Introduction to Oncogenes Flashcards
1
Q
What are the different stages of the cell cycle?
A
- Metaphase (M)
- G1 phase (G1)
- S phase (S)
- G2 phase (G2)
2
Q
Describe Metaphase
A
- 1st stage of cell cycle
- Contains M checkpoint which checks that chromosome spindle attachment was successful
- Checkpoint is regulated by procto-oncogenes (Ras, Myc)
3
Q
Describe G1 phase
A
- 2nd stage of cell cycle
- Includes G0 which is the resting state of the cycle
- Contains G1 checkpoint which checks for nutrients, growth factors, DNA damage
- Checkpoint is regulated by procto-oncogenes (Ras, Myc) and tumour suppressor (pRb)
4
Q
Describe S phase
A
- 3rd stage of cell cycle
- Site of DNA synthesis
- Contains S checkpoint which checks for cell size and DNA replication
- Checkpoint is regulated by tumour suppressor p53
5
Q
Describe G2 phase
A
- 4th stage of cell cycle
- Contains G2 checkpoint which checks for cell size and DNA replication
- Checkpoint is regulated by procto-oncogenes (Ras, Myc)
6
Q
What is a procto-oncogene?
A
Normal cellular genes which regulate cell growth and/or division and differentiation
7
Q
What is an oncogene?
A
A procto-oncogene that has been activated by mutation or overexpression
8
Q
What does an oncogene cause?
A
Deregulated cell division
9
Q
What was the first oncogene discovered in chicken?
A
- SCR oncogene was discovered in 1970
- c-SCR (procto-oncogene) -> v-SCR (oncogene)
10
Q
How many types of conversion of procto-oncogene -> oncogene are there?
A
2 main types
11
Q
What is the first way in which a procto-oncogene is converted into an oncogene?
A
- A mutation in the gene results in a different oncoprotein instead of the normal protein being expressed in the cell
- This protein produced is abnormal and has a different structure to the normal protein
12
Q
What is the second way in which a procto-oncogene is converted into an oncogene?
A
- A mutation in the gene results in the same protein being expressed but at higher levels resulting in more of the protein being produced than normal
13
Q
What are the 3 different changes that activate an oncogene?
A
- Point mutation
- Gene amplification
- Chromosomal translocation
14
Q
What is point mutation?
A
- Mutation within the gene which activates the oncogene
- Results in a mutant hyperactive growth-stimulating protein being produced in a normal amount
- eg KRAS in lung cancer
15
Q
What is gene amplification?
A
- Multiple copies of the gene results in the normal growth-stimulating protein being produced in excess
- eg c-myc in breast cancer
16
Q
What is chromosomal translocation?
A
- Gene is moved to a new DNA locus and is under new controls
- normal growth-stimulating protein is produced but in excess
17
Q
How many pathogenic alterations are required to activate an oncogene?
A
Only one pathogenic alteration on one copy of a procto-oncogene can transform it into an oncogene
18
Q
How many copies of an oncogene is sufficient to promote tumorigenesis?
A
A single copy
19
Q
What phenotype do oncogenes that cause cancer have?
A
A dominant phenotype
20
Q
Are procto-oncogene mutations inherited?
A
They are rarely inherited as they are somatic mutations which occur in non-germline cell types
21
Q
What are 4 different types of procto-oncogenes?
A
- Growth factor
- Growth factor receptor
- Signal transducers
- Transcription factor activators
22
Q
What is HER2 protein?
A
HER2/neu/ERBB2 gene encodes for part of the human epidermal growth factor response 2 protein (HER2)
23
Q
How is HER2 able to function?
A
- Receptor dimerisation is required for HER2 function
- Can be activated by heterodimerisation with HER3/EGFR
- Or can be activated by homodimerisation with another HER2 molecule
24
Q
What does the heterodimerisation of HER2 achieve?
A
- When HER2 is bound with a receptor-specific ligand, a signal cascade occurs which results in activation of transcription in genes
- This allows cell proliferation, survival and motility
25
What does the intracellular tyrosine kinase activity of HER2 achieve?
Allows HER2 to use ATP to phosphorylate and activate substrates
26
How is HER2 implicated in breast cancer?
- HER2 is amplified in approx 20% of invasive breast cancers
- It is associated with aggressive disease and poor prognosis
27
How much is HER2 proteins increased by if activated into an oncogene?
20 thousand copies before to 20 million after oncogene activation
28
What is the effect of multiple copies of HER2 proteins?
- Leads to excess activation due to an increase of heterodimers
- Leads to too much degradation of p27 due to an increase of homodimers
29
How can HER2 oncogene be treated?
- Target therapy through the use of two monoclonal antibodies
- Trastuzumab and Pertuzumab
- Only effective in HER2+ cancers (amplified HER2)
30
How does trastuzumab work?
- Binds to HER2 when it is overexpressed to increase p27 to aid the cell cycle
- Applied to HER2+ breast cancers in combination with chemotherapy
31
How does pertuzumab work?
- Inhibits dimerisation of HER2 with HER3
- Can be used in combination with trastuzumab
32
What is KRAS protein?
- Belongs to Ras proteins family which are cellular signal transducers
- Activated downstream of HER2
- Activated by receptor tyrosine kinases
33
How is KRAS activated?
- KRAS GDP is the inactive form and KRAS GTP is the active form
- Becomes activated when GTP is converted into GDP
- Becomes deactivated when the activated form binds with Pi
- Therefore works like an on/off switch
34
What is the importance of KRAS protein?
The signalling pathways control the transcription of genes when regulate cell growth and differentiation
35
What are some of the pathways KRAS activates?
1. MTORC1 pathway = cell survival, growth, migration
2. PLD pathway = endocytosis
3. RHO pathway = cytoskeleton, cell migration
36
How is KRAS mutated?
Point mutations in hotspots at codons 12/13 and in lower frequencies at 18/61/117/146
37
What does KRAS mutation result in?
- Reduced intrinsic GDP activity which leads to permanent activation of KRAS
- Leads to downstream signalling pathways causing malignant transformations
- This results in KRAS being in a permanent ‘on’ position leading to permanent cell growth and proliferation
38
Is the KRAS oncogene treatable?
Does not react to target therapy but recent research has promising data on small molecular inhibitors
39
What is the BCR-ABL1 oncogene?
- The fusion of protein making gene BCR and signal transducer gene Abl
40
How is the BCR-ABL1 oncogene formed?
- ABL gene is found in chromosome 9
- BCR gene is found in chromosome 22
- The parts of each chromosome containing the gene break off from the chromosome
- The parts of the chromosomes containing ABL and BCR fuse together through balanced translocation, to create changed chromosome 22, also known as Philadelphia chromosome (Ph’)
- The parts of the chromosomes not containing either gene also fuse to create changed chromosome 9
41
Why is Philadelphia chromosome (Ph’) important?
It appears in 95% of cases of chronic myeloid leukaemia (CML)
42
What does BCR do?
Encodes a protein that acts as a guanine nucleotide exchange factor for Rho GTPase proteins
43
What does ABL do?
Encodes a protein tyrosine kinase whose activity is tightly regulated
44
What does the BCR-ABL1 oncogene do?
- Produces BCR-ABL oncoproteins which results in unregulated protein tyrosine kinase activity
45
What are the effects of BCR-ABL oncoproteins?
1. Proliferation of progenitor cells in the absence of growth factors
2. Decreased apoptosis
3. Decreased adhesion to bone marrow stroma (triggers leukaemia)
46
What therapies inhibit BCR-ABL1?
- Easy to diagnose
- Drug imanitib specifically inhibits BCR-ABL1 from phosphorylating substrates in order to treat leukaemia
47
What is c-MYC protein?
- Belongs to Myc family which are genes that encode for transcription factors
48
How do MYCs work?
- They function in a complex with Max protein
- Activates a high number of genes that are involved in many cellular and molecular pathways
49
What are some molecular pathways activated by MYCs?
1. Increased transcription
2. Increased rRNA and protein synthesis
3. Increased glycolysis
50
What are some cellular pathways activated by MYCs?
1. Increased cellular proliferation
2. Increased metabolic transformation
3. Increased metastatic capacity
51
How does c-MYC become activated into an oncogene?
Pathogenic alterations involve gene retrovirus activation, amplifications and translocations
52
What is the retrovirus activation alteration of the c-MYC gene?
- Insertion of a retrovirus between exons 1 and 2 in c-MYC procto-oncogene in the same transcriptional orientation
- The procto-oncogene becomes activated leading to transcription of c-MYC mRNA which translates to produce c-MYC protein
- Commonly found in bursal lymphomas in chickens when retrovirus avian sarcoma leukosis virus (ASLV) is inserted
53
What is the translocation alteration of the c-MYC gene?
- Translocation between chromosome 8 (c-MYC procto-oncogene) and chromosome 14 (immunoglobulin heavy chain gene) resulting in their fusion into one gene
- Commonly observed in 85% of Burkitt’s lymphoma in humans
54
What therapies are there for c-MYC?
- Lack of strategies that directly target c-MYC
- Inhibitors of the translation caused and MYC protein destabilising drugs do show great promise
