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Eukaryotic Cell Cycle: Cyclin Dependent Kinases (CDKs) (Research Paper Sample)


RESEArch on the role of cyclin dependent kinases (Cdk) and cyclin in the regulation of the eukaryotic cell cycle.


Eukaryotic Cell Cycle
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Eukaryotic Cell Cycle
In living organisms, the cell, which is the smallest entity exhibiting all the life characteristics, forms the primary functional unit. The reproduction of these cells takes place through the means of cell cycle which involves a series of events resulting into cell division to for two daughters. It is therefore essential to understand the operation of cell cycle and its control (Harashima et al 2013). Four coordinated processes take place during the division cycle of most cells; cell growth, replication of DNA, duplicated chromosomes’ distribution to the daughter cells, and lastly, cell division.
Conserved regulatory apparatus controls the progression between the cell cycle stages which, besides coordinating various cell cycle events also acts as a link between the cell cycle and the extracellular signals controlling the proliferation of the cells. The human cells in culture illustrates a typical eukaryotic cell. Division normally takes place approximately every one day leading to two basic parts being formed; mitosis, which is the stage of nuclear division, and interphase, which refers to the period between mitoses. The mitosis phase, covering approximately 5% of the cell cycle, only lasts about an hour. The interphase stage sees the chromosomes decondensed and also their distribution inside the entire nucleus making it morphologically uniform (Lim et al 2013).
Cyclin dependent kinases (CDKs)
Cyclin dependent kinases (CDKs) are the major eukaryotic cell cycle regulators. Cyclin-dependent kinases (CDKs) refer to the protein-serine kind of kinases known to be requiring activation by complexation from cyclin, a separate non-catalytic regulatory subunit that supplies the CDKs with domains crucial for enzymatic activity (Manning et al 2002). CDKs are essential when it comes to cell division control and transcription modulation in response to a variety of extra and intracellular cues (Malumbres et al 2009). These kinases take part in cell cycle control which functions to move the cycle of the cell from one phase to the nextThey are always available in the cell cycle except that their regulators’ (specific kinase inhibitors and cyclins) levels does not remain constant during the cell cycle. In humans, and some other animals, the CDKs present include CDK1 (CDC2), CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, and CDK8 (Malumbres et al 2005).
CDK regulatory mechanisms
CDK activity has been found to being governed by a number of mechanisms during the cell cycle control. The cyclin subunit binding to the CDK forms the primary CDK activation mechanism. For a complete activation to be realized, phosphorylation of most CDKs by enzyme CAK is required at a conserved threonine (Santamaria et al 2007).
Activation of CDK by cyclin binding
CDK activation requires a cyclin subunit to be associated with it despite the different complex variation in interaction of CDK-cyclin biochemical features. Interaction of some CDK-cyclin pairs like CDK2-cyclin E, CDK2-cyclin A, and CDC2-cyclin B, proceed with high affinity when other components or modifications are absent (Desai et al 1995). In some complexes like the CDK7-cyclin and CDC2-cyclin A complexes, unless the cyclin is phosphorylated during the threonine residue activation, they will not tightly bind (Fisher et al 1995). Binding can be promoted in CDK7-cyclin H, being an unusual case, by use of Mat1, a third subunit leading to the formation of a trimeric complex, CDK7-cyclin H-Mat1. This is an active trimeric complex and would still remain active even when phosphorylation is absent (Nigg 1996).
More mysterious CDK-cyclin interactions also do exist. Taking an example of CDK4 and cyclin D binding which need serum-stimulated assembly factors to interact. Some CDK-cyclin subset complexes require to be activated by phosphorylation (Kitagawa et al 1996). There are cases where little effect on activity is realized due to CDK-cyclin binding alone like CDC2-cyclin B and where high-affinity cyclin binding is not possible without phosphorylation like CDC2-cyclin A (Desai et al 1995). The enzyme used in the phosphorylation of CDKs, CAK, has been greatly applied in CDK7-cyclin H-Mat1 complex and was the major CAK activity in eukaryotes like starfish, frog, and mammalian cell lysates (Nigg 1996).
Regulation of Cyclins
There are two identified critical cyclin regulation sites: gene transcription and protein degradation. The close parallel between cyclin mRNA levels and proteins illustrates the regulatory importance of the subunit cyclin gene transcription in mammalian cells. In higher eukaryotes, the cell cycle-dependent transcription concentrates almost entirely on the G1/S transition (Nasmyth 1996). It has been found that a family of transcription factors, E2F, plays an important role in the transcription of the genes essential for synthesis of DNA. It also aid in the transcription stimulation of cyclin A, cyclin E, and E2F itself (Morgan).
The function of E2F is inhibited by the protein pRb, which, during G1 binds E2F and represses E2F-dependent gene transcription. CDK4-cyclin D complexes during late G1 trigger release of E2F through phosphorylation of specific sites subset on pRb (Connell-Crowley et al 1997). Increase in E2F and cyclin E transcription is also realized leading to CDK2-cyclin E further phosphorylating pRb. These results in a positive feedback loop giving rise to transcription of sudden increase in E2F-dependent accompanied by onset of S phase. Soon after this, the DNA-binding activity of CDK2-cyclin A complexes is abolished by itself due to its increasing levels in which it binds and phosphorylate E2F. This inhibitory phosphorylation cannot be performed by CDK2-cyclin E hence E2F will not be activated until initiation of the S phase is complete.
Levels of cyclin are also extensively controlled by regulated proteolysis. Cyclin degradation is essential in the exit from mitosis control in which case mitotic cyclin destruction is required in order to allow telophase onset and also aid in the preparation of the next cell cycle (King et al 1996). In early frog embryo, it is crucial to regulate the destruction of cyclin in cases where there is no transcription and constant cyclin synthesis exist in the entire cycle. Cyclin B, which is a vertebrate cyclin, is regulated at subcellular location level. The cyclin is seen to be maintaining its location in the cytoplasm during an increase in its levels in the S and G2 phases and undergoes a dramatic translocation just before mitosis into the nucleus.
The Cell Cycle Clock
The CDK-regulatory mechanisms are designed to effect rapid and persistent CDK-activity changes via positive feedback mechanism which speed up activity changes during critical threshold states in the cell cycle. A program-like interlinked action of CDK-cyclin complexes makes the cell cycle system more useful. With this in place, activity changes in on CDK-cyclin complex performs two critical functions: it triggers cell cycle events and at the same time initiates next CDK-cyclin complex activation in the series. This forms a sequence of CDK oscillations that are completely interdependent leading to the cell cycle clock hence the timing of events of the cell cycle.
In the frog embryo’s cell division, after destruction of cyclin and removal from mitosis, continuous synthesis of cyclin B results in the constant accumulation of cyclin B hence CDC2-cyclin B complexes. Phosphorylation at Thr14/Tyr15 initially restrains the accumulated complexes until the level of CDC2-cyclin B, a threshold level, where sufficient activity of CDC2, essential for phosphorylation of CDC25 and Wee 1 is available. This leads to their activation and inactivation respectively.
A rapid, irreversible activation of a great number of inactive CDC2-cyclin B complexes is realized owing to the system of positive feedback. At this point also, a rapid mitotic state transition is generated via nuclear import of CDC2-cyclin B. After the lag phase, irreversible destruction cyclin is initiated by the activation of CDC2-cycline B. Inhibition of CDC2 via the same feedback mechanism of CDC25-Wee 1 that generated its activation originally can also be induced through the declining activity of CDC2 (Tyson et al 1996). Timing of the cell cycle clock in simple cell cycles, like that of an early frog embryo, does not depend on the events of the cell cycle being regulated as seen through the continuous occurrence of CDK oscillations when synthesis of DNA or mitosis are absent. However, in somatic cell cycles, if there is no smooth progress of the events of cell cycle, the CDK oscillator can be stopped.
In mammalian cells, damage of the DNA during G1 initiates p53-dependent transcription of cyclin kinases inhibitor, p21. During G1, the damage of DNA in vertebrates leads to a delay in the onset of mitosis which is achieved through enhancement of inhibitory phosphorylation of CDC2-cyclin B complexes. These mechanisms see to it that interdependence exists between the events of the cell cycle and the cell cycle clock (Elledge 1996).
Different Cell Cycle Events from One CDK
In higher eukaryotes and at different cell cycle stages, different processes are found to being induced by a single CDK owing to the differences in specificity of the substrate conferred directly or indirectly by associated cyclin subunits on the CDK subunit (Kellogg et al 1994, Hoffman et al 1993). Premature...
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