Cancer 2: Oncogenes + tumor suppressors Flashcards
What are the 6 main hallmarks of cancer cell phenotype?
Cancer cells… :
- Disregard of signals to stop proliferating.
- Disregard of signals to differentiate.
- Has capacity for sustained proliferation.
- Evades apoptosis.
- Has ability to invade.
- Has ability to promote angiogenesis –> as tumor grows there is increase in demand for nutrients
What is the function of proto-oncogenes?
Proto-oncogenes code for essential proteins involved in maintenance of cell growth, division and differentiation.
What happens when proto-oncogene becomes mutated?
mutation converts proto-oncogene to an oncogene
- -> a single mutation may be enough for conversion
- -> protein no longer responds to control influence
What are the different methods of oncogene activation?
- mutation in coding sequence –> forms aberrantly active protein
- gene amplication / multiple gene copies –> causes overproduction of normal protein)
- chromosomal translocation
OR - insertional mutagenesis
(e.g burkitt’s lymphoma)
–> strong enhancer can increase normal gene levels
(e.g philadelphia chromosome)
–> strong enhancer can form fusion gene
insertional mutagenesis - Viral infection
Proteins involved in signal transduction are potential critical gene targets (proto-oncogenes)
look at diagram on slide —
Activation of proto-oncogenes to oncogenes disrupts normal activity
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look at diagram on slide —
How does a mutant RAS form?
- mutant RAS = has aberrant activity
- GTP binds to RAS –> RAS becomes active
- Which activates RAF
- GTP is dephosphorylated to form –> GDP
- then GDP unbinds from RAS –> and signals to switch RAS off
- mutant RAS –> fails to dephosphorylate GTP
- -> so RAF remains active
- -> increased stimulus to proliferate
What are features of inherited cancer susceptibility?
discovery of Tumor suppressor genes
- Family history of related cancers.
- early age of onset.
- Bilateral tumours in paired organs.
(e. g in kidneys –> other kidney may also be affected) - Synchronous / successive tumours.
(constant development of tumor even after treatment) - Tumours in different organ systems of same individual.
- Mutation = inherited through germline.
What is retinoblastoma?
Malignant cancer of developing retinal cells.
- due to mutation of RB1 Tumor suppressor gene on chr 13q14
unilateral/ bilateral/ multifocal / one eye
Sporadic Retinoblastoma –> usually
Hereditary Retinoblastoma –>
Sporadic Retinoblastoma –> usually involves one eye
Hereditary Retinoblastoma –> unilateral/ bilateral + multifocal disease
Why does mutation of RB1 Tumor suppressor gene on chronic 13q14 cause retinoblastoma?
(i.e what does RB1 usually encode for)
- RB1 encodes for nuclear protein involved in regulation of cell cycle
- mutation –> causes disrupts normal cell cycle
What are some functional classes of tumor suppressor genes?
i.e what are functions of tumor suppressor genes
- 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
What is P53 gene?
P53 = tumor suppressor gene
- suppresses action of oncogene
- -> SPECIAL BECAUSE it requires a single mutational event on a single allele — > to cause problem
(acts like an oncogene )
How does P53 mutation cause tumor?
- P53 mutant –>
- it is dominant
- mutation of single copy = enough to get dysregulation of activity
What is APC tumor suppressor gene ?
Due to a deletion in 5q21 resulting in loss of APC gene (tumour suppressor gene).
- takes part in WNT signaling pathway
What does APC protein normally do?
- APC protein –> helps control activity of B-catenin
- thus prevents uncontrolled growth
note:
G0 - quiescent phase (not replicating)
G1 - Cell makes sure there is enough nutrients etc. to replicate
G2 - point of reflection
there is a checkpoint at the end of G1 phase
-
describe the formation of Philadelphia chromosome
- chr 9 + 22
ABL gene (normally on Chr9) = placed in appropriate position
next to BCR gene (on Ch22)
there is a translocation - so that new Chr 22 has both ABL + BCR gene
–> which can drive to form tumor like phenotype
CML
RAS SIGNALLING
in terms of RAS signaling how might RAF be activated to cause characteristic of oncogenes?
ras - on memb when it binds to GTP RAF associates with RAS when GTP = hydrolyses RAF is released and signalling stops
- when bound –> it is signaling to tell cells to divide
damage to RAF –> signal is permanently turned on –> cause constant division of cells
mutation of single copy of proto-oncogene –> oncogene
drives the cancer process
SRC gene is usually linked to cancer of ….
state its main mechanism
Breast/ lung /colon
via over expression/ C terminal deletion
note:
- proto oncogene - 1 damage –> dominant
- tumor suppressor genes –> needs both genes to be damaged to have tumor like effects
-
How would you treat retinoblastoma ?
remove affected eye
- but likely that retinoblastoma will also affect other eye
What is BRCA 1 gene?
- it is a tumor suppressor gene
- mutation = responsible for breast/ ovarian/ prostate cancer
