Transcript Cancer and the Cell Cycle

Cancer and the
Cell Cycle
Outline of the lecture
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What is cancer?
Review of the cell cycle and regulation of cell
growth
Which types of genes when mutated can 
cancer?
Roles for screening for mutations in specific
genes
Tumor suppressor p53
Have you figured it out?
Overview of Cancer
Cancer: Abnormal proliferation of cells forming cell masses
known as tumors.
Tumors
Benign
Slow growth rate
Malignant
Fast growth rate
Malignant Tumors
Malignant tumor cells have the
ability to travel through the
corporal fluids settling on other
tissues.
This process is known as metastasis.
From a single cell new tumors can arise
According to the American Cancer Society
25 % of deaths in U.S. are caused by cancer.
~ 564,630 Americans are expected to die of
cancers in 2006.
American Cancer Society (ACS): www:cancer.org
What is cancer?
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Cancer = uncontrolled proliferation of cells within
the body  tumor.
Tumor = clone of cells resulting from series of
sequential genetic mutations  loss of growth
control.
Cancer is also known as malignancy.
Development of cancer = oncogenesis
Study or treatment of cancer = oncology
Cancer is a multistep process.
Non-dividing cells
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This process continues, with each successive mutation
leading to a faster rate of cell division, slower rate of cell
death, and eventually loss of cell adhesion.
Review of the Eukaryotic Cell Cycle
The cell cycle
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The cell cycle has four phases:
 M,
during which the cell divides (undergoes
mitosis);
 G1, during which the cell grows larger;
 S , during which DNA synthesis occurs;
 G2, during which the cell continues to grow and
prepare for mitosis.
The cell cycle- regulation at several points
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G1 Restriction Point
 time
when the decision is made whether to
continue the cycle or to to exit the cycle in a
nondividing state called G0.
 Once the cell passes the restriction point in G1,
the cycle will continue until it is arrested at one
of several later checkpoints in response to
some problem that needs to be corrected.
The cell cycle- regulation at several points (cont’d.)
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Late G1 and late G2 checkpoints
If
DNA damage has occurred, these
checkpoints allow time for the damaged DNA
to be repaired before the cycle resumes.
Late G2 checkpoint also responds to the
presence of unreplicated DNA and prevents
mitosis from occurring until all of the DNA
has been copied.
In the event that a cell enters an S phase
with damaged DNA that can’t be repaired,
apoptosis may be triggered to prevent the
mutant cell from reproducing itself.
The cell cycle- regulation at several points (cont’d.)
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Late M phase checkpoint
Halts
the cell cycle until all of the
chromosomes are properly aligned.
What is G0 ?
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Cells in G0 may differentiate and assume
specialized functions.
A cell can remain in G0 indefinitely, or it may reenter the cell cycle in response to signals from
a variety of growth factors.
Seven levels of
regulation of
cell growth
An unrepaired
mutation in a gene
for a DNA-repair
protein, a cell-cycle
control protein, or
an anti-apoptosis
protein can
increase the
likelihood of a
cancer developing.
An Example of Cell Cycle
Regulation by a Serum Growth
Factor
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Cyclin D is made following the
binding of the serum growth factor
to its receptor and the ensuing
cascade of phosphorylations.
An Example of Cell Cycle Regulation by a
Serum Growth Factor
Where and what kinds
of mutations would lead
to permanent expression
of Cyclin D?
Phosphorylation of Rb is Regulated
in turn by Cyclin D
Genes whose
products move the
cell through S
phase.
Note multiple
examples of cell
cycle regulation
by tumor
suppressors
(white circles)
The Cell Cycle
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Cyclins, CDKs, and CDKIs
 Cyclins
and Cyclin Dependent Kinases
(CDKs) interact to move the cell cycle
forward.
 Cyclins, and Cdks act together as a dimer,
functioning as the regulatory and catalytic
subunits, respectively.
 Cyclins are degraded at the end of their
functional period, thus inactivating their
Cdk partner in the dimer.
 The assembly of the dimers is regulated by
other proteins.
The Cell Cycle
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Cyclins, CDKs, and CDKIs
 Cyclins,
CDKs, and cyclin dependent kinase
inhibitors, (CDKIs) interact to block phases
of the cycle.
Examples of Cell Cycle Regulation by a Serum
Growth Factor and by Tumor Suppressors
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Cyclin D associates with either Cdk4 or Cdk6.
P16 may block the assembly.
After assembly the Cdk becomes phosphorylated.
This may be blocked by either p21 or p27
The target of the active dimer is Rb1 which is bound to a
transcription factor called E2F.
The Rb1/E2F dimer blocks transcription of genes needed
to enter the S phase.
Phosphorylation of Rb results in its dissociation from E2F.
This results in activation of S phase genes.
 In addition to its ability to block the association of cyclin
D with a Cdk, P16 can also directly block the
phosphorylation of Rb.
Examples of Cell Cycle Regulation by Tumor
Suppressors
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P16, p21, and p27 are regulated by p53 (more on
this later) which blocks the cell cycle in the G1
phase if there is DNA damage.
P53, Rb1, p21, p16, and p27 are called tumor
supressors because their normal function is to
prevent the growth of cells with damaged DNA.
An Example of Cell Cycle Regulation by Tumor
Suppressors
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P53 also responds to unrepaired DNA damage by
triggering apoptosis (programmed cell death) of the
injured cell.
 P53
interacts with Bax, which, in turn activates
special enzymes called caspases.
 Bax
is member of the Bcl-2 family of proteins, but
unlike Bcl-2, which prevents apoptosis, Bax activates
apoptosis.
 Caspases
initiate a protease cascade that results in
digestion of the DNA.
 This ultimately leads to cell death.
Apoptosis –
in response to irreparable DNA damage
Bax
Note the role of
tumor suppressor
p53.
Which types of genes when mutated
can  cancer?
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Oncogenes = genes whose products turn DNA synthesis ON
Tumor suppressors/anti-oncogenes = genes whose products
turn DNA synthesis OFF
Genes whose products contribute to genomic stability, (e.g.)
repair DNA,
 limit synthesis to doubling the DNA content
 make sure DNA is completely doubled
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Genes whose products contribute to cell longevity
In each case, ask yourself: would the mutation contributing
to the development of cancer be an activating mutation or an
inactivating mutation?
Which types of genes when mutated
can  cancer?
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Oncogenes (turn DNA synthesis ON)
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In progression towards cancer, a gene for a protein that
normally stimulates DNA synthesis (proto-oncogene) is either
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consitutively expressed at high levels or
• Change in the regulation of the gene
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mutated such that protein product is constitutively active, i.e., can
not be inactivated
• Change in the protein for which the gene codes
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Note: be sure you can distinguish between these two types of
changes – in the regulation, or in the protein product itself.
Mutations in classes I-IV from Slide # 15 generally give rise to
dominantly active oncogenes.
 Examples: see next slide.
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Oncogenes
Which types of genes when mutated
can  cancer?
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Tumor suppressors/anti-oncogenes (turn DNA
synthesis OFF)
 In
the progression towards cancer, a gene for a
protein that normally inhibits DNA synthesis is either
 permanently
inactivated or
 mutated such that the protein product is inactive
 Mutations
in Class VI, cell-cycle control proteins, from
Slide #15.
 Examples:
 APC
inhibits Wnt gene product from activating myc
 Rb1 inhibits activation of transcription of DNA synthesis
genes
Which types of genes when mutated
can  cancer?
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Contributors to genomic stability
Some
tumor suppressors turn DNA synthesis
off when DNA is damaged.
The progression toward cancer occurs when a
gene for a protein which contributes to DNA
repair is
 permanently
inactivated or
 mutated such that protein product is inactive
Which types of genes when mutated
can  cancer?
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Contributors to genomic stability
Mutations
in repair genes increase likelihood
of mutations in proto-oncogenes and tumor
suppressors.
Examples:
 p53
gene product induces genes for DNA
repair
 MDM2 gene product destabilizes p53
 MutS and MutL gene products repair UV or
chemically damaged DNA
Which types of genes when mutated
can  cancer?
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Contributors to cell longevity (anti-apoptosis genes)
 Progression
toward cancer can occur when an antiapoptosis gene is
 constitutively
expressed or
 mutated such that protein product is constitutively
active
 Allows
survival of cells with oncogenic mutations
 Example: Bcl2
Roles for screening for mutations
in specific genes
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To determine
 Type
of cancer
 Familial predispositions
 Progression of the cancer