Cell Cycle + Cancer Flashcards
Describe the cell cycle
an ordered sequence of events in which a cell duplicates its contents and divides into two identical cells
What does each cell division produce in a unicellular organism?
an entirely new organism
What are cell divisions for in a multicellular organism?
countless cell divisions form a zygote
are required for growth
form complex organisms
T or F: as an adult, your cells stop dividing
false!! your cells must constantly occur in certain tissues to replace cells that die
What stages does interphase include?
G1 (gap 1 for growth)
G0 (not dividing)
S (DNA synthesis)
G2 (gap 2 for growth)
What does the M phase include?
prophase prometaphase metaphase anaphase telophase cytokinesis
What would happen if our cells suddenly stopped dividing?
we would die in a few days
T or F: the length of the cell cycle varies in different organisms and different cells
true
How long is the length of the cell cycle in embryonic cells? Give examples
very short
ex. 8 mins in fruit flies
ex. 30 mins in frogs
How long is the cell cycle in mammalian intestinal epithelial cells?
12 hours
How long is the cell cycle in human liver cells?
~1 year
If cells do not divide, what stage are they permanently in?
G0
What does terminally differentiated mean?
highly specialized cells (ex. nerve, muscle, red blood cells) are not able to divide
If terminally differentiated cells cannot divide, how are they replaced or repaired when they are damaged or die?
they are replenished by stem cell populations as needed
T or F: some cell types can induce non-dividing cells to leave G0 and re-enter G1
true
ex. adult liver will divide after injury
Give examples of cell types that are non-dividing but will be induced to leave G0 to re-enter G1
adult liver cells will divide after injury
lymphocytes will divide when exposed to specific antigens
T or F: it is common for non-dividing cells to be induced to leave G0 and re-enter G1
FALSE! it is rare
List 4 cell types that frequently divide
epithelial cells
spermatogonia
stem cells of various tissues (ex. blood)
meristem tissue in the root and shoot tips of plants
Describe multipotent cells
stem cells that are highly specialized and can:
self renew and
only produce cell types within one type of tissue or organ
What does totipotent mean?
undifferentiated cells which have the potential to become any type of cell
What is progression through the cell cycle primarily controlled by?
a group of proteins called Cyclin-Dependent Kinases (CDKs)
What are cyclins?
proteins that regulate CDK activity
What is the function of CDK?
to phosphorylate various targets in the cell
How are CDKs activated?
when cyclin binds tightly to the CDK
Is the concentration of cyclins constant or fluctuating throughout the cell cycle?
it fluctuates
What effect does the fluctuation of cyclin levels have on CDK activity?
CDK is always present throughout the cell cycle but the activity of CDK will fluctuate with the concentration of cyclin
What are the 3 types of cyclins in the cell cycle and when are they present?
G1/S cyclins = active in late G1
S-cyclins = present at S phase
M-cyclins = present at M-phase
What causes the rise and fall of cyclin concentration throughout the cell cycle?
the synthesis and degradation of cyclin proteins
What does the rise and fall of cyclin levels cause for CDK activity?
rise and fall of CDK activity which promotes cell cycle progression
What causes cyclin levels to fall?
cyclin degradation by proteasomes
What causes proteasomes to degrade cyclins?
a polyubiquitin chain (molecular tag) is added to a cyclin protein
What is a polyubiquitin chain?
a molecular tag made of several ubiquitin molecules added to a substrate like cyclin which targets it to be destroyed in proteasomes, inactivating CDK
How is CDK inactivated?
when its bound cyclin is tagged with a polyubiquitin chain, it is targeted to be destroyed by proteasomes and detached from the CDK
unbound CDK = inactive
What adds the polyubiquitin chain to a cyclin?
a series of enzymes = E1-E3 ubiquitin ligases
What happens to the degraded cyclin?
proteasomes degrade cyclin back into its individual amino acids
Describe the proteasome
a compartmentalized protease with sequestered active sites
aka a large protein machine with a central cylinder and stoppers at both ends
What is the proteasome analogous to?
a garburator
Where does a protein to be degraded enter the proteasome?
through a pore in the stopper into the central cylinder
What forms the central cylinder/chamber of the proteasome?
proteases
What direction do the central chamber proteases of a proteasome face?
they face the inside of the chamber
Describe how a protein is degraded by the proteasome
the stopper proteins of the proteasome bind proteins with polyubiquitin chains and use ATP to unfold them into the chamber
What happens to the ubiquitins attached to a protein to be degraded when it enters the proteasome?
they do not enter the chamber and they are recycled
What are the 2 kinases that phosphorylate CDK to activate or inhibit it?
activating kinase
inhibitory kinase
T or F: the two kinases phosphorylate CDK at the same site
false, at different sites on CDK
Where does the inhibitory kinase add a phosphate on CDK?
to the inhibitory P site on CDK
Where does the activating kinase add a phosphate on CDK?
to the activating P site on CDK
What is the activity level of a fully phosphorylated CDK (has both inhibitory and activating kinases bound)?
partly active
What is required for the CDK to become fully activated?
an activating phosphatase must remove the phosphate from the inhibitory P site
What P site will the activating phosphatase dephosphorylate CDK?
the inhibitory P site
What is required for the phosphatase to be able to properly function?
it must be activated by phosphorylation
How is the phosphatase activated?
CDK is a kinase, so it can phosphorylate its own activating phosphatase in order to remove the inhibitory phosphate
What is the purpose of both P sites being phosphorylated if one must be dephosphorylated for full activity?
having both P sites phosphorylated means the CDK is partially active
a partially active CDK is required to phosphorylate/activate the phosphatase which can remove the inhibitory phosphate from the CDK and allow the CDK to become fully active
Once the phosphatase is activated, what happens?
the phosphatase can activate a LOT of CDK in a short time by removing the inhibitory phosphate = a positive feedback loop
What causes the very steep increase in CDK activity in a cell?
the positive feedback loop of the slightly active CDK activating a phosphatase by phosphorylation and then the phosphatase activating the CDK by dephosphorylating the inhibitory P site
What causes the steep decline of CDK activity?
proteasome mediate degradation of cyclin
What controls progression through the cell cycle?
checkpoints
What occurs at a checkpoint?
cell mechanisms pause the progress of the cell cycle if a process has occurred incorrectly or if the conditions are not favourable to progress
What are the 3 main checkpoints?
G1 checkpoint: between G1 (or G0) and S phase
G2 checkpoint: between G2 and M phase
M checkpoint: between metaphase and anaphase
What happens if a cell does not pass a checkpoint?
the cell cycle is temporarily paused and the cell can use the delay to repair the damage or defect
What happens if the damage or defect of a cell is irreparable?
checkpoint mechanisms send out a signal to permanently stop the cell cycle progression or for apoptosis
What is another name for the G1 checkpoint?
the restriction checkpoint
Describe the G1/restriction checkpoint
it is the point where the cell is irreversibly committed to cell division
At the G1 checkpoint, what are the 3 options?
- proceed to S phase
- pause and repair damage/defect
- withdraw from cell cycle and go to G0 if terminally differentiated
What 5 things are required at the G1 checkpoint?
specific signals (ex. growth factors)
adequate nutrition
sufficient energy reserves
sufficient cell size
undamaged DNA
What is the purpose of the G2 checkpoint?
to prevent the final entry into the M phase if conditions are not met
What 5 things are required at the G2 checkpoint?
sufficient cell size
adequate nutrients
sufficient energy stores
**chromosomes have all been replicated
**replicated DNA is not damaged
What are the 2 major requirements checked for at the G2 checkpoint?
all chromosomes have been replicated
replicated DNA is not damaged
Give some examples of different types of damage to DNA
single-strand break
mis-matched
damaged base
double-strand break
intra-strand crosslink
inter-strand crosslink
T or F: most types of DNA damage can be repaired
true
Why is it essential that DNA damage is repaired at the G2 checkpoint before the cell enters mitosis or meiosis?
because mammalian cells that undergo cell division are more easily transformed into cancerous cells with uncontrollable and unregulated growth and the risk is even higher if DNA is damaged
What does DNA damage in mammalian cells lead to?
the activation of the p53 protein
How is p53 activated?
by phosphorylation
How often is p53 synthesized? How quickly or slowly is it degraded? What does this result in (in terms of its levels in normal cells)?
regularly synthesized + degraded rapidly = low levels in normal cells
Is p53 normally high or low in cells?
low
How is a p53 protein degraded? When does this occur?
the protein Mdm2 binds to p53 and promotes ubiquitination so that p53 is degraded by a proteasome
this will happen to p53 when there is no DNA damage
What happens when p53 is activated?
it is phosphorylated which means Mdm2 cannot bind to it = no ubiquitination = p53 is stable and active and concentrations can rise in the cell
Describe p53
‘the guardian of the genome’
a transcription factor that is activated and in high concentration when there’s DNA damage
it has many functions in preventing cancer
What is the function of p53?
to prevent cancer by up-regulating expression of certain genes which prevents the replication of damaged DNA
What are 6 specific ways that p53 prevents cancer?
when DNA is damaged, p53:
arrests cell division
arrests cell growth
promotes DNA repair
prevents angiogenesis
affects glucose metabolism
can promote apoptosis if needed
What is one example of a gene that is regulated by p53?
p21
Describe what happens when p21 is up-regulated by activated p53
p21 will bind to and inhibit the S-cyclin/CDK complex - contributes to arresting the cell cycle when there’s damaged DNA
What is the M checkpoint also called?
the spindle checkpoint
What is the purpose of the M checkpoint?
to assess whether all the sister chromatids are correctly attached to spindle microtubules prior to the irreversible splitting during anaphase
What can happen if sister chromatids are not correctly attached to spindle microtubules and anaphase occurs?
aneuploidy (abnormal chromosome number)
T or F: aneuploidy can be repaired
false!! this type of DNA damage cannot be repaired because anaphase is not reversible
Give an example of aneuploidy and how it occurs
Down’s syndrome occurs when there’s an extra chromosome 21
What is required at the M checkpoint?
all chromosomes are properly attached to the spindle microtubules
Where does the cell progress if it passes the M checkpoint?
completes mitosis from anaphase onward
T or F: most cells arrest the cell cycle once they have differentiated
true
What can happen to a cell if the cell cycle doesn’t arrest when it should?
that cell can become cancerous
Why is it called cancer?
because cancer means ‘crab’ and the cells that invade surrounding tissues have projections that look like pincers
What causes cancer?
uncontrolled cell division arising from a single cell that contains mutations in specific genes = the original cell and all daughter cells ignore normal cell division checkpoints
What are the 2 basic properties of cancer?
uncontrolled growth
ability to invade and colonize areas normally reserved for other cells
T or F: cancer is genetic and therefore always heritable
false. cancer is genetic but it is not usually inherited
How does most cancer arise?
usually not in germ-line cells (not heritable)
usually in somatic cells during an individual’s lifetime from errors in DNA replication
What 2 things affect mutation rates? give examples
cellular environment
mutagens
ex. UV radiation, chemical exposure, radiation, heat, cigarette smoke, pollution, age, genetics
Approximately how many Canadians will develop cancer in their lifetime? Why is this number actually not as large as it could be?
2 in 5
when you consider that we have trillions of cells and there’s billions of cell divisions every dat with a guaranteed rate of mutation and mutagens increase that basal rate, 40% is actually not that big
Why does the risk of cancer increase with age?
because you need a substantial number of mutations in a single gene to occur in order to develop a cancerous tumour and rate of mutations increases with more cell divisions
the longer you live, the more cell divisions occur = more mutations
What tissues do the most common cancers arise in? Why? Give examples
in epithelial tissues because these cells undergo a relatively high level of cell division
ex. breast, colon, prostate, lung
What are some examples of behaviours of cancer cells as a result of their mutations?
unresponsiveness to external signals
loss of attachment to ECM and substrata
no contact inhibition
no regulation of cell division
avoidance of apoptosis
lack of differentiation
ability to enter and survive in foreign tissues
Why is the loss of attachment of cancer cells to the ECM bad?
this allows them to spread and invade other areas
What does no contact inhibition mean in regards to cancer cells?
they do not stop growing when they touch other cells = this results in tumours
Why is it bad that cancer cells do not differentiate?
because differentiation would normally stop cell division = another way they maintain uncontrolled division
What are 3 ways in which cancer cells are able to enter and survive in foreign tissues?
they can survive with low oxygen away from blood vessels
they can bypass cell-cell junctions and create intercellular pathways
they can secrete proteases to degrade the ECM
How many layers do normal cells grow in a petri dish? What about cancer cells? Why?
normal: 1 layer thick because they stop growing when they touch each other (contact inhibition)
cancer: multiple layers because they do not have contact inhibition and can pile on top of each other
T or F: mutations that result in cancer are always in genes that somehow affect cell division
true
What are the 2 kinds of genes that relate to cancer?
tumour suppressor genes
protooncogenes
What is the normal function of tumour suppressor genes?
to restrict the cell cycle
What is an example of a protein coded for by a tumour suppressor gene?
p53
What happens when there’s mutations in a tumour suppressor gene?
the genes are turned off and the cell cycle is not restricted = cells can divide without needing to pass checkpoints which can lead to replicating damaged DNA
What kind of genes are considered tumour suppressor genes?
ones that promote differentiation
What kind of mutation occurs when a tumour suppressor gene is mutated?
a loss of function mutation
How many alleles need to be mutated in a tumour suppressor gene to result in a loss of function?
both
What is the normal function of proto-oncogenes?
to promote cell division
What is an example of a protein that is coded for by proto-oncogenes?
CDKs
What happens to proto-oncogenes when they are mutated?
they are turned on permanently and they are not regulated properly = constant cell division
What kind of a mutation results when a proto-oncogene is mutated?
gain of function
What are proto-oncogenes called after they are mutated?
oncogenes
How many alleles must be mutated to result in a mutated proto-oncogene?
only one
What does mutations in both proto-oncogenes and tumour suppressor genes cause?
tumour growth
What are 4 examples of mutations to a proto-oncogene that can turn it into an oncogene?
deletion or point mutation in coding sequence
regulatory mutation
gene amplification
chromosome rearrangement
What are 3 examples of genes that can be mutated to cause cancer?
cell signalling pathway genes (ECM signals, survival signals, growth + differentiation signals) - ex. RTK
cell cycle regulation genes (checkpoint genes)
apoptotic genes
What is the most commonly mutated gene in human cancers?
p53
in what ways are cancer cell genomes unstable?
they have big genomic changes and often show abnormal chromosomes with large deletions, translocations, inversion, and excessive heterochromatin
In a karyotype, how would you know if you’re looking at a cancer cell genome?
the chromosomes will be multiple colours due to a lot of rearrangement
What are two words for a cluster of abnormal cells growing out of control?
tumour or neoplasm
What are the 2 types of tumours?
malignant
benign
What is the major similarity and difference between malignant and benign tumours?
Similarity: they are both clusters of abnormal cells growing out of control
Benign tumours are not yet invasive
malignant tumours are cancerous because they are invasive
Describe benign tumours
slow-growing, non-invasive cluster of abnormal cells growing without regulation
What can limit the growth of benign tumours?
being covered by connective tissue sheaths
Are benign tumours generally easy or difficult to remove? why?
they can be covered and therefore isolated in a connective tissue sheath = clean edges and easy to remove
T or F: the removal of a singular benign tumour usually results in a complete cure
true
How can benign tumours be harmful?
they can compress adjacent tissues and block important structures with important functions (ex. trachea or a lumen)
if the tumour is of endocrine tissue it could result in uncontrolled hormone secretion and cause disease
they have a high likelihood of becoming cancerous
Explain why malignant tumours are always harmful
they are invasive so they can disrupt the tissue and spread (usually by losing attachment to ECM or basement membrane) and metastasize by entering blood or lymph and move around the body
Describe the process of cancer
a single mutation in a single cell which promotes growth or division will produce a lot of daughter cells
daughter cells accumulate their own mutations
each mutation increases ability of the cancer cell to grow, divide, evade apoptosis, and invade other tissues
How many mutations do cancers usually carry? Are they dependent or independent mutations? Are they common mutations?
usually many independent, rare mutations
Describe angiogenesis
the development of new blood vessels
How do large tumours metastasize?
they form their own vasculature (angiogenesis) to help them receive oxygen and perform lots of cellular respiration to produce lots of ATP = lots of growth
Where does the development of blood vessels occur in an embryo?
in every part of an embryo
What drives the development of blood vessels in an embryo?
a growth factor called VEGF
Describe VEGF
A growth factor / ligand that binds to RTKs and activates signalling pathways
it drives the development of blood vessels
How do growing tumours perform angiogenesis?
they express VEGF, the growth factor that signals for the development of blood vessels
Describe the process of metastasizing
a growing tumour expresses VGEF which induces blood vessels to form and invade the tumour mass = allowing the tumour to conduct cellular respiration and produce ATP to grow –> tumour can metastasize and move through the blood to other parts of the body
What are metastases?
secondary tumours
T or F: a primary tumour is usually traceable from metastasis
true
Are metastases usually removable by surgery?
No
Is it generally metastases or the primary tumour that results in the death of a cancer patient?
metastases
How can tumours effect organ function?
Once a primary or secondary tumour reaches a significant mass, the organ can no longer function properly
