Carla - Proto-oncogenes Flashcards
What is the hypothetical series of events to form a cancer cell?
- Initial mutation inactivates a negative cell cycle regulator
- Next mutation overactivates a positive cell cycle regulator
- Third mutation inactivates a genome stability factor
- Additional mutations accumulate rapidly
- Cancer cell formed
What are proto-oncogenes?
Genes whose products promote cell growth and division
Positive cell cycle regulators
What do proto-oncogenes encode?
Transcription factors that stimulate expression of other genes
Signal transduction molecules that stimulate cell division
Cell-cycle regulators that move through the cell cycle
What is an oncogene?
A gene which can transform a cell into a tumour cell
What must happen to proto-oncogenes for them to become oncogenes?
They must gain an amplification or activating mutation that results in them gaining the ability to transform a cell into a cancer cell
What do oncogenes cause to happen to cells?
(4)
Hyperactive growth and division
Protection against apoptosis
Loss of respect for normal tissue boundaries
Ability to become established in diverse tissue environments
What causes the conversion of proto-oncogenes to oncogenes?
This happens through genetic alteration
It typically leaves a gene continuously switched on
Give five types of oncogenes
Ras
Myc
CDK4
BCR/ABL
BCL-2
What are the three RAS isoforms?
H-Ras
K-Ras
N-Ras
How does Ras acct as an oncogene?
The active or mutant versions are found in many cancers e.g. colorectal
What is Ras?
Gene that encodes p21
What are the two types of Myc?
c-Myc
N-Myc
How does Myc act an oncogene?
(3)
It is over expressed in colorectal and breast cancers
It is rearranged in lymphomas
It is amplified in breast cancers and neuroblastomas (n-Myc)
How does CDK4 act as an oncogene?
Its mutated in familial melanoma
It has sporadic mutations in other tumours
How does BCR/ABL act as an oncogene?
Chimeric gene produced from the fusion of genes through chromosomal rearrangements -> The Philadelphia Chromosome
Cause of most chronic myelogenous leukaemias
How does BCL-2 act as an oncogene?
It is overexpressed due to a t translocation in follicular lymphoma
What type of mutation in Ras is commonly seen in cancer?
A single point mutation is seen
What does the most common point mutation in Ras do?
(2)
The mutation results in the conversion of a Glycine to a Valine
This valine forms a protein that hydrolysis GTP to GDP very inefficiently
How does Ras normally function?
It switches between active and inactive conformations
What does a Ras mutation do to its activation?
It inhibits Ras GTPase activity thus locking it permanently in the active state
What is Myc
A family of regulator genes and proto-oncogenes that code for transcription factors
What does Myc do?
Responsible for:
-proliferation
-differentiation
-apoptosis
-metabolism
What % of cancers are caused by Myc mutations?
40%
What does c-Myc encode?
A transcription factor that forms a hetero-dimeric complex Max
What is Max?
Myc-associated factor X
What does the c-Myc/Max complex do?
Regulates the expression and activity of:
- cell cycle regulatory proteins
-Cyclins,
-CDKs,
-CDK inhibitors and
-E2F
What is induction of c-Myc needed for?
It is necessary to drive quiescent cells into the S phase
Cancer cells contain hundred of extra copies of proto-oncogenes, comment on these?
(3)
These extra copies exist as:
Extrachromosomal bodies (double minutes)
OR
Extensive tandem repeat insertions within the chromosome
Comment on the over expression of Myc
Forms extrachromosomal bodies
Mutation arises from too many copies of the gene being present (mutation not in the gene itself)
What is a chromosomal translocation?
A chromosomal rearrangement in which part of one chromosome is detached by double stranded DNA and subsequently joined to a second non-homologous chromosome
What does chromosomal translocation result in?
Results in the tightly regulated promoter or regulatory elements for one gene being replaced by the regulatory DNA sequence elements a highly active promoter
What causes mutations?
(8)
Chemicals
Radiation
Some viruses
Tobacco smoke
Red meat
Nitrites
Alcohol
Mould
