Transcript Chapter 12 Presentation-The Cell Cycle

The Cell Cycle Gone Awry
Cancer and Mitosis
Cancer Cells
• Mutagens give rise to cancer cells.
• There are a wide variety of mutagens
which cause changes to our DNA:
• Chemicals
• UV radiation
• Ionizing radiation
• Mutations can also arise spontaneously
due to cellular errors.
Cancer Cells
• Cancer cells don’t respond normally to the
body’s control mechanisms.
• They don’t heed the normal signals which
regulate the cell cycle.
• Some don’t need growth factors to grow
and divide, while other cancer cells even
make their own.
Cancer Cells
• Many cancer cells also fails to exhibit
what is known as density dependent
inhibition--an external physical factor
regarding mitosis that stops the division
of crowded cells.
Cancer Cells
• Normal cells usually divide 20-50x in the
process of aging and then die.
• Cancer cells are seemingly immortal
because they will continue to divide
forever if they are given a continuous
supply of nutrients.
• HeLa cells.
Cancer Cells
• Cancer cells have a high mitotic index.
That is with cancer, there are often more
cells undergoing mitosis compared to the
number not undergoing mitosis.
Metastasis
• Primary tumors are the original tumor in
the organism.
• From there, tumors metastasize, or
spread to other parts of the body where
they form new, secondary tumors.
Cancer Development
• There is a multistep model that explains
cancer development.
• Numerous changes must occur in the DNA
in order for a cell to become cancerous.
• But before we begin, there are a few
terms we need to discuss.
Cancer Cells
• These terms will help you to understand
what’s going on.
• Apoptosis
• Gate Keepers (Promoters)
• Caretakers
• p53
• Oncogene
• Proto-oncogene
• Tumor Suppressor Genes
Apoptosis
• Apoptosis is programed cell death, and is
a normal process that occurs in living
organisms.
Gate Keepers and Caretakers
• There are 2 general groups of tumor
suppressor genes:
• Gate Keepers (Promoters)
• Caretakers
Gate Keepers and Caretakers
• Gate Keepers act as “a set of breaks” on
cellular proliferation.
• Caretaker genes are genes whose
products protect the integrity of the
genome by repairing damaged DNA.
Gate Keepers and Caretakers
• When gate keeper genes mutate or are
damaged, they lose their ability to
regulate cell division, kick-start repair
mechanisms, or both.
• Mutations in these genes, therefore, allow
mutations in other areas of the genome
go unchecked, potentially giving rise to
tumors.
Gate Keepers and Caretakers
• When caretaker genes mutate or are
damaged, they lose their ability to repair
DNA damage (or care for the genome).
• Thus, mutations in other areas of the
genome accumulate and often give rise to
tumors.
• BRCA1 and BRCA2 genes.
BRCA1 17q21: This gene encodes a nuclear phosphoprotein that plays a role in maintaining genomi
Inherited mutations in BRCA1 and this gene, BRCA2, confer increased
stability, and it also acts as a tumor suppressor. The encoded protein combines with other tumor
eloping breast or ovarian cancer. Both BRCA1 and BRCA2 are
suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein
nance of genome stability, specifically the homologous recombination
complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product
e-strand DNA repair. The BRCA2 protein contains several copies ofassociates
a
with RNA polymerase II, and through the C-terminal domain, also interacts with histone
the BRC motif, and these motifs mediate binding to the RAD51
deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded
h functions in DNA repair. BRCA2 is considered a tumor suppressor
breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited
ith BRCA2 mutations generally exhibit loss of heterozygosity (LOH)breast
of
cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays
p53
• p53 is a tumor suppressor gene known as
the “guardian of the genome”-it acts as a
gate keeper.
• The p53 gene makes p53 protein which does
many different things.
•It can arrest cell proliferation by holding the cell
cycle at the G1/S checkpoint when DNA damage is
p53 17q13.1: This gene encodes a tumor suppressor protein containing
recognized.
transcriptional activation, DNA binding, and oligomerization domains. The encoded
protein responds to diverse cellular stresses to regulate expression of target genes,
thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in
metabolism. Mutations in this gene are associated with a variety of human cancers,
including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of
this gene and the use of alternate promoters result in multiple transcript variants and
isoforms. Additional isoforms have also been shown to result from the use of
alternate translation initiation codons (PMIDs: 12032546, 20937277). [provided by
RefSeq, Feb 2013] - See more at:
http://www.cancerindex.org/geneweb/TP53.htm#sthash.FG0ISunq.dpuf
p53
•This protein is what binds to the DNA and
regulates the expression of genes that control the
cell cycle.
•p53 also activates repair proteins when the DNA
has sustained damage.
•It can initiate apoptosis if the DNA damage is
irreparable.
p53
• Once activated, it functions as an activator
for a number of different genes most
notably, p21.
• When tumor suppressor genes such as
p53 get damaged or undergo a mutation,
they lose their ability to regulate cell
proliferation.
Oncogenes and Proto-Oncogenes
• Proto-oncogene is the name given to the
normal form of genes which promote and
regulate cell proliferation.
• Oncogenes are mutant forms of protooncogenes that cause cancer.
Oncogenes and Proto-Oncogenes
• When a proto-oncogene undergoes a
mutation that doesn’t get repaired, it
becomes an oncogene.
Oncogenes and Proto-Oncogenes
• Under normal conditions, cells undergo a
programmed form of cell death when
damaged beyond repair (apoptosis).
Oncogenes and Proto-Oncogenes
• Activated oncogenes now promote cell
proliferation by encoding proteins that
increase expression of the normal genes
involved in regulating the cell cycle.
• Thus, it is easy to see how damaged DNA
leads to runaway cell division resulting in
tumor growth.
Tumor Suppressor Gene
• Tumor suppressor genes are found in the
genomes of cells and work to inhibit cell
division.
• They encode proteins that bind to various
parts of the cell cycle machinery
preventing runaway cell division.
So What’s Going On?
• How does this all fit in with mitosis?
• Recall that the cell cycle is a carefully
coordinated sequence of events that gives
rise to genetically identical daughter cells.
Cancer
• In its simplest form, cancer is runaway cell
division; an out of control cell cycle.
• If unchecked, that initial rogue cell
becomes a tumor--a group of cells with an
aberrant cell cycle.
Cancer Cells p53
• There are genes for certain components
of the pathway that act as tumor
suppressors.
• The p53 gene codes for a transcription
factor protein that promotes the synthesis
of cell cycle-inhibiting proteins.
Cancer Cells
• Some tumor suppressor proteins from p53
can repair damaged DNA, while others
control the adhesion of cells to each other
or to the extracellular matrix (density
dependence).
• Still others are components of the cellsignaling pathway that inhibits the cell
cycle.
Cancer Cells
• Normal p53 acts to control tumor
formation using two mechanisms:
• 1. It activates p21 in response to DNA
damage/stress.
• 2. It controls tumor formation by inducing
apoptosis.
1. p21 Activation
• Most notably, p53 expression activates
p21 whose protein product halts the cell
cycle at G1 and S by binding to and
inhibiting the cyclin-dependent kinases
needed by the S phase.
• This is the halt step that allows time for
the cell to repair the DNA.
1. p21 Activation
• Under normal conditions, p53 activates an
inhibitor gene (p21) when DNA is damaged.
• As a result, p21 protein arrests the cell
cycle and prevents cell proliferation.
•We don’t want a damaged cell dividing.
• If p53 function is lost, the p21 gene is not
activated and p21 protein will not be available to
act as the stop signal for cell division.
1. p21 Activation
• Since the p21 protein is not available and
there is no stop signal for cell division, the
cell will continue through the cell cycle
despite damage to DNA.
• An increase in mutant cell proliferation
(tumor formation) often results.
Cancer Cells p53
• p53 also activates expression of a group of
miRNAs that act to inhibit the cell cycle.
• It can also directly turn on genes involved
in DNA repair.
• When the DNA is beyond repair, it activates
suicide genes stimulating apoptosis.
2. Induction of Apoptosis
• 2. When a cell is damaged beyond repair,
a normal-functioning p53 gene acts to
induce cell death (apoptosis) and stops
the cell from proliferating.
• The immune system recognizes the dead cell
and cleans it up.
Cancer Cells p53
• For example, exposure to UV light can damage
DNA. This triggers the signaling pathway-through p53--that blocks the cell cycle until
the damage has been repaired.
• If the damage cannot be repaired, apoptosis
is stimulated.
• If p53 does not act this way, the damage could
contribute to the formation of a tumor as a
result of the chromosomal abnormalities and
cell division would perpetuate the abnormality.
Cancer Cells and p53
• Thus, we can see how p53 acts as a gate
keeper and is involved in a number of
different pathways to prevent a cell from
passing on mutations.
Ras
• Another group of proto-oncogenes
belongs to the Ras is a family of genes.
• When a mutation occurs in a Ras gene, it
can become an oncogene and possibly
result in the formation of a tumor.
• Ras genes code for Gproteins that relay
signals from growth
factor receptors on the
plasma membrane to a
cascade of protein
kinases.
• At the end of the
pathway is the synthesis
of a protein that
stimulates the cell cycle.
Ras
37
Ras
• Under normal conditions, the pathway will
not operate unless triggered by the
appropriate growth factor.
Ras
• Certain mutations in the ras gene lead to
production of a hyperactive Ras protein
that triggers the kinase cascade in the
absence of growth factor.
• This then turns on genes associated with
cell growth and differentiation.
Ras
• Since these signals result in cell growth
and mitosis, overactive Ras signaling can
lead to cancer.
The Takeaway
• There are a number of other genes that
have been shown to play a role in caring
for the genome and suppressing tumor
formation.
• The study of these genes and their
proteins have enabled us to better
understand the cell cycle and how it
works.