Oncogenes and tumour Suppressants Flashcards
1
Q
State the 6 Hallmarks of Cancer
A
- Disregard of signals to stop proliferating
- Disregard of signals to differentiate
- Capacity for sustained proliferation
- Evasion of apoptosis
- Ability to invade
- Ability to promote angiogenesis
Soon to be added:
- Avoiding Immune destruction
- Deregulates cellular energetics
- Genome instability and mutation
- Tumour-promoting inflammation
2
Q
Which are the steps in the Cell Cycle that ensure genetic fidelity?
A
- G0 - the cell is in a quiescent phase - it is not replicating
- G1 - the cell makes sure that it has enough nutrients, nucleotides etc. to replicate
- At the end of G1, the cell has a checkpoint where you get growth arrest to ensure the genetic fidelity of the cell
- Specific proteins accumulate/are destroyed during the cycle e.g. cyclins, Cdks, Cdk inhibitors
- Permanent activation of a cyclin can drive a cell through a checkpoint
3
Q
Describe Proto-oncogenes, their expression and their mutation
A
- Proto-oncogenes code for essential proteins involved in maintenance of cell growth, division and differentiation
- It changes the activation of the protein and it can therefore not work properly
- Mutation can convert a proto-oncogene into an oncogene, whose protein product no longer responds to control influences
- Oncogenes can be aberrantly expressed, over-expressed or aberrantly active
- E.g. Myc, Ras, ERB, Sis
- A proto-oncogene can be converted to an oncogene by a single mutation
4
Q
How can Oncogene Activation occur?
A
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Insertional mutagenesis
- Viral infections – some viruses insert their genome into our DNA and usually this isn’t a problem as much of our DNA does not code but if it’s in a coding region, this could be cancer.
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Mutation in the coding sequence
- Point mutation or deletion
- Gene amplification is the production of multiple gene copies
- It can occur due to problems with a polymerase protein
- A protein may block the DNA polymerase so the polymerase repeatedly backs up to go over the area a few times creating many identical genes.
- Having multiple copies of a gene will lead to overproduction of the gene product
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Chimeric genes are genes that are formed by combinations of portions of one or more coding sequences to produce new genes (e.g. the swapping of tips of chromosomes)
- This can be a problem if one of the pieces of translocated DNA is a promoter, leading to upregulation of the other gene portion (this occurs in Burkitt’s Lymphoma)
- This can also be a problem if the fusion gene formed produces an abnormal protein (e.g. Philadelphia chromosomes in CML)
- This is known as Chromosomal translocation
It can affect the binding of a protein and it can not be controlled anymore
5
Q
Give an Example of Chromosomal Translocation in Cancer
A
- This is the Philadelphia Chromosome that is formed by the translocation of chromosome segments from chromosomes 9 + 22
- This is an example of INSERTIONAL MUTAGENESIS
- The two key areas that are translocated are:
- ABL - chromosome 9
- BCR - chromosome 22
- The resulting BCR-ABL fusion gene leads to the development of cancer
- Prognostic indicator for leukaemia
- It encodes a tyrosine kinase receptor that does not switch off and thus drives uncontrolled proliferation
6
Q
Describe Oncogene activation
A
- Proteins that are involved in signal transduction pathways are potentially critical gene targets (proto-oncogenes)
- Activation of proto-oncogenes to oncogenes can disrupt normal activity
- It can lead to downstream activation of signalling pathways such that they no longer respond to the upstream stimuli
- Examples:
- Tyrosine kinase receptors EC – met, neu.
- Tyrosine kinase receptors IC – src, ret.
- Transcription factors – myc, fos, jun.
- GPCR g-proteins – ras, gip-2.
- Kinases – raf, pim-1.
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7
Q
Describe Ras activity and how it can be mutated, what are its results?
A
- Normally, upon binding GTP, Ras becomes active and activates the kinase cascade leading to the production of gene regulatory proteins
- Dephosphorylation of the GTP to GDP to switch Ras off
- Mutant Ras will fail to dephosphorylate GTP meaning that the GTP persists so Ras remains active, ability to not depend on a growth signal and cannot signal (colorectal cancer)
- The Ras pathway is part of a much more complex signalling cascade called the mitogen-activated protein kinase cascade (MAPK)
- g-coupled protein receptors
8
Q
Give a summary of Ras Signalling:
A
Binding of the ligand to the receptors, then you get phosphorylation, then mek, erk, which will have an effect on the transcription factor on the cells DNA
9
Q
Oncogenes and Human Tumours
A
- Ras codes for a family of proteins such as Ki-Ras and Ha-Ras, which are membrane bound GTPases that are important in the stimulation of cell proliferation
- Problem is that cancer is multiple diseases
- Different location of the mutation will have a different effect on the toumour that is created, drugs for the sae mutations might not work in all places
10
Q
State the function of Tumour Suppressor Genes, how could things go wrong?
A
- Typically proteins whose function is to regulate cellular proliferation and maintain cell integrity (e.g. retinoblastoma)
- Regulate and maintain integrity (stop anything bad from happening), each cell has two copies and mutation or deletion of one of the genes is insufficient to promote cancer
- Each cell has two copies of each tumour suppressor gene
- Mutation or deletion of just one gene copy is usually insufficient to promote cancer
- Mutation or loss of both copies means loss of control
11
Q
Which are the features of Inherited Cancer Susceptibility?
A
This has led to the discovery of tumour suppressor genes. Features include:
- Family history of related cancers
- Unusually early onset
- Bilateral tumours in paired organs
- Synchronous or successive tumours (of the same type pf cancer or the same cancers that run in the family)
- Tumours in different organ systems in same individual
- Mutation inherited through the germline (braca’s mutation)
12
Q
Give an example of Example of Inherited Cancer
A
- Inherited pre-disposition
- It is a malignant cancer of developing retinal cells
- Sporadic disease usually involves one eye
- Hereditary causes can be unilateral or bilateral and multifocal
- It is caused by mutation of the RB1 tumour suppressor gene on the chromosome 13q14, cell cycle control genes
- RB1 encodes a nuclear protein that is involved in regulation of the cell cycle
- Treatment is to remove the eye
13
Q
What are the different Functional Classes of Tumour Suppressor Genes?
A
- Regulate cell proliferation
- Maintain cellular integrity
- Regulate cell growth
- Regulate the cell cycle
- Nuclear transcription factors
- DNA repair proteins
- Cell adhesion molecules
- Cell death regulators
- OVERALL: THEY SUPPRESS THE NEOPLASTIC PHENOTYPE
14
Q
State some examples of Tumour Suppressor Genes and Human Tumours
A
P53 is really difficult to target, it would not produce a viable offspring if they were inherited
The fact that they cause syndromes tells you that they cause a lot
15
Q
What type of gene is p53, how can it be mutated? - The Guardian of the Genome
A
- When p53 is bound to MDM2 it is inactive
- It is the gradian of the genome, some of them are non-driving mutations (that the arose as the result of the initial mutation) together with driving mutations (also what effect you’ll have to normal tissues)
- P53 is important in a wide range of activities, including regulation of p53 target genes and protein-protein interactions
- P53 can be activated by many different types of cellular stresses
- Although p53 is a tumour suppressor gene, mutants of p53 act in a DOMINANT manner and mutation of a single copy is sufficient to get dysregulation of activity
- Phosphorylation of p53 destabilises it so that it isn’t degraded so quickly and can exert its effects
- Early malignancies and rare tumours
- Phosphorylation is triggered by cellular stress
16
Q
Describe how the APC Tumour Suppressor Gene works - Familial Adenomatous Polyposis Coli (APC)
A
- Due to deletion in 5q21 resulting in loss of APC gene (TSG)
- It is involved in cell adhesion and cell signalling, dysregulation of signallinf and dysregulation of cell protection
- People with the APC mutation develop multiple benign adenomatous polyps in the colon
- There is a 90% risk of developing colon cancer
- APC participates in the WNT signalling pathway to alter transcription and growth
- APC protein helps control the activity of Beta-catenin - thereby preventing uncontrolled growth
- Mutation of APC is a frequent event in colon cancer
17
Q
Give a simplistic Overview of the Route to Cancer
A
18
Q
The Development of Colorectal Cancer
A
- The APC gene in the normal epithelium gets mutated and becomes inactive (loss of TSG) leading to hyperproliferation of the epithelium
- DNA hypomethylation (an epigenetic change) combined with a K-ras mutation (oncogene) will make the polyps develop into adenomas (low risk vs high risk adenoma)
- The mutation of p53 (the guardian of the genome) will result in the development of carcinoma
- The carcinoma can then go on to metastasise
- Both tumour suppressor genes and oncogenes are involved in the development of colorectal cancer
- Cancer can be triggered by:
- Oncogene + TSG.
- Proto-oncogene + defective TSG.
- Oncogene + defective TSG.
- Cancer is achieved via multiple mutations such as in colo-rectal cancer.
- Apc – hyperproliferation.
- K-ras – adenoma.
- p53 – carcinoma.
- Metastasis.
19
Q
State the differences between Oncogenes and Tumour Suppressor Genes
A
