a compiled presentation on cell cycle.its check points and regulation

1. 1
The Cell Cycle,its check
points and regulation
Sanju Kaladharan.

2. 2
Phases of the Cell Cycle
• The cell cycle consists of
• Interphase – normal cell activity
• The mitotic phase – cell divsion
INTERPHASE
Growth
G 1
(DNA synthesis)
Growth
G2
CellDivsion

3. 3
Functions of Cell Division
20 µm100 µm 200 µm
(a) Reproduction. An amoeba,
a single-celled eukaryote, is
dividing into two cells. Each
new cell will be an individual
organism (LM).
(b) Growth and development.
This micrograph shows a
sand dollar embryo shortly after
the fertilized egg divided, forming
two cells (LM).
(c) Tissue renewal. These dividing
bone marrow cells (arrow) will
give rise to new blood cells (LM).

4. 4
Cell Division
•An integral part of the cell cycle
•Results in genetically identical daughter cells
•Cells duplicate their genetic material
•Before they divide, ensuring that each daughter cell
receives an exact copy of the genetic material, DNA

5. 5
DNA
• Genetic information - genome
• Packaged into chromosomes
50 µm
Figure 12.3

6. 6
DNA And Chromosomes
• An average eukaryotic cell has about 1,000 times more DNA then an
average prokaryotic cell.
• The DNA in a eukaryotic cell is organized into several linear
chromosomes, whose organization is much more complex than the
single, circular DNA molecule in a prokaryotic cell

7. 7
Chromosomes
• All eukaryotic cells store genetic information in chromosomes.
• Most eukaryotes have between 10 and 50 chromosomes in their body cells.
• Human cells have 46 chromosomes.
• 23 nearly-identical pairs

8. 8
Structure of Chromosomes• Chromosomes are composed of a complex of DNA and protein called
chromatin that condenses during cell division
• DNA exists as a single, long, double-stranded fiber extending
chromosome’s entire length.
• Each unduplicated chromosome contains one DNA molecule, which
may be several inches long

9. 9
Structure of ChromosomesEvery 200 nucleotide pairs, the DNA wraps twice around a group
of 8 histone proteins to form a nucleosome.
Higher order coiling and supercoiling also help condense and
package the chromatin inside the nucleus:

10. 10
5 µm
Pair of homologous
chromosomes
Centromere
Sister
chromatids
Karyotype• An ordered, visual representation of the chromosomes in a cell
• Chromosomes are photographed when they are highly condensed, then photos of the
individual chromosomes are arranged in order of decreasing size:
• In humans each somatic cell has 46 chromosomes, made up of two sets, one set of
chromosomes comes from each parent

11. 11
Chromosomes
•Non-homologous chromosomes
•Look different
•Control different traits
•Sex chromosomes
•Are distinct from each other in their
characteristics
•Are represented as X and Y
•Determine the sex of the individual, XX being
female, XY being male
•In a diploid cell, the chromosomes occur in pairs.
The 2 members of each pair are called homologous
chromosomes or homologues.

12. 12
Chromosomes• A diploid cell has two sets of each of its chromosomes
• A human has 46 chromosomes (2n = 46)
• In a cell in which DNA synthesis has occurred all the chromosomes are
duplicated and thus each consists of two identical sister chromatids
Maternal set of
chromosomes (n = 3)
Paternal set of
chromosomes (n = 3)
2n = 6
Two sister chromatids
of one replicated
chromosome
Two nonsister
chromatids in
a homologous pair
Pair of homologous
chromosomes
(one from each set)
Centromere

13. 13
Homologues
• Homologous chromosomes:
•Look the same
•Control the same traits
•May code for different forms of each trait
•Independent origin - each one was inherited from a
different parent

14. 14
Chromosome Duplication
• In preparation for cell division, DNA is replicated and the chromosomes condense
• Each duplicated chromosome has two sister chromatids, which separate during cell division
0.5 µm
Chromosome
duplication
(including DNA
synthesis)
Centromere
Separation
of sister
chromatids
Sister
chromatids
Centrometers Sister chromatids
A eukaryotic cell has multiple
chromosomes, one of which is
represented here. Before
duplication, each chromosome
has a single DNA molecule.
Once duplicated, a chromosome
consists of two sister chromatids
connected at the centromere. Each
chromatid contains a copy of the
DNA molecule.
Mechanical processes separate
the sister chromatids into two
chromosomes and distribute
them to two daughter cells.

15. 15
• Because of duplication, each condensed chromosome consists of 2
identical chromatids joined by a centromere.
• Each duplicated chromosome contains 2 identical DNA molecules
(unless a mutation occurred), one in each chromatid:
Chromosome Duplication
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Two unduplicated
chromosomes
Centromere
Sister
chromatids
Sister
chromatids
Duplication
Non-sister
chromatids
Two duplicated chromosomes

16. 16
Structure of Chromosomes
• The centromere is a constricted region of the chromosome containing a specific
DNA sequence, to which is bound 2 discs of protein called kinetochores.
• Kinetochores serve as points of attachment for microtubules that move the
chromosomes during cell division:
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Metaphase chromosome
Kinetochore
Kinetochore
microtubules
Centromere
region of
chromosome
Sister Chromatids

17. 17
Structure of Chromosomes• Diploid - A cell possessing two copies of each chromosome
(human body cells).
• Homologous chromosomes are made up of sister chromatids
joined at the centromere.
• Haploid - A cell possessing a single copy of each chromosome
(human sex cells).

18. 18
Phases of the Cell Cycle
• Interphase
• G1 - primary growth
• S - genome replicated
• G2 - secondary growth
• M - mitosis
• C - cytokinesis

19. 19
Interphase
• G1 - Cells undergo majority of growth
• S - Each chromosome replicates (Synthesizes) to
produce sister chromatids
•Attached at centromere
•Contains attachment site (kinetochore)
• G2- Chromosomes condense - Assemble machinery
for division such as centrioles

20. 20
Mitosis
Some haploid & diploid cells divide by mitosis.
Each new cell receives one copy of every chromosome
that was present in the original cell.
Produces 2 new cells that are both genetically identical
to the original cell.
DNA duplication
during interphase
Mitosis
Diploid Cell

21. 21
Mitotic Division of an Animal Cell
G2 OF INTERPHASE PROPHASE PROMETAPHASE
Centrosomes
(with centriole pairs) Chromatin
(duplicated)
Early mitotic
spindle
Aster
Centromere
Fragments
of nuclear
envelope
Kinetochore
Nucleolus Nuclear
envelope
Plasma
membrane
Chromosome, consisting
of two sister chromatids
Kinetochore
microtubule
Nonkinetochore
microtubules

22. 22
METAPHASE ANAPHASE TELOPHASE AND CYTOKINESIS
Spindle
Metaphase
plate Nucleolus
forming
Cleavage
furrow
Nuclear
envelope
formingCentrosome at
one spindle pole
Daughter
chromosomes
Mitotic Division of an Animal Cell

23. 23
G2 of Interphase
• A nuclear envelope bounds
the nucleus.
• The nucleus contains one or
more nucleoli (singular,
nucleolus).
• Two centrosomes have
formed by replication of a
single centrosome.
• In animal cells, each
centrosome features two
centrioles.
• Chromosomes, duplicated
during S phase, cannot be
seen individually because
they have not yet condensed.
The light micrographs show dividing lung cells
from a newt, which has 22 chromosomes in
its somatic cells (chromosomes appear blue,
microtubules green, intermediate filaments
red). For simplicity, the drawings show only
four chromosomes.
G2 OF INTERPHASE
Centrosomes
(with centriole pairs) Chromatin
(duplicated)
Nucleolus Nuclear
envelope
Plasma
membrane

24. 24
Prophase
• The chromatin fibers become
more tightly coiled, condensing
into discrete chromosomes
observable with a light
microscope.
• The nucleoli disappear.
• Each duplicated chromosome
appears as two identical sister
chromatids joined together.
• The mitotic spindle begins to form.
It is composed of the centrosomes
and the microtubules that extend
from them. The radial arrays of
shorter microtubules that extend
from the centrosomes are called
asters (“stars”).
• The centrosomes move away from
each other, apparently propelled
by the lengthening microtubules
between them.
PROPHASE
Early mitotic
spindle
Aster
Centromere
Chromosome, consisting
of two sister chromatids

25. 25
Metaphase
• Metaphase is the longest stage of
mitosis, lasting about 20 minutes.
• The centrosomes are now at
opposite ends of the cell.
•The chromosomes convene on the
metaphase plate, an imaginary
plane that is equidistant between
the spindle’s two poles. The
chromosomes’ centromeres lie on
the metaphase plate.
• For each chromosome, the
kinetochores of the sister
chromatids are attached to
kinetochore microtubules coming
from opposite poles.
• The entire apparatus of
microtubules is called the spindle
because of its shape.
METAPHASE
Spindle
Metaphase
plate
Centrosome at
one spindle pole

26. 26
The Mitotic Spindle
• The spindle includes the centrosomes, the spindle
microtubules, and the asters
• The apparatus of microtubules controls chromosome
movement during mitosis
• The centrosome replicates, forming two centrosomes
that migrate to opposite ends of the cell
• Assembly of spindle microtubules begins in the
centrosome, the microtubule organizing center
• An aster (a radial array of short microtubules) extends
from each centrosome

27. 27
The Mitotic Spindle• Some spindle microtubules attach to the kinetochores of
chromosomes and move the chromosomes to the metaphase
plate
• In anaphase, sister chromatids separate and move along the
kinetochore microtubules toward opposite ends of the cell
Microtubules Chromosomes
Sister
chromatids
Aster
Centrosome
Metaphase
plate
Kineto-
chores
Kinetochore
microtubules
0.5 µm
Overlapping
nonkinetochore
microtubules
1 µmCentrosome

28. 28
Anaphase
• Anaphase is the shortest stage of
mitosis, lasting only a few minutes.
• Anaphase begins when the two sister
chromatids of each pair suddenly part.
Each chromatid thus becomes a full-
fledged chromosome.
• The two liberated chromosomes begin
moving toward opposite ends of the cell,
as their kinetochore microtubules
shorten. Because these microtubules are
attached at the centromere region, the
chromosomes move centromere first (at
about 1 µm/min).
• The cell elongates as the
nonkinetochore microtubules lengthen.
• By the end of anaphase, the two ends of
the cell have equivalent—and
complete—collections of chromosomes.
ANAPHASE
Daughter
chromosomes

29. 29
Telophase
• Two daughter nuclei begin to
form in the cell.
• Nuclear envelopes arise from
the fragments of the parent
cell’s nuclear envelope and
other portions of the
endomembrane system.
• The chromosomes become
less condensed.
• Mitosis, the division of one
nucleus into two genetically
identical nuclei, is now
complete.
TELOPHASE AND CYTOKINESIS
Nucleolus
forming
Cleavage
furrow
Nuclear
envelope
forming

30. 30
Mitosis in a plant cell
1 Prophase.
The chromatin
is condensing.
The nucleolus is
beginning to
disappear.
Although not
yet visible
in the micrograph,
the mitotic spindle is
staring to from.
Prometaphase.
We now see discrete
chromosomes; each
consists of two
identical sister
chromatids. Later
in prometaphase, the
nuclear envelop will
fragment.
Metaphase. The
spindle is complete,
and the chromosomes,
attached to microtubules
at their kinetochores,
are all at the metaphase
plate.
Anaphase. The
chromatids of each
chromosome have
separated, and the
daughter chromosomes
are moving to the ends
of cell as their
kinetochore
microtubles shorten.
Telophase. Daughter
nuclei are forming.
Meanwhile, cytokinesis
has started: The cell
plate, which will
divided the cytoplasm
in two, is growing
toward the perimeter
of the parent cell.
2 3 4 5
Nucleus
Nucleolus
ChromosomeChromatine
condensing

31. 31
Cytokinesis
• Cleavage of cell into two
halves
– Animal cells

Constriction belt of
actin filaments
– Plant cells

Cell plate
– Fungi and protists

Mitosis occurs
within the nucleus

32. 32
Cytokinesis In Animal And Plant Cells
Daughter cells
Cleavage furrow
Contractile ring of
microfilaments
Daughter cells
100 µm
1 µmVesicles
forming
cell plate
Wall of
patent cell Cell plate
New cell wall
(a) Cleavage of an animal cell (SEM) (b) Cell plate formation in a plant cell (SEM)

33. 33

34. 34
Genome
•The genome is all the DNA in a cell.
•All the DNA on all the chromosomes
•Includes genes, intergenic sequences, repeats
•Specifically, it is all the DNA in an organelle.
•Eukaryotes can have 2-3 genomes
•Nuclear genome
•Mitochondrial genome
•Plastid genome
•If not specified, “genome” usually refers to the
nuclear genome.

35. 35
Cell cycle regulation

36. 36
Check points
• A checkpoint is a stage in the
eukaryotic cell cycle at which the
cell examines internal and
external cues and "decides"
whether or not to move forward
with division.
• There are a number of
checkpoints, but the three most
important ones are:
• The G1 check point atG1/S
transition
• The G2 checkpoints at G2/M
transition
• The spindle checkpoint, at the
transition from metaphase to
anaphase.

37. 37
G1 checkpoint
• The G1 checkpoint is the main
decision point for a cell – that is,
the primary point at which it
must choose whether or not to
divide.
• Once the cell passes the
G1 checkpoint and enters S
phase, it becomes irreversibly
committed to division.
• That is, barring unexpected
problems, such as DNA damage
or replication errors, a cell that
passes the G1 will continue the
rest of the way through the cell
cycle and produce two daughter
cells.

38. 38
• At the G1 checkpoint, a cell checks whether internal and external
conditions are right for division. Here are some of the factors a cell
might assess:
• Size. Is the cell large enough to divide?
• Nutrients. Does the cell have enough energy reserves or available
nutrients to divide?
• Molecular signals. Is the cell receiving positive cues (such as growth
factors) from neighbors?
• DNA integrity. Is any of the DNA damaged?
• If a cell doesn’t get the go-ahead cues it needs at the G1 checkpoint,
it may leave the cell cycle and enter a resting state called G0. Some
cells stay permanently in G0 , while others resume dividing if
conditions improve.

39. 39
G2 checkpoint
• To make sure that cell division
goes smoothly (produces
healthy daughter cells with
complete, undamaged DNA),
the cell has an additional
checkpoint before M phase,
called the G2 checkpoint. At this
stage, the cell will check:
• DNA integrity. Is any of the DNA
damaged?
• DNA replication. Was the DNA
completely copied during S
phase?

40. 40
• If errors or damage are detected, the cell will pause at the G2
checkpoint to allow for repairs.
• If the checkpoint mechanisms detect problems with the DNA, the
cell cycle is halted, and the cell attempts to either complete DNA
replication or repair the damaged DNA.
• If the damage is irreparable, the cell may undergo apoptosis, or
programmed cell.
• This self-destruction mechanism ensures that damaged DNA is not
passed on to daughter cells and is important in preventing cancer.

41. 41
The spindle checkpoint
• The M checkpoint is also known
as the spindle checkpoint: here,
the cell examines whether all
the sister chromatids are
correctly attached to the
spindle microtubules.

42. 42
• Because the separation of the sister chromatids during anaphase is
an irreversible step, the cycle will not proceed until all the
chromosomes are firmly attached to at least two spindle fibers from
opposite poles of the cell.
• It seems that cells don't actually scan the metaphase plate to
confirm that all of the chromosomes are there. Instead, they look for
"straggler" chromosomes that are in the wrong place (e.g., floating
around in the cytoplasm.
• If a chromosome is misplaced, the cell will pause mitosis, allowing
time for the spindle to capture the stray chromosome.

43. 43
Cell cycle regulators
• Growth factors stimulate the production of signals of
• two types:
• 1. Positive regulators of the cell cycle that control the
• changes necessary for cell division.
• 2. Negative regulators that control the positive regulators.

44. 44
POSITIVE REGULATORS OF THE
CELL CYCLE
• The cycle starts when a growth factor acts on a quiescent cell,
provoking it to divide.
• Growth factors stimulate production of the cell cycle regulators,
which are coded for by the delayed response genes.
• Two families of proteins, cyclins and cyclin-dependent kinases (cdks),
control progress through the cycle.
• The cdks, functioning sequentially, phosphorylate various proteins
(e.g. enzymes)—activating some and inhibiting others—to coordinate
their activities.

45. 45
• Cyclins are among the most important core cell cycle regulators.
Cyclins are a group of related proteins, and there are four basic types
found in humans and most other eukaryotes:
• G1 Cyclins,G1/S cyclins, S cyclins, and M cyclins.
• As the names suggest, each cyclin is associated with a particular
phase, transition, or set of phases in the cell cycle and helps drive the
events of that phase or period.
• For instance, M cyclin promotes the events of M phase, such as
nuclear envelope breakdown and chromosome condensation

46. 46

47. 47
Cyclin-dependent kinases
• In order to drive the cell cycle forward, a cyclin must activate or
inactivate many target proteins inside of the cell.
• Cyclins drive the events of the cell cycle by partnering with a
family of enzymes called the cyclin-dependent kinases(Cdks).
• A lone Cdk is inactive, but the binding of a cyclin activates it,
making it a functional enzyme and allowing it to modify target
proteins.

48. 48
• Cdks are kinases, enzymes that phosphorylate (attach phosphate
groups to) specific target proteins.
• The attached phosphate group acts like a switch, making the
target protein more or less active.
• When a cyclin attaches to a Cdk, it has two important effects: it
activates the Cdk as a kinase, but it also directs the Cdk to a
specific set of target proteins, ones appropriate to the cell cycle
period controlled by the cyclin.
• For instance, G1/S cyclins send Cdks to S phase targets (e.g.,
promoting DNA replication), while M cyclins send Cdks to M phase
targets (e.g., making the nuclear membrane break down).

49. 49

50. 50
• In general, Cdk levels remain relatively constant across the cell cycle,
but Cdk activity and target proteins change as levels of the various
cyclins rise and fall.
• In addition to needing a cyclin partner, Cdks must also be
phosphorylated on a particular site in order to be active, and may
also be negatively regulated by phosphorylation of other sites.

51. 51
Maturation-promoting factor (MPF)
• A famous example of how cyclins and Cdks work together to control
cell cycle transitions is that of maturation-promoting factor (MPF).
•
• ike a typical cyclin, M cyclin stays at low levels for much of the cell
cycle, but builds up as the cell approaches the G2/M transition.
• As M cyclin accumulates, it binds to Cdks already present in the cell,
forming complexes that are poised to trigger M phase.
• Once these complexes receive an additional signal (essentially, an
all-clear confirming that the cell’s DNA is intact), they become active
and set the events of M phase in motion

52. 52
The MPF complexes add phosphate tags to several different
proteins in the nuclear envelope, resulting in its breakdown (a key
event of early M phase), and also activate targets that promote
chromosome condensation and other M phase events.

53. 53
The anaphase-promoting
complex/cyclosome (APC/C)
• In addition to driving the events of M phase, MPF also triggers its
own destruction by activating the anaphase-promoting
complex/cyclosome(APC/C), a protein complex that causes M cyclins
to be destroyed starting in anaphase.
• The destruction of M cyclins pushes the cell out of mitosis, allowing
the new daughter cells to enter G1.
• The APC/C also causes destruction of the proteins that hold the sister
chromatids together, allowing them to separate in anaphase and
move to opposite poles of the cell.

54. 54
• Like a Cdk, the APC/C is an enzyme, but it has different type of
function than a Cdk. Rather than attaching a phosphate group to its
targets, it adds a small protein tag called ubiquitin (Ub).
• When a target is tagged with ubiquitin, it is sent to the proteasome,
which can be thought of as the recycle bin of the cell, and destroyed.
•
• For example, the APC/C attaches a ubiquitin tag to M cyclins, causing
them to be chopped up by the proteasome and allowing the newly
forming daughter cells to enter G1 phase.

55. 55
• The APC/C also uses ubiquitin tagging to trigger the separation of
sister chromatids during mitosis. If the APC/C gets the right signals at
metaphase, it sets off a chain of events that destroys cohesin, the
protein glue that holds sister chromatids together
• The APC/C first adds a ubiquitin tag to a protein called securin,
sending it for recycling. Securin normally binds to, and inactivates, a
protein called separase.
• When securin is sent for recycling, separase becomes active and can
do its job. Separase chops up the cohesin that holds sister
chromatids together, allowing them to separate.

56. 56

57. 57
NEGATIVE REGULATORS OF THE
CELL CYCLE
• One of the main negative regulators is the Rb protein that—while it
is hypophosphorylated—holds the cycle in check. Inhibitors of the
cdks also serve as negative regulators, their main action being at
check point 1.
• There are two families of inhibitors:
1. The CIP family (cdk inhibitory proteins, also termed KIP or kinase
inhibitory proteins)—proteins p21, p27 and p57.
2. The Ink family (inhibitors of kinases)—proteins p16, p19 and p15.
• The action of p21 serves as an example of the role of a cyclin/cdk
inhibitor.
• Protein p21 is under the control of the p53 gene—a particularly
important negative regulator which is relevant in carcinogenesis—
that operates at check point 1.

58. 58

59. 59

60. 60
Checkpoints and regulators
• Cdks, cyclins, and the APC/C are direct regulators of cell cycle
transitions, but they aren’t always in the driver’s seat. Instead, they
respond to cues from inside and outside the cell.
• These cues influence activity of the core regulators to determine
whether the cell moves forward in the cell cycle.
• Positive cues, like growth factors, typically increase activity of Cdks
and cyclins, while negative ones, like DNA damage, typically decrease
or block activity.
•

61. 61
• As an example, let's examine how DNA damage halts the cell cycle in
G1.
• DNA damage can, and will, happen in many cells of the body during
a person’s lifetime (for example, due to UV rays from the sun).
• Cells must be able to deal with this damage, fixing it if possible and
preventing cell division if not.
• Key to the DNA damage response is a protein called p53, a famous
tumor suppressor often described as “the guardian of the genome.”

62. 62
• p53 works on multiple levels to ensure that cells do not pass on their
damaged DNA through cell division.
• First, it stops the cell cycle at the G1 checkpoint by triggering
production of Cdk inhibitor (CKI) proteins.
• The CKI proteins bind to Cdk-cyclin complexes and block their activity
(see diagram below), buying time for DNA repair. p53's second job is
to activate DNA repair enzymes.
• If DNA damage is not fixable, p53 will play its third and final role:
triggering programmed cell death so damaged DNA is not passed on.

63. 63

64. 64
• By ensuring that cells don't divide when their DNA is damaged, p53
prevents mutations (changes in DNA) from being passed on to
daughter cells.
• When p53 is defective or missing, mutations can accumulate quickly,
potentially leading to cancer.
• Indeed, out of all the entire human genome, p53 is the single gene
most often mutated in cancers
• p53 and cell cycle regulation are key topics of study for researchers
working on new treatments for cancer

65. 65
cancer
Cancer cells manifest, to varying degrees, four characteristics that
distinguish them from normal cells. These are:
• uncontrolled proliferation
• dedifferentiation and loss of function
• invasiveness
• metastasis.

66. 66

67. 67
Cell cycle regulators and cancer

68. 68
• In general, however, mutations of two types of cell cycle regulators
may promote the development of cancer: positive regulators may be
overactivated (become oncogenic), while negative regulators, also
called tumor suppressors, may be inactivated.

69. 69
Oncogenes
• Positive cell cycle regulators may be overactive in cancer.
• For instance, a growth factor receptor may send signals even when
growth factors are not there, or a cyclin may be expressed at
abnormally high levels.
• The overactive (cancer-promoting) forms of these genes are
called oncogenes, while the normal, not-yet-mutated forms are
called proto-oncogenes.
• This naming system reflects that a normal proto-oncogene can turn
into an oncogene if it mutates in a way that increases its activity.

70. 70
• Mutations that turn proto-oncogenes into oncogenes can take
different forms.
• Some change the amino acid sequence of the protein, altering its
shape and trapping it in an “always on” state.
• Others involve amplification, in which a cell gains extra copies of a
gene and thus starts making too much protein.
• In still other cases, an error in DNA repair may attach a proto-
oncogene to part of a different gene, producing a “combo” protein
with unregulated activity

71. 71

72. 72
• Many of the proteins that transmit growth factor signals are encoded
by proto-oncogenes.
• Normally, these proteins drive cell cycle progression only when
growth factors are available.
• If one of the proteins becomes overactive due to mutation,
however, it may transmit signals even when no growth factor is
around.
• In the diagram above, the growth factor receptor, the Ras protein,
and the signaling enzyme Raf are all encoded by proto-oncogenes

73. 73
• Overactive forms of these proteins are often found in cancer cells.
• For instance, oncogenic Ras mutations are found in about 90% of
pancreatic cancers
• .
• Ras is a G protein, meaning that it switches back and forth
between an inactive form (bound to the small molecule GDP) and
an active form (bound to the similar molecule GTP).
• Cancer-causing mutations often change Ras’s structure so that it
can no longer switch to its inactive form, or can do so only very
slowly, leaving the protein stuck in the “on” state

74. 74
Tumor suppressors
• Negative regulators of the cell cycle may be less active (or even
nonfunctional) in cancer cells.
• For instance, a protein that halts cell cycle progression in
response to DNA damage may no longer sense damage or trigger
a response. Genes that normally block cell cycle progression are
known as tumor suppressors.
• Tumor suppressors prevent the formation of cancerous tumors
when they are working correctly, and tumors may form when they
mutate so they no longer work.

75. 75
• One of the most important tumor suppressors is tumor protein
p53, which plays a key role in the cellular response to DNA
damage. p53 acts primarily at G1 checkpoint controlling G1/s
transition, where it blocks cell cycle progression in response to
damaged DNA and other unfavorable conditions
• When a cell’s DNA is damaged, a sensor protein activates p53,
which halts the cell cycle at the G1 checkpoint by triggering
production of a cell cycle inhibitor.
• This pause buys time for DNA repair, which also depends on p53,
whose second job is to activate DNA repair enzymes.
• If the damage is fixed, p53 will release the cell, allowing it to
continue through the cell cycle.
• If the damage is not fixable, p53 will play its third and final role:
triggering apoptosis (programmed cell death) so that damaged
DNA is not passed on.

76. 76

77. 77
• In cancer cells, p53 is often missing, nonfunctional, or less active than
normal.
• For example, many cancerous tumors have a mutant form of p53
that can no longer bind DNA.
• Since p53 acts by binding to target genes and activating their
transcription, the non-binding mutant protein is unable to do its job

78. 78
• When p53 is defective, a cell with damaged DNA may proceed with
cell division.
• The daughter cells of such a division are likely to inherit mutations
due to the unrepaired DNA of the mother cell.
• Over generations, cells with faulty p53 tend to accumulate
mutations, some of which may turn proto-oncogenes to oncogenes
or inactivate other tumor suppressors.
• p53 is the gene most commonly mutated in human cancers, and
cancer cells without p53 mutations likely inactivate p53 through
other mechanisms (e.g., increased activity of the proteins that cause
p53 to be recycled)

79. 79
Thank you