Running Head: Cell Cycle Progression: A Coordinated Act of Cyclins, Cdks and Checkpoints

Cell Cycle Progression: A Coordinated Act of Cyclins, Cdks and Checkpoints

Cell Cycle
Cell division takes place in the eukaryotic cells right from zygote formation till the cell
matures. For the cell division to take place a series of events occur which is called as "cell cycle"
which results in duplication of genome and seperation of complete sets of chromosomes. The cell
cycle includes three phases viz. interphase, mitosis and cytokinesis. Interphase in turn consists of
G1 (Gap 1), S, and G2 (gap 2). Although mitosis and cytokinesis are two different phases, they
happen in quick succession, that they are almost considered as the same.
G0 phase
This phase commonly refers to quiescent cells (cells which have stopped dividing). Senescence is
common for differentiated cells. Neurons for example are permanently in quiescent state. Exampes
of cells in semi-permanent senescence is liver and kidney cells.epithelial cells for example never
enter senescence state.
Interphase
This is the stage where nutrients required for cell division is accumulated. Interphase takes
about 90 percentage of the total time of the cell cycle. Interphase consists of three stages viz. G1,
S, and G2. In the S phase replication of DNA takes place.
G1 phase
The word G indicates Gap. It signifies the time period from the end of the M phase of the
previous cycle till the start of DNA transcription. Growth in number of orgenelles, supply of proteins
and size happens in this stage.
S phase
S phase starts with DNA replication. Here each chromosome is separated into two sister
chromatids. To avoid mutation, cells replicate as fast as possible.
G2 phase
The cells continue to grow after replication. The time period from the S phase to the Mitosis
is called as Gap 2.
Mitosis

Cell Cycle Progression: A Coordinated Act of Cyclins, Cdks and Checkpoints

The time period of Mitosis is very short. Nuclear division which is also called as karyokinesis
takes place in this phase. Mitosis again consists of five phases viz. prophase, metaphase,
anaphase, telophase and cytokinesis.
The cell division starts with the sister chromatids attaching itself to fibres in the opposite
ends of the cell (Maton, Anthea et al. 1997). Next cytokinesis takes place in which nuclei, orgelles
such as mitochondria etc. cytoplasm, and cell membranes are separated in equal share in to two
new cells. Mitosis is found to occur exclusively in eukaryotic cells.

Regulation of Cell Cycle

Cell cycle regulation mechanisms vary from cells to cells. Regulation mechanisms are
complex in complex organisms. However, many of the molecules that control cell cycle is found to
be common among most of the eukaryotic cells. Such molecules are cyclin-dependent kinases
(CDKs), cyclines, etc. Paul M. Nurse, Leland H. Hartwell, and R. Timothy Hunt won the 2001 Nobel
Prize in Medicine for the discovery of CDKs and cyclins.
Cyclins
Cyclins are proteins that act as catalysts for cyclin dependent kinase (CDK) enzymes.
Cyclins together with dependent kinases form maturation promoting factor. The concentration of the
cyclins increases or decreases through-out the cell cycle. Molecular level signals at specific points
of the cycle determine when cyclins are produced or broken down. The cyclins expressed in the G1
phase are called as cyclins D, whose presence signals the start of the new cell cycle. S Cyclins
such as Cyclin E which is produced during S phase induces DNA replication. M Cyclins i.e. Cyclin B
induces mitosis in cells.
Cyclin Dependent Kinases(CDKs)
CDKs are small proteins that are phosphorylated by cyclins at serine and threonine
substrates. Four CDKs viz. CDK1, 2, 3 and 4 are prominently involved in control cell cycle
mechanisms (Margon O. David, 2007). Kinases are inactive for most of the time. Only when they
combine with cyclins they become active. All the CDKs have ATP binding sites, which are present
as clefts in the protein structure. Without cyclin the T-loop covers the cleft, thereby inhibiting the
process.
The cyclin-CDK complexes follow the same activities as the cyclins in the individual phases.
Every cyclin-CDK complex has its own functions. The G1 cyclin-CDK complex, for example triggers
the cell to go into the Synthesis phase. This triggers the transcription factors to be expressed and
subsequently the synthesis of S cyclins. These enzymes are responsible for DNA replication. The
CDK complexes with S cyclin carry out phosphorylation reactions makes sure that the DNA is
replication only once. Phosphorylation and dephosphorylation by Wee1 and Myt1 kinases of the
CDKs control triggers in CDK/cyclin complex.

Cell Cycle Progression: A Coordinated Act of Cyclins, Cdks and Checkpoints

CDK inhibitory proteins

The CDKs are normally found with small inhibitory proteins and is very important for cell
cycle regulation (Sherr and Roberts, 1999). Three different proteins called as, p21Cip1, p27Kip1
and p57Kip2, are found to form the CDK inhibitory Proteins.
Maturation Promoting Factor
One of the most well-known CDK-cyclin complexes is the maturation promoting factor or
MPF. MPF is formed at the end of the Gap2 phase and triggers the cell's entry into the Mitosis
phase. MPF phosphorylates proteins and also activates them which trigger the dissolution of the
nuclear envelope. MPF concentration is higher in the metaphase of mitosis stage. But the
concentration drops in other stages for the cell to go through other stages. During anaphase, MPF
helps in degradation of cyclin. The increase/decrease in the concentration of MPF, itself acts as a
feedback system to control its own cycle. The absence of CDK results in the cell to entering
telophase, after which cell cycle continues normally.
The Rb/E2F
The interaction between cyclins, CDKs is an area of great interest for the scientists as the
understandings of these leads to better cancer treatments. The well-known tumor suppressor gene
pRb is involved in S phase of the cell cycle such as expression through transcription of cyclin E of S
cyclins. The pRb family proteins exert this activity through bonds with transcription factors such as
E2F/DP heterodimers (Stevaux and Dyson, 2002). These bonds prevent E2Fs activation from
catalysing transcription. To inhibit expression of genes repressive E2Fs bond with pRb protein
family.
Check-points
Checkpoints are mechanisms that makes sure if the cell division in eukaryotic cells has
happened without altercations. There are three checkpoints in the regulation cell cycle. These check
points are present at Gap1, M, and Gap2 phases. These checkpoints assess the damage to the
DNA. The checkpoint present in G1 phase is called as the restriction point which is controlled by
CDK inhibitor p16. The G2 checkpoint is activated by Cdc25. In the metaphase checkpoint the
Anaphase promoting complex, ensures cyclin B degradation, which initiates separation of sister
chromatids (Karp, Gerald (2005).

Conclusion
With modern methods available to study the cell mechanisms and gene expressions, the
scientific community has revealed a great deal of information which helps in understanding the
complexity of biological systems in minute levels. Still there is a lot to be studied and revealed as
the complexity of organisms increase, the need for sophisticated method of study also increases.

Cell Cycle Progression: A Coordinated Act of Cyclins, Cdks and Checkpoints

References
Karp, Gerald (2005). Cell and Molecular Biology: Concepts and Experiments (4th ed.).
Hoboken, New Jersey: John Wiley and Sons. pp. 5989.
Maton, Anthea; Hopkins, Jean Johnson, Susan LaHart, David, Quon Warner, David, Wright,
Jill D (1997). Cells: Building Blocks of Life. New Jersey: Prentice Hall. pp. 704.
Morgan, David O. (2007). The Cell Cycle: Principles of Control. London: New Science Press,
1st Ed.
Sherr, C.J., and Roberts, J.M. (1999). CDK inhibitors: positive and negative regulators of
G1-phase progression. Genes Dev. 13, 15011512.
Stevaux, O., and Dyson, N.J. (2002). A revised picture of the E2F transcriptional network
and RB function. Curr. Opin. Cell Biol. 14, 684691.