Lecture 19 - Oncogenes Flashcards
What is ment by hallmarks of cancer.
Collections of mechanisms that allow cancer to develop
Monoclonal all are derived from a single cell. But not identical.
A typical adult tumour may have 5-8 driver mutations (and hundreds of passenger mutations)
* Driver mutation - mutation that directly or indirectly confers a selective growth advantage to the cell in which it occurs. (occurs first)
○ Early driver mutation typically give cells a growth advantage
* Passenger mutation - mutation that has no direct or indirect effect on the selective growth advantage of the cell in which it occurred. Once uncontrolled division starts mutations are more likely. (leads to genetic differences between cells)
Name some distinguishable charachteristics of cancer cells
Cancer cells acquire distinguishable biological characteristics during their evolution
All the ways a cell can become cancerous:
1. Self-sufficiency in growth signalling
2. Insensitive to signals supressing growth
3. Activating invasion and metastasis
4. Enabling replicative immortality
5. Inducing angiogenesis
6. Ability to avoid apoptosis
7. Deregulating cellular energetics
8. Avoiding immune destruction
9. Genome instability and mutation (how DNA repairs itself etc.)
Tumour promoting inflammation
What are oncogenes?
Dominantly acting (only need one copy to be mutated to cause cancer) cancer-susceptibility genes
* They have normal roes as proto-oncogenes - function in growth signalling pathways that promote cell proliferation or inhibit apoptosis.
* An oncogenes arises from a genetic change that leads to an increase in the activity of protein
* Oncogenic mutations are genetically dominant - mutation of a single allele is sufficient to make a significant contribution to the development of cancer
How do oncogenes drive increased cell proliferation.
- Self-sufficiency in growth signalling - no longer rely on exogenous signals
- Ability to evade growth suppressors
- Resistance to apoptosis
- Replicative immortality
The are six major functional classes of cellular oncogenes that work in cell growth signalling or apoptosis
- Secreted growth factors/mitogens - E.g. epidermal growth factor
- Growth factor/mitogen receptors - E.g. epidermal growth factor receptor
- Signal transduction component
- Transcription factors
- Cell cycle regulators/drivers
Cell death inhibitors
What are the three types of genetic mutations can turn proto-oncogenes into oncogenes.
- Translocation or transposition: gene moved to new locus under new controls (new promoter more active = more transcription)
- Gene amplification - multiple copies of gene
- Point mutation within the gene - codes for hyperactive or degradation resistant protein
What are mitogens and how can they cause cancer?
Mitogens stimulate cell division by binding to a receptor in cell membrane
Gene encoding epidermal growth factor receptor (EFGR) mutated in 40-50% of brain tumours, 20% of breast cancers and 15-30% of ovarian cancers
EFGR mutations include:
1. Amplification - more receptors - lower threshold for capture of mitogen
2. Deletion - results in truncated receptor that lacks extracellular domain - triggers intracellular signalling in absence of mitogen - constitutively active
Mutation of ECFR promotes proliferation by constitutive activation of pathway from growth factor receptor
(self-sufficiency in growth signalling)
How can the Ras protein lead to cancer.
- Signalling protein - activated by growth factor binding to receptor
- Ras protein bound to GDP - inactive
- When mitogen bound -GDP- exchanged for GTP activates signalling by Raf kinase
- Normally activation of Ras is transient (only occurs when mitogen bounds)
- Ras intrinsic GTPase activity hydrolysis GTP to GDP
- 30% of cancers have Ras mutations
- Mutations at codons 12, 13, 61 compromise GTPase activity - signalling pathway becomes constitutively active. Active independent of mitogen binding.
- Sustained signalling in absence of mitogen
(self-sufficiency in growth signalling)
Myc
How can mutations to transcription factors lead to cancer.
- Myc protein - acts in nucleus to stimulate cell growth and division
- Oncogenic mutation lead to increased expression of Myc
- Amplification (of myc transcription factor) - hundreds of copies of a structurally normal oncogene as a result of complex rearrangements that bring together sequences from several different chromosomes
- Myc protein - acts in the nucleus to stimulate cell growth and division.
- Oncogenic mutations lead to increased expression of Myc
○ Point mutation that stabilises Myc (usually rapidly turned over)
○ Translocation results in increased gene expression
E.g. Burkitt’s lymphoma - translocation brings MYC gene under the control of the sequences that normally drive the expression of antibody genes in B lymphocytes (under control of much more active promoter) - mutant B cells proliferate and form a tumour
(self-sufficiency in growth signalling)
What is the role of cell cycle regulators in cancer
Cell cycle regulators
E.g. Cyclin D and Cdk4 (G1-Cdk)
* CCND1 gene encodes cyclin D and is amplified in a wide range of cancers
* Cyclin D overexpression of cyclin D promotes unscheduled entry into S phase
* CDK4 gene encoding Cdk4 is amplified in some tumours including 12% of gliomas, and 11% of sarcomas
* Inappropriate expression of G1 Cdk drives progression through start in the absence of mitogen stimulation.
G1 cyclins drive the progression through the restriction point (G1/S) by regulating gene transcription
In G0 and early G1, transcription activator E2F is bound to and inhibited by Rb protein
To enter the cell cycle Cyclin D associates with Cdk4 or Cdk6 - G1 Cdk
* G1 Cdk phosphorylates Rb - releases E2F
* E2F activates transcription of genes required for G1/S transition
Amplification/overexpression of CCND1 (cyclin D) or CDK4 (Cdk4) leads to unregulated phosphorylation of Rb
How do oncogenes blocking apoptosis cause cancer.
Oncogenes - cell death inhibitors block apoptosis
Apoptosis – activation of intracellular death programme resulting in controlled cell suicide.
Apoptotic cells undergo characteristic changes:
* Cells shrink and condense
* Cytoskeleton collapses
* Nuclear envelope disassembles
* Nuclear chromatin condenses and breaks into fragments.
Cell surface chemically altered – ‘eat me’ signal – engulfed by neighbouring cell or macrophage
Apoptosis is neat and tidy way to get rid of unwanted cells
Extrinsic pathway – triggered by extracellular signal proteins binding to cell surface death receptors
Intrinsic pathway – depends on the release into the cytosol of mitochondrial proteins that are normally in the intermembrane space
What is the role of Bcl2 family proteins in cancer.
The intrinsic pathway of apoptosis is tightly regulated by Bcl2 family proteins.
(Bcl2 in the proto-oncogenic form is anti-apoptotic which is necessary when at appropriate levels)
Increased levels of activated Bcl2, brought about through, for example, oncogene activation leads to blocking of apoposis. (cancer)
Increaed Bax due to p53 activation results in Bax homodimers and induction of apoptosis.
How does MDM2 regulate TSG activity.
MDM2 – ubiquitin ligase
Regulates levels of p53 – required for damage checkpoint activation
In absence of DNA damage MDM2 ubiquitinates lysine’s in the p53 C-terminal domain, targeting it for degradation
Any remaining p53 is exported from the nucleus
In presence of DNA damage MDM2 and p53 are phosphorylated, disrupting interaction, allowing p53 accumulation
MDM2 – amplification of MDM2 found in 19/28 tumour types – common in tumours of adipose tissue (42%), soft tissue sarcomas (20%)
MDM2 mutations prevent accumulation of p53
(Evasion of growth suppressors and resisting cell death)
How can telomerases cause cancer.
- Normal cells in culture cease to divide after 50-70 doublings – senescent – Hayflick limit
- Most somatic cells have low levels of telomerase – consequently telomeres get shorter with successive division (see lecture 5 for activity of telomerase)
- Senescent behaviour of normal cells is associated with changes to structure of telomeres – shortening becomes critical and cells withdraw from cell cycle
- Cancer cells in culture divide indefinitely – immortalised
- Oncogenic mutations reactivate telomerase expression
- Telomerase activity detected in all major cancer types
(Enabling replicative immortality)
