the second arrest takes place at the metaphase II stage, the stage from which it is released when fertilization takes place. The maturation-promoting factor, which consists of cyclin B1 (CCNB1) and cyclin-dependent kinase 1 (CDK1), is responsible for regulating meiotic resumption and progression, while CDK1 is the unique CDK that acts as the catalytic subunit of maturation-promoting factor. Recent studies showed that except for cyclin B1, multiple cyclins interact with CDK1 to form complexes, which are involved in the regulation of meiotic progression at different stages. Here, we review and discuss the control of oocyte meiotic progression by cyclins A1, A2, B1, B2, B3, and O.
Topics: Animals; Cell Cycle; Cyclins; Female; Meiosis; Oocytes
PubMed: 31347666
DOI: 10.1093/biolre/ioz143 -
FEBS Letters Oct 2019The primary function of cyclin-dependent kinases (CDKs) in complex with their activating cyclin partners is to promote mitotic division in somatic cells. This canonical... (Review)
Review
The primary function of cyclin-dependent kinases (CDKs) in complex with their activating cyclin partners is to promote mitotic division in somatic cells. This canonical cell cycle-associated activity is also crucial for fertility as it allows the proliferation and differentiation of stem cells within the reproductive organs to generate meiotically competent cells. Intriguingly, several CDKs exhibit meiosis-specific functions and are essential for the completion of the two reductional meiotic divisions required to generate haploid gametes. These meiosis-specific functions are mediated by both known CDK/cyclin complexes and meiosis-specific CDK-regulators and are important for a variety of processes during meiotic prophase. The majority of meiotic defects observed upon deletion of these proteins occur during the extended prophase I of the first meiotic division. Importantly a lack of redundancy is seen within the meiotic arrest phenotypes described for many of these proteins, suggesting intricate layers of cell cycle control are required for normal meiotic progression. Using the process of male germ cell development (spermatogenesis) as a reference, this review seeks to highlight the diverse roles of selected CDKs their activators, and their regulators during gametogenesis.
Topics: Animals; Cell Cycle Checkpoints; Cell Differentiation; Cell Proliferation; Cyclin-Dependent Kinases; Cyclins; Gene Expression Regulation; Haploidy; Male; Meiosis; Mice; Nuclear Proteins; Recombination, Genetic; Signal Transduction; Spermatogenesis; Spermatozoa; Stem Cells
PubMed: 31566717
DOI: 10.1002/1873-3468.13627 -
International Journal of Molecular... Feb 2023Gastric cancer predominantly occurs in adenocarcinoma form and is characterized by uncontrolled growth and metastases of gastric epithelial cells. The growth of gastric... (Review)
Review
Gastric cancer predominantly occurs in adenocarcinoma form and is characterized by uncontrolled growth and metastases of gastric epithelial cells. The growth of gastric cells is regulated by the action of several major cell cycle regulators including Cyclins and Cyclin-dependent kinases (CDKs), which act sequentially to modulate the life cycle of a living cell. It has been reported that inadequate or over-activity of these molecules leads to disturbances in cell cycle dynamics, which consequently results in gastric cancer development. Manny studies have reported the key roles of Cyclins and CDKs in the development and progression of the disease in either in vitro cell culture studies or in vivo models. We aimed to compile the evidence of molecules acting as regulators of both Cyclins and CDKs, i.e., upstream regulators either activating or inhibiting Cyclins and CDKs. The review entails an introduction to gastric cancer, along with an overview of the involvement of cell cycle regulation and focused on the regulation of various Cyclins and CDKs in gastric cancer. It can act as an extensive resource for developing new hypotheses for future studies.
Topics: Humans; Cyclin-Dependent Kinases; Cyclins; Stomach Neoplasms; Cell Cycle; Cell Division
PubMed: 36769170
DOI: 10.3390/ijms24032848 -
The EMBO Journal Dec 1994Cyclins are important regulators of cell cycle transitions through their ability to bind and activate cyclin-dependent protein kinases. In mammals several classes of...
Cyclins are important regulators of cell cycle transitions through their ability to bind and activate cyclin-dependent protein kinases. In mammals several classes of cyclins exist which are thought to co-ordinate the timing of different events necessary for cell cycle progression. Here we describe the identification of a novel human cyclin, cyclin F, isolated as a suppressor of the G1/S deficiency of a Saccharomyces cerevisiae cdc4 mutant. Cyclin F is the largest cyclin, with a molecular weight of 87 kDa, and migrates as a 100-110 kDa protein. It contains an extensive PEST-rich C-terminus and a cyclin box region that is most closely related to cyclins A and B. Cyclin F mRNA is ubiquitiously expressed in human tissues. It fluctuates dramatically through the cell cycle, peaking in G2 like cyclin A and decreasing prior to decline of cyclin B mRNA. Cyclin F protein accumulates in interphase and is destroyed at mitosis at a time distinct from cyclin B. Cyclin F shows regulated subcellular localization, being localized in the nucleus in most cells, with a significant percentage of cells displaying only perinuclear staining. Overexpression of cyclin F, or a mutant lacking the PEST region, in human cells resulted in a significant increase in the G2 population, implicating cyclin F in the regulation of cell cycle transitions. The ubiquitous expression and phylogentic conservation of cyclin F suggests that it is likely to coordinate essential cell cycle events distinct from those regulated by other cyclins.
Topics: Amino Acid Sequence; Base Sequence; Cell Compartmentation; Cell Cycle; Cell Cycle Proteins; Cell Nucleus; Cloning, Molecular; Cyclin B; Cyclins; DNA, Complementary; F-Box Proteins; F-Box-WD Repeat-Containing Protein 7; Fluorescent Antibody Technique; Fungal Proteins; G2 Phase; Humans; Molecular Sequence Data; Precipitin Tests; RNA, Messenger; Recombinant Proteins; Saccharomyces cerevisiae Proteins; Sequence Homology, Amino Acid; Suppression, Genetic; Ubiquitin-Protein Ligases; Yeasts
PubMed: 7813445
DOI: 10.1002/j.1460-2075.1994.tb06955.x