Tumour pathology 4 and 5 Flashcards
Describe the outer membrane of a cell?
Bilayer of molecules with lipid end and water soluble end.
Lipid ends in the middle and water soluble on inside and outside.
Describe how a ligand binding to a receptor brings about the start of a signal transduction pathway?
A ligand attaches to the receptor on the outside of cell, changes the shape of the inside part of the receptor.
The changed inside part of the receptor now recruits a molecule.
The messenger molecule can be activated and released and travel to its target in the cytoplasm or nucleus (signal transduction molecules).
Give an example of a signal transduction molecule?
BRAF
How is activation and inhibition of a target molecule achieved?
changing a molecule’s shape
recruiting and adding another molecule (e.g. phosphate group)
What is a transcription factor?
binds segments of DNA called promoters (not the actual gene sequence that’s going to be made into a protein).
Promoters bound to sequence of DNA that may or may not be made into RNA.
Transcription factor can inhibit or more usually activate transcription of the gene by recruitment of enzyme that transcribes DNA into RNA.
What are the regulatory sequences and how are they involved in control of the gene?
They are lots of other DNA sequences- which help control the gene
Describe the cell cycle?
G1 (Gap or Growth phase 1)
-many of cells sit in G1 most of the time
S phase
-synthesis of DNA occurs
G2 (2nd gap or growth phase)
-period of rapid cell growth in preparation for mitosis
M phase- mitotic phase where cell division occurs
What is the restriction point in G1?
In G1 there is a point of no return called the Restriction Point (also known as the Start or G1/S checkpoint) beyond which the cell commits to the cell cycle and no longer needs growth factors.
What is the G2-M checkpoint?
this checkpoint stops the cell cycle if there is DNA damage
Describe how growth factor molecules push cell to the G1 restriction point?
The growth factor molecule (a ligand) binds its specific receptor ( a growth factor receptor) and sets off a signal transduction pathway.
The effect is to push the cell along G1 towards the restriction point.
Lots of molecules affect different things in G1 and push the cell along G1 towards the restriction point.
What is the molecular switch at the restriction point in G1?
Restriction point at molecular level involves phosphorylation of a protein.
If only a few phosphate groups are present, cell stays in G1.
If numerous phosphate groups are present- cell progresses through rest of G1 and through rest of cell cycle
What causes phosphorylation?
there are numerous molecules that actually affect the enzymes that phosphorylate
for e.g. kinases
and other things that inhibit these enzymes and decrease phosphorylation
When is the transcription factor, E2F, bound?
proteins with only a few phosphate groups bind a transcription factor called E2F
so the normal state of this protein is active when it can bind E2F molecules
Why can E2F not be added to molecule with numerous phosphate groups?
When numerous phosphate groups are added to the protein it changes shape and releases the E2F molecules.
Protein is inactive as it cannot bind E2F molecules.
What happens after E2F molecules are released?
The E2F molecules then bind various target DNA regulatory sequences (such as promoters) and the cell cycle goes ahead
Describe the need of growth factors before and after G1 restriction point?
so growth factors push G1 towards the restriction point but are not needed beyond the restriction point
What is the protein that is considered the switch of the restriction point?
retinoblastoma gene product
What does the retinoblastoma gene product act as in its normal, unphosphorylated (active form)?
acts as a tumour suppressor gene as it blocks the cell cycle from going ahead.
Which multiple inputs promote the phosphorylation of the retinoblastoma gene product?
lots of glucose
lots of growth factors
Which inputs promote the inhibition of phosphorylation?
lack of nutrients such as glucose
lack of growth factors
To recap : from growth factor molecule to entering the S phase?
The growth factor m molecule sets off a pathway of molecules which ends up with phosphorylation of the retinoblastoma gene product, and the cell may then enter S phase and go through the cell cycle………
Why do growth factors have two parts to them?
Sometimes cells have inactive growth factor receptors that come together to form the active receptor when the growth factor binds. An example of a part of a receptor that does this is HER-2.
What happens when there is DNA damage?
Damage (for example radiation damage) increases a molecule called p53.
What happens when P53 increases in amount?
blocks (via other molecules) the formation of phosphorylated retinoblastoma gene product. And thus blocks G1 from progressing
What is P53 itself?
It is a transcription factor
How can P53 also block the G2-M checkpoint?
can switch on and off certain other proteins from being made, block the G2-M checkpoint.
What is the normal function of P53?
to stop cells dividing when they have damaged DNA
How is DNA damage (due to radiation or chemotherapy)- how is it repaired?
Mismatch repair genes – eg MLH1 gene – the product of this gene (along with many proteins) helps recognise and replace DNA base mismatches.
How does the mismatch repair gene, MLH1, stop the cell cycle?
MLH1 induces p53 which stops the cell cycle
What is an oncogene?
a mutated gene that causes cancer
What is a proto onco-gene and it’s role?
onco gene before mutated
and often to promote the cell to go through the cell cycle
What are growth factors?
most are proto oncogenes- the mutated version that makes them function much more is an oncogene.
How can oncogenes cause cancer?
one way is when a growth factor receptor protein has a mutation that means it is overexpressed
What is the definition of a tumour suppressor gene (anti oncogene)?
a gene that regulates cell division and when active tends to stop cell cycle
Give characteristics of tumour suppressor gene?
these genes tend to control or even block proto oncogenes
How do tumour suppressor genes cause cancer?
cause cancer when they have mutations or environmental factors that inactivate them
Mutations in these genes may cause cancer in various ways – one simple way is that a mutation causes them to loose their function
How do oncogenes go wrong in cancer?
Mutations – that increase the amount of oncogene product – for instance a growth factor receptor that is increased in amount – HER-2
Mutations – that allow the protein product to work independently of its control mechanism – for instance a signal transduction molecule that continues to work all the time – BRAF
How do tumour suppressor genes go wrong in cancer?
Mutations – that stop the protein product from working – for instance– the retinoblastoma gene product
Environment – for instance a viral protein binds the protein product and stops it working – p53
Mutation – that stop a protein working – eg the MLH1 mismatch repair protein
What are the inherited causes of carcinogenesis?
Inherited from a parent who also has that abnormal gene
But can sometimes be a ‘de novo’ mutation in the cells of the testis or ovary of the parent (parent does not have this abnormal gene in their other cells)
One good example: retinoblastoma, a malignant tumour of the eye in children, runs in some families - autosomal dominant
What are environmental causes of carcinogenesis?
Chemicals (eg: smoking, alcohol)
Radiation (eg: UV)
Infection (eg: human papilloma virus)
Other
All of the above increase the risk of damage (eg breaks, or mutations) to DNA
What can go wrong with HER-2 in breast cancer?
Mutation-can get overexpression of HER-2
Receptor can bind more growth factors
makes it much easier for pathway to be upregulated and pushes cell cycle (G1) forwards
What is the BRAF gene on its own?
a proto-oncogene
What can go wrong with BRAF in malignant melanoma- a type of skin cancer?
Commonest mutation in BRAF in malignant melanoma changes a glutamic acid for valine at amino acid number 600 - often called BRAF V600E (oncogene)
this switches the BRAF on all the time and pushes the cell cycle forwards
What causes mutation?
BRAF are very rarely caused by hereditary abnormalities in gene.
Environmental:
harmful chemicals from smoking
alcohol
radiation from sun damaging DNA inside cells
What can go wrong with the retinoblastoma gene product in retinoblastoma?
normally have two copies of retinoblastoma gene making retinoblastoma gene product
In hereditary cases mutation causes one gene to stop producing protein – but still leaves other gene producing protein
But, if there is another mutation the protein is lost from the cell and the E2F molecules are released and can progress the cell cycle- then retinoblastoma malignancy of the eye can occur
How can MLH1 go wrong in colon cancer?
Mutation in MLH1 can cause reduction in the amount of its protein - leads to decreased mismatch repair - mismatch of base pairs of DNA remains.
When this mutation remains and is then replicated and then repaired again all sorts of damage ensues…eg the enzyme that replicates DNA (DNA polymerase) may slip..cell starts to accumulate all sorts of mutations as it divides - Colon cancer
How can tumour suppressor genes lose their function?
In tumour suppressor genes, both copies of genes need to be abnormal in order for tumour suppressor genes to lose their function.
Describe how smoking can lead to mutations in the cell?
Numerous chemicals in cigarette smoke - metabolised to carcinogens in liver - released into circulation - damage DNA - numerous mutations - eg mutations in p53
Describe how radiation can lead to mutations in the cell?
Sunlight UV radiation lands on the top part of the bottom of the lip of the mouth - mutations in several genes eg mutations in p53- increased risk of cancer
Describe how human papilloma virus can lead to mutations in cell?
Infection of cervix - produces E6 protein which binds and inactivates p53. [Also produces E7 protein which binds and inactivates retinoblastoma gene product.] Increased risk of subsequent uncontrolled cell division - precancer - cancer
Where does p53 block the cell cycle from progressing?
G1 restriction and G2-M checkpoint
What often comes before a gene in the genetic code?
regulatory sequence- instructs whether or not to produce a protein
How is regulatory sequence controlled?
by binding of transcription factors
What is c-MYC?
transcription factor, signaling molecule
-increases many proteins which push the cell towards cell division
-increases other proteins which stop cell death
Overall effect is to promote increased number of cells- it is a proto-oncogene
Describe how overexpressed c-myc comes about and how it acts as an oncogene.? via translocation
normally c-MYC protein product is tightly controlled.
Normally regulatory sequence in front of c-MYC gene
Bit of end of chromosome 8 breaks off and floats off to other part of cell
And attaches to chromosome 14 .
At the join the c-MYC DNA sequence and immunoglobulin regulatory sequence are now joined.
Immunoglobulin is made in abundent quantities , for e.g. immunoglobulin regulatory sequence always turned on in b cells
and therefore could result in huge increase in c-MYC protein and this will increase production of proteins that prevent apoptosis.
Abnormal B cells will be very likely to proliferate and promote cancer
What environmental agents promote cancer?
Chemicals (eg: smoking, alcohol)
Radiation (eg: UV)
Infection (eg: human papilloma virus)
Other
All of the above increase the risk of damage (eg breaks, or mutations) to DNA
Chemicals (eg: smoking, alcohol)
Radiation (eg: UV)
Infection (eg: human papilloma virus)
Other
note that the environmental agent acts on the pre-existing normal gene [or its protein product], causing it to be abnormal
How does alcohol increase risk of cancer?
Small amounts – completely metabolised in liver
Larger amounts - converted to acetylaldehyde (causes the red flushing of the face in some people) which then gets into systemic circulation - causes double strand breaks of DNA in many genes -increased risk of cancer
Describe inherited predisposition?
Gene is already abnormal in cells – for example a pre-existing mutation
It is not certain that cancer will occur but environmental mutations can then make it highly likely that cancer does occur
Describe inherited causes of carcinogenesis?
Inherited from a parent who also has that abnormal gene
But can sometimes be a ‘de novo’ mutation in the germ cell of the testis or ovary (parent does not have this abnormal gene in most of their cells)
Describe retinoblastoma?
a malignant tumour of the eye in children, runs in some families - autosomal dominant – in retinoblastoma the abnormal gene – the retinoblastoma gene – does not hold on to E2F molecules well - cells enter S phase easily - 2nd environmental mutation in cell - retina malignancy in childhood
Describe Epstein Barr virus?
Many people infected – upper respiratory infection
Some people – prolonged infection
Virus infects B cells
Causes B cells to proliferate
But….most people do not get cancer as proliferation of B cells eventually stops
What if another event is occurring at same time as EBV?
Epstein-Barr infection causing B cell proliferation and…..
c-myc being translocated and produced in large amounts…..
- are 2 steps which together can lead to cancer – in particular one type of Burkitt lymphoma, and is a good example of the multistep nature of carcinogenesis
