10: Oncogenes and Tumor Suppressor genes Flashcards
What are the 6 original hallmarks of cancer?
SARCOMA
S – Self-sufficiency of growth signaling
A – Apoptosis evasion
R – Resistance to anti-growth factor signaling
CO – Continuous replication (Immortality)
M – Metastasis
A – Angiogenesis
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What are the 4 additional Hallmarks of cancer?
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What are proto-oncogenes?
Genes that code for essential proteins involved in maintenance of cell growth, division and differentiation
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What happens when a proto-oncogene mutates?
It can convert into an oncogene
- no longer responds to control influences
- can be aberrantly expressed, over-expressed or aberrantly active
What kind of mutations normally occur in proto-oncognes that convert them into oncogenes?
A single mutation can be enough:
- point mutation
- deletion
- Gene-amplification
- Chromosomal translocations / Insertional mutagenes
- E.g. Philadelphia chromosome – > hyperactiveness of transcribed gene
- E.g. Burkitts lymphoma –> stonger enhancer in front of gene increase normal protein levels
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What kind of mutation is the phildelphia chromosome?
How does it lead to the formation of cancer?
It is a chromosomal translocation resulting in
- via the BCR-ABL gene fusion product
- BCL causes permanent activation of the ABL-gene product
- ABL is important in proliferation
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Name some commonly mutated oncogenes and their location/MOA
- Transcription factors
- c-Myc
- JUN
- RAS, raf –> activation of kinase cascade
- Tyrosin kinases
- SRC
–> Leading to permanent activation of proliferation!
What are the characteristics of tumor-supressor genes?
- Normally proteins that regulate (supress) cell proliferation and function
- Each cell: 2 copies of each TSG
- normally loss of both copies required to induce malignancy
explain how tumour suppressor genes have been discovered through heritable malignancies
Via the Retinoblastoma gene, development of the 2 hip hypothesis
- Each cell has 2 copies of a TSG
- Need loss of both copies for Cancer
- If one is already damaged –> can be inherited and only one hit is required to develop malignangy, leading to
- Family history of related cancers.
- Unusually early age of onset.
- Bilateral tumours in paired organs.
- Synchronous or successive tumours.
- Tumours in different organ systems in same individual.
- Mutation inherited through the germline.
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Explain the role of APC in Familial adenomatous polyposis coli
APC is a tumor supressor gene, regulating the break down of ß-catnin
- Damage on APC can be inherited leading to
- formation of multiple benign adenomatous polyps of the colon.
- There is a 90% risk of developing colorectal carcinoma.
At the example of colorectal cancer, explain how gene mutations can lead to cancer
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When does p53 get activated?
It gets activated at cellular damage
- cellular stress
- hypoxia
- nitric oxide
- oxidative stress
- Damage
- oncogene activation
- Double strand breaks
- Telomere erosion
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How does p53 get activated?
Via inhibiton of MDM2
- Normally: MDM2 inhibits p53 activtiy
- When activated: sets off repair mechanisms
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Explain the function of PTEN and its role in carciogenesis
It is a Tumor supressor gene
- PTEN can induce apoptosis by inhibiting the phosphorylation of PIP2 into PIP3 (and thereby the pro survival signaling)
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Explain the role of BRCA in carciogenesis
BRCA is a tumor supressor gene normally
- repairing DNA damage
- often mutated in Breast cancer