DEPARTMENT OF BIOTECHNOLOGY
FACULTY OFENGINEERING & TECHNOLOGY
LT1. Cell cycle regulation
Content Outline
1. What is cell cycle?
2. Phases of cell cycle
3. The master regulator: Cyclin dependent kinase ( CdK)
4. Cell cycle checkpoints
5. Cell cycle regulation
6. Test your understanding
7. References & Further reading
What is cell cycle?
The cell cycle is the process a cell undertakes to replicate all of its material and divide into two
identical cells. In this article, we will look at the different stages of the cell cycle and what happens
in each stage.
Phases of the Cell Cycle
•The cell cycle is a 4-stage process consisting of Gap 1 (G1), Synthesis, Gap 2 (G2) and mitosis.
An active eukaryotic cell will undergo these steps as it grows and divides. After completing the
cycle, the cell either starts the process again from G1 or exits the cycle through G0. From G0, the
cell can undergo terminal differentiation.
•The stages in the cell cycle between one mitosis and the next, which include G1, S and G2, are
known collectively as the interphase.
G1 phase
Cell increases in size
Cellular contents duplicated
S phase
DNA replication
Each of the 46 chromosomes (23 pairs) is replicated by the cell
G2 phase
Cell grows more
Organelles and proteins develop in preparation for cell division
M phase
Mitosis followed by cytokinesis (cell separation)
Formation of two identical daughter cells
G0 phase
While some cells are constantly dividing, some cell types are at rest. These cells may exit G1 and
enter a resting state called G0. In G0, a cell is performing its function without actively preparing to
divide. G0 is a permanent state for some cells, while others may re-start division if they get the right
signals.
cyclins and cyclin-dependent kinases (CDKs) : The master regulator of cell
cycle
•CDKs are important master regulators of the cell cycle. Their role is to phosphorylate proteins on
either S or T amino acids and thereby regulate the activity of those proteins. Yeast have just one
CDK (Cdk1), while ‘metazoans’ (animals) like us have nine, of which four are really critical to the
cell cycle.
•The levels of these proteins remain pretty constant throughout the cell cycle, yet their levels of
activity rise and fall cyclically. CDKs need to hydrolize ATP for energy in order to perform
phosphorylation. They have an ATP binding cleft whose ability to bind ATP is regulated by two
mechanisms. First, CDKs have a ‘flexible T loop’ which contains a threonine (T) residue which
normally blocks the ATP binding cleft, but not when the T is phosphorylated. Second, cyclins bind
CDKs and induce a conformational change that also helps to expose the ATP binding
cleft. Therefore a fully active CDK is one which is both phosphorylated at the T on the T loop and is
bound to a cyclin.
The various activities of the cell cycle, then, are determined by the combination of cyclins and
CDKs that are active at each stage, as shown in the following table:
All cyclins contain a conserved 100 amino acid ‘cyclin box.’ Cyclin/CDK complexes regulate the cell
cycle both by promoting activites for their respective stages, and by inhibiting activites for future cell
cycle stages that must not yet be reached. Therefore cyclins must be able to be both
generated and degraded in order for the cell cycle to proceed.
Cell-Cycle checkpoints
•Cell proliferation is the process that results in an increase of the number of cells, and is defined by the balance
between cell divisions and cell loss through cell death or differentiation. ( Nature)
•Cell proliferation is regulated by a coordinated entry into the cell cycle
https://bio.libretexts.org/Bookshelves/Human_Biology/Book%3A_Human_Biology_(Wakim_and_Grewal)/07%3A
_Cell_Reproduction/7.2%3A_Cell_Cycle_and_Cell_Division
Regulation of cell cycle
•It is during G1 that the cell is particularly susceptible to control of cell cycle progression at a
number of restriction points, which determine whether the cell will re-enter the cycle, withdraw from
it, or withdraw and differentiate.
•Checkpoints at the beginning of DNA synthesis and in G2 determine the integrity of the DNA and
will halt the cell cycle to allow DNA repair or entry into apoptosis if repair is impossible
Control of proliferation is regulated by
extracellular factors as well as intracellular factors.
Extracellular factors is related to environmental
condition provided to cells.
Extracellular control are regulated by mitogenic
growth factors, such as epidermal growth factor
(EGF), fibroblast growth factors (FGFs), or platelet-
derived growth factor (PDGF).
Example of extracellular signal
•Low cell density permit entry of cells into cell cycle, or negative acting such as high cell density which signals
inhibition of proliferation of normal cells
Intracellular regulation of cell proliferation
•Intracellular control is mediated by positive-acting factors such as the cyclins.
•cell cycle progression are the cyclin-dependent kinases (CDKs). These are serine/threonine protein kinases that
phosphorylate key substrates to promote DNA synthesis and mitotic progression.
•Cyclin-binding allows inactive CDKs to adopt an active configuration akin to monomeric and active kinases.
•Negative-acting factors such as p53, p16 and p21 or the Rb gene product block cell cycle progression at
restriction points or checkpoints.
Role of regulatory gene elements in cell cycle regulations
p53: p53, also known as TP53 or tumor protein is a gene that codes for a protein that regulates the cell cycle and
hence functions as tumor suppression. If damaged DNA is detected at any checkpoint, activation of the checkpoint
results in increased protein p53 production. In the cell, p53 protein binds DNA, which in turn stimulates another
gene to produce a protein called p21 that interacts with a cell division-stimulating protein (cdk2). When p21 is
complexed with cdk2 the cell cannot pass through to the next stage of cell division.
p21: p21 mediates its various biological activities primarily by binding to and inhibiting the kinase
activity of the cyclin-dependent kinases (CDKs) CDK2 and CDK1 (also known as CDC2) leading to
growth arrest at G1/S phases in the cell cycle
pRb: The Rb protein is a tumor suppressor, which plays a pivotal role in the negative control of the
cell cycle and in tumor progression. It has been shown that Rb protein (pRb) is responsible for a
major G1 checkpoint, blocking S-phase entry and cell growth. t regulates cell growth and keeps
cells from dividing too fast or in an uncontrolled way.
Test your understanding
Which of the following statements regarding cyclin-dependent protein kinase is not correct?
a. Their activity is regulated by cyclins
b. They can alter the activity of proteins involve in the progression of cells through cell cycle
c. Their activity fluctuates during cell cycle
d. Each type of cell contains one specific form
Cdk2/cyclinE functions in ____________
a. G2/M transition
b. G2
c. M
d. G1/S transition
In which phase of cell cycle is DNA replicated
a. G1 phase
b. S phase
c. G2 phase
d. M phase
Cyclin dependent kinases which control progression through cell cycle checkpoints are totally activated by which
of the following?
a) Binding to cyclin, plus phosphorylation by a Cdk activating protein kinase
b) Binding to cyclins
c) Phosphorylation by Cdk activating protein kinase
d) Phosphorylation by a tyrosine kinase
At which cell cycle checkpoint, cell cycle is halted if cell’s DNA is damaged?
a) G1 – S
b) S – G2
c) G2 – M
d) G0 – G1
References & Further reading
References
1. https://www.cureffi.org/2013/04/06/cell-biology-08-cell-cycle-regulation-and-
checkpoints/https://www.bosterbio.com/protocol-and-troubleshooting/western-blot-principle
2. https://teachmephysiology.com/basics/cell-growth-death/cell-cycle/
3. http://www.wormbook.org/chapters/www_cellcyclereguln/cellcyclereguln.html
4. https://www.sciencedirect.com/topics/neuroscience/cell-cycle-regulation
Further reading
1. King R.J.B., Cancer Biology, Addision Wesley Longmann Ltd, U.K., 1996.
2. Ruddon.R.W., Cancer Biology, Oxford University Press, Oxford, 1995.
3. Maly B.W.J., Virology a practical approach, IRL press, Oxford, 1987.
4. Dunmock. N.J and Primrose S.B., Introduction to modern Virology, Blackwell Scientific Publications, Oxford,
1988.
