Cell cycle cyclin-dependent kinase

Cell cycle is one of the physiological processes in which the role of uhiquitin—proteasome-mediated proteolysis is well established. With the advent of yeast mutants that interfered with various phases of the cell cycle, cyclin-dependent kinases (Cdks) were found to have a critical role in regulating the cell cycle. Typically, Cdks activated hy regulatory proteins are known as cyclins. Different Cdk—cyclin complexes are formed at specific stages of the cell cycle such as the S-phase (in which DNA synthesis occurs) and the metaphase. The transition from metaphase to anaphase depends on degradation of cyclins. " " Systematic biochemical studies showed that cyclins were substrates for the uhiquitin—proteasome pathway (Table 5). 

In order to pass the different phases of the cell cycle, mammaUan cells require cyclin-dependent kinases (Cdks). These Cdks (Cdkl, Cdk2, Cdk4, and Cdk6) are serine/threonine protein kinases which are only catalytically active if regulatory molecules termed cyclins are bound. Cyclins received their name as they are synthesized and degraded during each cell cycle [14]. 

Cell Cycle Control. Figure 1 Cell cycle regulation by Cyclin dependent kinases (CDKs). Different cyclins bound to different CDKs promote the transition from one cell cycle phase into another. CDK-dependent phosphorylation of Rb is required to release active E2F transcription factors, which promotes entry into S phase. 

Figure 36-21. Schematic illustration of the points during the mammalian cell cycle during which the indicated cyclins and cyclin-dependent kinases are activated. The thickness of the various colored lines is indicative of the extent of activity.

Table 36-7. Cyclins and cyclin-dependent kinases involved in cell cycle progression.

Rosenblatt, J., Yong, G., and Morgan, D. O. (1992). Human cyclin-dependent kinase 2 is activated during the S and G2 phases of the cell cycle and associates with cyclin A. Proc. Natl. Acad. Sci. USA 89 2824-2828. 

Barres BA, Lazar MA, Raff MC 1994 A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development. Development 120 1097-1108 deNooij JC, Letendre MA, Hariharan IK 1996 A cyclin-dependent kinase inhibitor, Dacapo, is necessary for timely exit from the cell cycle during Drosophila embryogenesis. Cell 87 ... 

Durand B, Gao FB, Raff M 1997 Accumulation of the cyclin-dependent kinase inhibitor p27/ Kipl and the timing of oligodendrocyte differentiation. EMBO J 16 306-317 Durand B, Fero ML, Roberts JM, Raff MC 1998 p27Kipl alters the response of cells to mitogen and is part of a cell-intrinsic timer that arrests the cell cycle and initiates differentiation. Curr Biol 8 431-440... 

Hong Y, Roy R, Ambros V 1998 Developmental regulation of a cyclin-dependent kinase inhibitor controls postembryonic cell cycle progression in Caenorhabditis elegant. Development 125 3585—3597... 

Rani, C. S., Abe, A., Chang, Y., Rosenzweig, N., Saltiel, A. R., Radin, N. S., and Shayman, J. A., 1995, Cell cycle arrest induced by an inhibitor of glucosylceramide synthase. Correlation with cyclin-dependent kinases. J. Biol. Chem. 270 2859-2867. 

The cell cycle is a key process that recurs in a periodic manner. Early cell cycles in amphibian embryos are driven by a mitotic oscillator. This oscillator produces the repetitive activation of the cyclin-dependent kinase cdkl, also known as cdc2 [131]. Cyclin synthesis is sufficient to drive repetitive cell division cycles in amphibian embryonic cells [132]. The period of these relatively simple cell cycles is of the order of 30 min. In somatic cells the cell cycle becomes longer, with durations of up to 24 h or more, owing to the presence of checkpoints that ensure that a cell cycle phase is properly completed before the cell progresses to the next phase. The cell cycle goes successively through the phases Gl, S (DNA replication), G2, and M (mitosis) before a new cycle starts in Gl. After mitosis cells can also enter a quiescent phase GO, from which they enter Gl under mitogenic stimulation. 

The periodic recurrence of cell division suggests that globally the cell cycle functions like an autonomous oscillator. An extended model incorporating the sequential activation of the various cyclin-dependent kinases, followed by their inactivation, shows that even in the absence of control by cell mass, this sequence of biochemical events can operate as a limit cycle oscillator [145]. This supports the union of the two views of the cell cycle as dominoes and clock [146]. Because of the existence of checkpoints, however, the cell cycle stops at the end of certain phases before engaging in the next one. Thus the cell cycle looks more like an oscillator that slows down and makes occasional stops. A metaphor for such behavior is provided by the movement of the round plate on the table in a Chinese restaurant, which would rotate continuously under the movement imparted by the participants, were it not for frequent stops. 

HDAC inhibitors can also operate independent of p53. HDAC inhibitors are able to upregulate p21, a cyclin-dependent kinase. They can also target TOB-l,i< p27 P ," GADDTS. CYCLIN Bl, CYCLIN Dl, and CYCLIN A genes. Downregulation of genes such as can also be achieved by HDAC inhibitors. All of these contribute to cell cycle progression and apoptosis of the cancer/tumor cells. 

The second project on which I have been working recently, in collaboration with Michele Pagano, is the mode of the degradation of p27 . p27 is an inhibitor of mammalian G1 cyclin-dependent kinases such as Cdk2/cyclin E, which is responsible for driving cells fi om G1 to the S-phase of the cell cycle (reviewed in Sherr Roberts, 1999). Levels of p27... 

Cell Cycle Regulation by Cyclin-Dependent Kinases... 

Hengst, L., Dulic, V., Slingerland, J., Lees, E., and Reed, S. (1994). A cell cycle regulated inhibitor of cyclin-dependent kinases, Proc Natl Acad Sci USA 91, 5291-5295. 

Abstract Inhibitors of the kinases controlling the cell cycle have emerged as an important therapeutic modality for the treatment of cancer. Drug discovery efforts have focused on inhibitors of the cyclin-dependent kinases, the Aurora kinases, and Polo-like kinases. Agents for each kinase are now advancing in human clinical trials. In this review we will summarize the work in this area with special emphasis on the structural biology and structure-activity relationships developed for the many chemotypes explored. 

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