L19: Oncogenes

Question 1

Typical early driver mutations confer…

Answer 1

…a growth advantage

Question 2

What are oncogenes?

Answer 2

They arise from proto-oncogenes, which normally operate in a cell in growth signalling pathways that promote cell proliferation/ inhibit apoptosis. This is as a result of genetically dominant mutations.

Question 3

How do oncogenes drive increased cell proliferation?

Answer 3

• Self-sufficiency in growth signalling
• Ability to evade growth suppressors
• Resistant to apoptosis
• Replicative immortality

Question 4

Give the 6 major classes of cellular oncogenes

Answer 4

• Secreted GFs/ mitogens
• GF/ mitogen receptors
• Signal transduction component
• Transcription factors
• Cell cycle regulators/drivers
• Cell death inhibitors

Question 5

Give the 3 types of mutations that induce an oncogene form a proto-oncogene

Answer 5

1. Translocation/transposition (gene moved to a new locus under new controls)
   -> Normal growth-stimulating protein in excess
2. Gene amplification
   -> Normal growth-stimulating protein in excess
3. Point mutation within the gene
   -> Hyperactive or degradation-resistant protein

Question 6

Mitogen receptors class: example gene and key mutations

Answer 6

EGFR (epidermal GF receptor)
1. Amplification (more receptors, lower threshold for capture of mitogen)
2. Deletion (truncated receptor w/ no extracellular domain so intracellular domain becomes constitutively activated)

Question 7

Signal transduction component class: example, key mutation

Answer 7

Ras (GTPase protein)
Normally inactive w/ GDP attached; when mitogen binds, phosphorylated to GTP which activates signalling by Raf kinase. Ras GTPase activity hydrolyses GTP, turning off this signal.
Mutations in codons 12, 13, 61 compromise this activity
-> sustained signalling

Question 8

Transcription factor class: example and key mutation

Answer 8

Myc Protein (acts in nucleus to stimulate cell division)
- Amplification
- Point mutation (stabilises Myc, not degraded so remains active)
- Translocation (incr. gene expression)

Question 9

Burkitt’s Lymphoma

Answer 9

Translocation brings MYC gene under the control of sequences that normally drive the expression Ab genes in B lymphocytes - mutant B cells proliferate and form a tumour

Question 10

Cell cycle regulator class: examples

Answer 10

• CCND1 gene (encodes Cyclin D) - overexpression promotes unscheduled entry into S phase
• CDK4 gene can also be amplified - overexpression drives progression through start in the absence of mitogen stimulation

Question 11

Apoptotic cells: steps

Answer 11

• Cells shrink and condense
• Cytoskeleton collapses
• Nuclear envelope disassembles
• Nuclear chromatin condenses and breaks into fragments
• Cell surface chemically altered, signals to be engulfed by neighbouring cell or macrophage

Can be triggered by external signal proteins binding to death receptors (extrinsic pathway) or by the release of mitochondrial proteins into the cytosol (intrinsic pathway)

Question 12

Intrinsic apoptosis pathway (Bcl2 family)

Answer 12

• Bax is pro-apoptotic whereas Bcl2 is ant-apoptotic
• Normally the two exist as a heterodimer and are carefully balanced
• Increased Bax due to p53 activation induces apoptosis
• Increased Bcl2 activation blocks apoptosis, inducing immortality

Question 13

MDM2 activity + mutation

Answer 13

• MDM2 is a ubiquitin ligase which regulates TSG (p53) activity
• In the absence of damage, it ubiquitinates lysines in the p53 C-terminal domain, targeting them for degradation
• When damage occurs, both are phosph., breaking up their interaction -> p53 accumulates -> progression halted
• Amplification of MDM2 prevents this

Question 14

Telomerase

Answer 14

• Prevents shortening of telomeres (normally occurs with each division -> Hayflick limit)
• Oncogenic mutations reactivate telomerase expression
  -> immortalised (divide indefinitely)