Oncogenes Flashcards
What are oncogenes derivatives of?
Proto-oncogenes
Are oncogene mutations dominant or negative?
Dominant - only one allele needs to be mutated
What are oncogenes?
Positive regulators of cell growth and proliferation
What stages in the pathway to proliferation are a potential target for oncogenic transformation?
Growth factors
Growth factor receptors
Signal transducers
Nuclear proteins, transcription factors and coactivators
Mechanisms of mutations for an oncogene
Point mutations/ deletion Chromosomal amplification Chromosomal translocation Retroviral insertion Retroviral transduction
Are tumour suppressor genes dominant or negative?
Negative
2 examples of oncogenes which are caused by deletion or point mutations
Ras
Raf
2 examples of oncogenes which are caused by gene amplification
Abl
Myc
Example of an oncogene which are caused by chromosomal rearrangement - inset an enhancer
Ig enhancer: Myc
What is the chromosomal rearrangement required to produce the Ig enhancer Myc?
t[8:14]
Example of an oncogene which are caused by chromosomal rearrangement - gene fusion
BCR:Abl
What is the chromosomal rearrangement required to produce BCR:Abl
t[9:22]
What does gene fusion cause?
Excessive production of hyperactive fusion protein in the cell
Give an example of a virus which is inserted into a chromosome to induce insertional mutagenesis
ALV
3 examples of oncogenes which are caused by retroviral transduction
Ras
Abl
ErbB2
What causes activation of Ras in cancer making it constitutively active?
Viruses
Mutations
What are the 3 forms of Ras
H-
Ki-
N-
When is Ras normally activated in a cell?
When it is bound to GTP
What are the effectors of Ras?
MAPK pathway
PI3K pathway
Rac
Ral
How do you activate Ras?
Mutations at 12, 13 and 61 - constitutive Ras activation
NF1 deletion - no GAP to convert it back to RasGDP
What is NF1?
Neurofibromin
negative regulator of Ras
GAP- GTPase activator protein
What are the 3 forms of Raf?
A-
B-
C-
What causes activation of Raf in cancer making it constitutively active?
Viruses
Mutations
What is Raf?
A serine/threonine kinase
What is the most common Raf mutation?
V600E (85% of mutations)
What domain is Raf commonly mutated?
Clustered kinase domain
What causes activation of c-Abl in cancer making it constitutively active?
Viruses
Mutations
Chromosomal translocations
What is Abl?
a tyrosine kinase
What is the philadelphia chromosome?
t[9:22]
What disease is associated with Abl mutations?
Leukaemias
How is Abl inactive in normal cells?
The N-terminal cap covers the active site of the catalytic domain
Why is Abl active in tumour cells?
The N-terminal cap is changed to BCR and therefore does not inhibit the active site of the catalytic domain
What causes activation of EGFR in cancer making it constitutively active?
viruses
mutations
what is EGFR?
A receptor tyrosine kinase
How is EGFR overactivated?
Mutated so it does not need EGF
EGF is overexpressed so EGFR is always saturated
Where s c-Myc located?
Nucleus
What causes activation of c-Myc in cancer making it constitutively active?
Chromosomal translocation
What cancer is associated with c-Myc?
Burkitt lymphoma
What is c-Myc
a transcription factor
also regulates translation
How does Myc promote cell cycle progression?
Binds to MAX as a heterodimer
binds to the promoter of target genes
activates cyclins
promote cell cycle progression
Why is c-Myc only generally a cell proliferation promoter?
If it is injected into a fibroblast without serum, it will stimulate apoptosis
Give an example drug treatment for BCR:Abl, how it works and for what disease
Gleevac
Structural deregulation of the kinase domain in BCR-Abl by binding to it
Chronic myeloid leukaemia
Give 2 examples drug treatment for EGFR, how it works and for what disease
Getfitinib
Binds to the active site and blocks it in EGFR ErbB2
Non-small cell lung cancer, and other cancers
Herceptin
Ab against the EGF binding site
Currently in clinical use, so no specific cancer
