Control of cell cycle progression by phosphorylation of cyclin-dependent kinase (CDK) substrates

Cell Cycle and Cancer Unit, St Vincent's Institute of Medical Research, The University of Melbourne, Fitzroy, Melbourne, Victoria 3065, Australia.
Bioscience Reports (Impact Factor: 2.64). 03/2010; 30(4):243-55. DOI: 10.1042/BSR20090171
Source: PubMed


The eukaryotic cell cycle is a fundamental evolutionarily conserved process that regulates cell division from simple unicellular organisms, such as yeast, through to higher multicellular organisms, such as humans. The cell cycle comprises several phases, including the S-phase (DNA synthesis phase) and M-phase (mitotic phase). During S-phase, the genetic material is replicated, and is then segregated into two identical daughter cells following mitotic M-phase and cytokinesis. The S- and M-phases are separated by two gap phases (G1 and G2) that govern the readiness of cells to enter S- or M-phase. Genetic and biochemical studies demonstrate that cell division in eukaryotes is mediated by CDKs (cyclin-dependent kinases). Active CDKs comprise a protein kinase subunit whose catalytic activity is dependent on association with a regulatory cyclin subunit. Cell-cycle-stage-dependent accumulation and proteolytic degradation of different cyclin subunits regulates their association with CDKs to control different stages of cell division. CDKs promote cell cycle progression by phosphorylating critical downstream substrates to alter their activity. Here, we will review some of the well-characterized CDK substrates to provide mechanistic insights into how these kinases control different stages of cell division.

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Available from: Randy Suryadinata, Jul 15, 2014
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    • "In early G1 phase, Cyclin D binds to Cdk4 and/or Cdk6 to form cyclin-Cdk complexes, resulting in the activation of Cdks. Phosphorylation of Rb protein by the Cyclin D-Cdk4/6 complex in turn allows the expression of other cell cycle genes, such as Cyclin E. Association between Cyclin E and Cdk2 then leads to the phosphorylation and degradation of p27, allowing the transition from G1 to S phase [26], [27], [43]. The regulation of cyclins and Cdks expression by OEOA, together with the ability of OEOA to suppress RAMP expression, strongly suggest that OEOA inhibits proliferation of leukemia cells by modulating cell cycle protein expression. "
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    ABSTRACT: Oleanolic acid (3β-hydroxy-olea-12-en-28-oic acid) is a natural pentacyclic triterpenoic acid found in many fruits, herbs and medicinal plants. In the past decade, increasing evidence has suggested that oleanolic acid exhibits inhibitory activities against different types of cancer including skin cancer and colon cancer, but not leukemia. We report here that a derivative of oleanolic acid, olean-12-eno[2,3-c] [1], [2], [5]oxadiazol-28-oic acid (designated OEOA) effectively blocks the proliferation of human leukemia cells. OEOA significantly reduces cell proliferation without inducing cell death in three types of leukemia cell lines, including K562, HEL and Jurket. Moreover, exposure of K562 cells to OEOA results in G1 cell cycle arrest, with a concomitant induction of cyclin-dependent kinase inhibitor p27 and downregulation of cyclins and Cdks that are essential for cell cycle progression. Interestingly, OEOA also enhances erythroid differentiation in K562 cells through suppressing the expression of Bcr-Abl and phosphorylation of Erk1/2. These findings identify a novel chemical entity for further development as therapeutics against leukemia.
    PLoS ONE 05/2013; 8(5):e63580. DOI:10.1371/journal.pone.0063580 · 3.23 Impact Factor
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    • "The cell cycle in eukaryotic organisms is a very well-regulated process, divided in four phases: G1 (cell enlargement), S (DNA replication), G2 and M (cytokinesis) (Suryadinata et al., 2010). In general, cells from differentiated animal tissues, such as hepatocytes, are arrested in the G1 – S transition (Nelsen et al., 2003). "
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    ABSTRACT: During seed germination, metabolism is reactivated, DNA is repaired and cell division is restarted in the meristems. The mechanisms that co-ordinate cell growth and division in maize embryonic axes during germination are not well understood. However, the presence of a factor similar to IGF (insulin-like growth factor) that accelerates germination has been reported. In the present work, the regulation of the cell-cycle restart by bovine insulin [which has been demonstrated to produce similar effects as insulin-like growth factor of maize (ZmIGF) in maize seeds] was studied in germinating embryonic axes. Our results showed that bovine insulin differentially stimulates growth, S6K phosphorylation, S6rp transcript accumulation on the polysomal fraction, as well as de novo DNA synthesis in the radicles and the coleoptiles of the embryonic axis. A stronger and earlier effect was observed in radicles compared to coleoptiles; therefore, the effect of insulin on the cell cycle of the root meristem was studied by flow cytometry. The G1–S transition was stimulated and cell proliferation was induced. Furthermore, it was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) that bovine insulin increased E2F and PCNA (proliferating cell nuclear antigen) transcription after 15 h of germination and PCNA de novo synthesis at 15 h of germination. These results show that bovine insulin preferentially stimulates growth in the radicles of germinating embryonic axes and suggest that its effect on the G1–S transition and the activation of cell proliferation is mediated by the induction of E2F and PCNA transcription.
    Seed Science Research 03/2013; 23(01). DOI:10.1017/S0960258512000281 · 1.70 Impact Factor
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    • "The key cell cycle drivers are the Cyclin-dependent kinases (CDK), a family of serine/threonine kinases. Different CDKs play a role at different steps of the cell cycle: CDK2, 4, and 6 are active during G1, CDK2 during G1 and S phase and CDK1 during G2 and mitosis [8,9,10]. CDK activity is controlled by several mechanisms, which include the accumulation of the activating subunit Cyclin, the subcellular localization, CDK phosphorylation status, and CDK inhibitors (CKI). "
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    ABSTRACT: The maintenance of genome integrity is important for normal cellular functions, organism development and the prevention of diseases, such as cancer. Cellular pathways respond immediately to DNA breaks leading to the initiation of a multi-facetted DNA damage response, which leads to DNA repair and cell cycle arrest. Cell cycle checkpoints provide the cell time to complete replication and repair the DNA damage before it can continue to the next cell cycle phase. The G2/M checkpoint plays an especially important role in ensuring the propagation of error-free copies of the genome to each daughter cell. Here, we review recent progress in our understanding of DNA repair and checkpoint pathways in late S and G2 phases. This review will first describe the current understanding of normal cell cycle progression through G2 phase to mitosis. It will also discuss the DNA damage response including cell cycle checkpoint control and DNA double-strand break repair. Finally, we discuss the emerging concept that DNA repair pathways play a major role in the G2/M checkpoint pathway thereby blocking cell division as long as DNA lesions are present.
    12/2012; 2(4):579-607. DOI:10.3390/biom2040579
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