CELL CYCLE CONTROL

Cell proliferation and

its regulation
 Significance:
1. For the growth and development of a
multicellular organism, and for the
generation of offspring;
2. Produce new organisms in unicellular
species;
3. Renew the aging, apoptotic cells, and
damaged tissue;
Cell proliferation is one of the most important
characters for life
Overview of the cell
cycle
 The most basic function of the cell
cycle is to duplicate accurately the
vast amount of DNA in the
chromosomes and then segregate the
copies precisely into two genetically
identical daughter cells.
Cell cycle phases:

 Interphase: G1- S - G2

 M phase: Mitosis,
Cytokinesis
Different cell cycle length
Some eukaryotic cell cycle
times
Biochemical events of
cell cycle
 G1 phase: Cells synthesize proteins (RNA)
for the DNA replication. Uncondense
chromatin.
 S phase: Synthesis of DNA and Histones
 G2 phase: Synthesis of a few proteins
(RNA)
 M phase: Mitosis and cytokinesis
 Chromosome condense, Mitotic spindle,
Contractile ring
 Two daughter cells
Three categories of cells:
 (1)Cycling cells: Dividing continuously—
Stem cells
 (2)G0 cells: Do not divide normally, but
divide when given an appropriate stimulus:
liver cells, lymphocytes
 (3)Terminally differentiated cells: Highly
specialized, have lost the ability to divide
until they die: muscle cells, red blood cells,
nerve cells
Embryo cells can transform into Cycling
cells, G0 cells and Terminal cells.
Three principal checkpoints control the
cell cycle in eukaryotes
 Cell growth is assessed at the G1
checkpoint

 Located near the end of G1 this checkpoint makes

a key decision of whether the cell should divide,
delay division, or enter a resting stage.
 The cell begins to copy its DNA, initiating S phase
 The G1 checkpoint is where eukaryotes typically
arrest the cell cycle if environmental conditions
make cell division impossible, or if cell passes into
G0 for extended period.
The success in DNA replication is
assessed at G2 checkpoint

 The second checkpoint, which occurs at

the end of G2 triggers the start of M
phase. If this checkpoint is passed, the
cell initiates many molecular processes
that signal the mitosis.
 Mitosis is assessed at the M checkpoint.
Occuring at metaphase, the third checkpoint
triggers the exit from mitosis and cytokinesis
and the beginning of G1
Molecular Mechanisms of Cell Cycle
Control

 A set of proteins, sensitive to the

condition of the cell interact at the
checkpoints to trigger the next event of
the cell cycle

 Two key types of protein participate in

this interaction: cyclin- dependent protein
kinases and cyclins
The cyclin control
system
 Cyclin- dependent protein-kinases (Cdks) are
enzymes that phosphorylate ( add phosphate
group) to the serine and threonine amino acids
of important cellular enzymes and other
proteins
 At the G2 checkpoint Cdk phosphorylates
histones, nuclear membrane filaments and
microtubule accociated proteins that form
mitotic spindle
 Phosphorylation of these components initiates
activities that carry the cycle past the
checkpoint into mitosis
 Cyclins are proteins that bind to
Cdks, enabling the Cdks to function
as enzymes. Cyclins are so named
because they are destroyed and
resynthesized during each turn of the
cell cycle.
Cdk is a protein kinase that activates numerous
cell proteins by phosphorylating them. Cyclin is a
regulatory protein required to activate Cdk;
Cdk doesn’t function unless cyclin is bound to it.
The G2 checkpoint

 During G2 the cell gradually accumulates G2 cyclin.

This cyclin binds to Cdk to form a complex, called MPF
(mitosis promoting factor). At first, MPF is not active.
But eventually, other cellular enzymes phosphorylate
and activate a few molecules of MPF. The activated
MPFs in turn increase the activity of enzymes that
phosphorylate MPF, setting up a positive feedback that
leads to a very rapid increase in the cellular
concentration of activated MPF. When the level of MRF
exceeds the threshold necessary to trigger mitosis, G2
phase ends.
 The length of time the cell spends in M
phase is determined by the activity of
MPF, for one of its many functions is to
activate proteins that destroy cyclin. As
mitosis proceeds to the end of metaphase,
Cdk levels stay relatively constant, but
increasing the amounts of G2 cyclin are
degraded, causing progressively less
MRF to be available and so initiating the
events that end mitosis. After mitosis the
gradual accumulation of new cyclin starts
the next turn of the cell cycle
The G 1 Checkpoint

 The G1 checkpoint is thought to be regulated in

a similar manner. In unicellular organisms the
main factor, triggering DNA replication is cell
size. Yeast cells grow and divide as rapidly as
possible and they make start decision by
comparing the volume of cytoplasm to the size
of the genome. As a cell grows its cytoplasm
increases in size, while the amount of DNA
remains constant. Eventually the threshold
ratio is reached that promotes the production of
cyclins and this triggers next round of DNA
replication and cell division
As the cell cycle passes through the G 1 and G 2 checkpoints , Cdk
becomes associated with different cyclins and, as a result, activates
different cellular processes. At the completion of each phase, the
cyclins are degraded bringing Cdk activity to a halt until the next set
of cyclins appears.
 For cell division to take place in normal tissues,
number of conditions must be optimal:
 1. there must be available space for the new cell
 2. signals must be properly communicated
 3. the dividing cell must be attached to a surface

 Contact with neighboring cells suppresses cell

division in normal cells, a condition called contact
inhibition
 Normal cells receive signals of various
kinds from their external environment
and do not divide unless they receive
signals that send them out of the G0
resting stage and into the G1 phase of
the cell cycle.
 This signals are usually small
molecules, called growth factors,
secreted by other cells into the
spaces between cells. Like most
molecules, growth factors cannot
cross the cell membrane.
How growth factors signal cell division in normal
cells
 The multistep process that tells cells to divide is
shown
 The first messengers cytokines, bind to specific
receptors, molecules that extend through the
membrane of the cell.
 Binding of a growth factor to its specific receptor on
the exterior of the membrane changes the portion of
the receptor molecule that is on the interior of the
membrane.
 The changes are then passed along through the
cytoplasm to the nucleus of the cell by a network of
molecules, called second messengers.
 In response to second messengers, the
concentration of cyclins in the nucleus
change.
 The growth factor itself remains outside
the cell, but information has been
transmitted across the cellular
membraneand to the cell nucleus,
triggering cell division.
 Most cells have an additional requirement:
they divide only if they are attached to the
surface.
 A normal cell may be prevented from dividing
if loses the ability to adhere to external
surface.
 Even in the presence of growth factors, tissue
cells do not divide unless they are attached.
 The response of a cell to divide thus
depends on the presence and normal
functioning of signal molecules, receptors for
these signals, second messengers and cyclin
nuclear proteins, and attachment to an
external support .
 Normal cells of most tissues seem to have a limit to
the number of times that they can divide. After certain
number of divisions the cells die even when optimal
conditions exist. There seems to be a biological clock
that keeps track of the number of cell divisions.
 One candidate for this clock is the end portion of each
chromosome, called a telomere. Telomeres are
thought to function in maintaining the integrity of
chromosomes. Each time cell divides, a few dozen
base pairs are lost from the telomere. The
chromosome becomes progressively shorter on a
molecular scale, although it does not lose enough
length for this to be visible microscopically. When the
telomere has shortened to a certain length, the cell
can no longer divide.
 In bacteria and in the cells that produce
gametes in eucaryotes, an enzyme called
telomerase restores the bases lost from
telomeres, thus maintaining the length of the
chromosome. These cells can thus continue to
divide indefinitely.
 Telomerase is active in cancer cells. Cancer
cells have no limit to the number of times that
they can divide and are therefore considered
immortal.
Cancer results when cell
division is uncontrolled

 In cancer cells control of cell division has been lost.

 The process that a cell undergoes in changing from a
normal cell to an unregulated, less differentiated,
immortal cell is called transformation.
 The transformed state is passed to all progeny cells.
 Cancer can result from the transformation of just a
single cell.
 After cells have been transformed, they exhibit
many characteristics that differ from those of
normal cells.
 Characteristics of normal
cells and transformed cells
Cellular NORMAL TRANSORMED
behavior
Limit to a number of cell Finite No limit
divisions
Differentiation Present Inhibited
Nutrient requirement Slower Faster
Contact inhibition Present None
Requirement for attachment Present Low

Secretion of protein Low High

degrading enzymes
Genetic material Stable Unstable
 Cancer cells continue to divide indefinitely.
In many cases cancer cells are less
differentiated than the cells from which they
arose.
 Transformed cells are not inhibited by
contact with other cells. In tissue culture,
their growth doesn’t stop when they have
formed one –cell- thick monolayers, but
instead continues, forming piles of cells
growing over on top of each other.
 Cancer cells grow this way inside organisms,
and the growing piles of cells are called
tumors.
 Transformed cells grow without the need to be
attached.
 Cells become transformed when they are
dividing, cells that are terminally differentiated
and will never again divide cannot become
transformed, for example nerve cells in the
brain and muscle cells of the heart.
 In contrast, many types of cancer arise from
the transformation of stem cells (cells in
undifferentiated state).
 The genetic basis of cancer

 A transformed cell is a less differentiated

“immortal cell” that no longer responds to the
signals that normally regulate cell division and
cell differentiation. These signals have not
been completely identified, but this much
seems certain: cancerous growth signals are
aberrant forms of the normal growth signals,
and the aberration is located in the cell’s DNA.
 The normal growth regulatory genes fall
into two categories:
 Genese encoding proteins that promote
cell division (proto-oncogenes) and
genes whose protein products normally
inhibit cell division ( tumor suppressor
genes). Mutations in either type of
regulatory gene increase the probability
that cancer will arise.
Oncogenes and proto-
oncogenes
 The genes whose
products are the
growth factors,
receptors, second
messengers, and
cyclins are proto-
oncogenes
 Proto- oncogenes are genes whose products
signal and regulate normal cell division.
 The abnormal mutated forms of these proto-
oncogenes that lead to cell transformation and
cancer are called oncogenes.
 Oncogenes differ from proto- oncogenes in
any of three of basic ways: the timing and
quantity of their expression, the structure of
their protein-products, anee td the degree to
which their protein- products, and the degree
to which their protein products are regulated
by cellular signals. The expression of aproto-
oncogene responds to cellular controls, but
the expression of an oncogene does not.
 The protein product of an oncogene may differ
by as little as a sinlgle amino acid from the
protein product of a corresponding proto-
oncogene, but this small change in structure
can be enough to remove the protein from
control by the cell’s regulatory mechanism.
 The mutation of a protooncogene to an
oncogene can alter the cell division
signals at any of five steps an trigger
uncontrolled cell division. One type of
oncogene for a modified growth factor
receptor that, unlike its normal proto-
oncogene counterpart, continuously
activates second messengers ( thus
triggering cell division) without having
bound its usual growth factor cytokines.
 Another type of oncogene causes a cell to
secrete growth factors for which it has receptors,
allowing the cell to stimulate itself to divide
rather than needing signals from its neigbors.
 A third type of oncogene codes for altered
cellular second messenger molecules that carry
‘ activate cell division commands’ across the
cytoplasm in the absence of any growth factor
signal from outside the cell. Still other
oncogenes alter the regulatory steps inside the
nucleus , affecting the concentrations of cyclins
or of certain DNA-binding proteins.
 Tumor suppressor genes

 The protein products of tumor suppressor genes normally

repress cell division. If these genes are altered, their
repressor activity may be removed. Inactivation of cell
division repressor leads to cell division. A tumor
suppressor gene, p53, is mutated in as many as 55% of
noninherited cancers. When something goes wrong inside
a cell, the normal p53 protein halts cell division and
causes the abnormal cell to die. When the p53 gene is
mutated, the altered p53 protein doesn’t halt cell division,
and cells with damaged DNA continue to live and divide,
passing on their accumulated mutations to their progeny
cells