Tumour Supressor Genes

Question 1

What are tumour supressor genes?

Answer 1

Genes whose ABSENCE leads to a cancerous phenotype

Normal function is to suppress growth or promote apoptosis

Usually recessive at cellular genetic level
= but often show dominant inheritance in cancer predisposition syndromes

e.g. RB and p53

(Extra reading - more examples)
= BRACA1/2 = breast cancer
= PTEN = breast, prostate, thyroid + more
= APC = colon and rectal cancer
= NF1 = neurofibromatosis
= STK11 = lung , pancreatic
= CDKN2A = melanoma, pancreatic

Question 2

What is Rb?

Answer 2

Retinoblastoma = childhood cancer (typically under 5)

2 forms
= Unilateral - no family history, can be cured by removing tumour
= Bilateral - family history, life-long increased risk of developing other cancer types

Discovered due to Knudson’s two-hit hypothesis for retinoblastoma

= there are inactivating mutation found across RB1 gene
(characteristic of TSGs)

Question 3

What does Rb do?

Answer 3

= negatively regulates proliferation

1. unphosphorylated Rb binds E2Fs, preventing S phase entry
2. Rb is phosphorylated by Cdk, releasing E2Fs
3. E2Fs upregulate genes required for entry to S phase

Question 4

What is p53?

Answer 4

= a tumour supressor
(“guardian of the genome”)

gene = TP53

p53
= transcription factor that regulates genes involved in:
- cell cycle arrests (e.g. p21CIP1 / WAF1)
- DNA repair (e.g. XPA)
- inhibition of angiogenesis (e.g. TSP-1)

= often mutated in cancer

Question 5

How is p53 stabilised (activated) following cell stress?

Answer 5

ATM / ATR
= examples of p13 kinase-like kinases (PIKKs)
= aided by other accessory proteins
= they surveil the genome for DNA damage
= activate signal transduction pathways
(= the DNA damage response - more complex)

Chk1 / Chk2 kinase activation

Phosphorylation of p53
= goes from Mdm2 bound inactive version (p53 ubiquitylation and degradation in proteasomes)

= disrupts binding of Mdm2 = does NOT ubiquitylate p53
= stable, active p53
= enables very quick response to stress rather than waiting for transcription / translation
= active p53 binds to regulatory region of p21 gene (example)

Question 6

What is p21? (CDKN1A)

Answer 6

A target gene for p53 that inhibits cell cycle progression

= active p53 binds to regulatory region of p21 gene (example)
= stabilisation of p53 drives transcription of p21
= p21 binds to CDKs inhibiting their function and causing cell cycle arrest

Question 7

What are some examples of other p53 targets?

Answer 7

Involved in
= Apoptosis
= Metabolism
= Autophagy
= Translation control
= Feedback mechanisms
= Cell cycle arrest
= DNA repair

Question 8

What does oncogenic signalling lead to? What are other ways to achieve this?

Answer 8

Oncogenic signalling activates p53
= leads to cell cycle arrest or apoptosis

= there are many ways cancer cells evade apoptosis not just loss of p53 function

(Extra reading)
= also over-expression of anti-apoptotic proteins (e.g. Bcl-2, Mcl-1)
= dysregulation of PI3K/Akt signalling pathway
= inactivation of death receptor pathway
= altered expression of microRNAs

Question 9

What are telomeres?

Answer 9

= the ends of chromosomes are protected by telomeres (think shoelaces)

= telomeres get progressively shorter with successive generations
( due to synthesising primer in lagging strand that isn’t replicated)

Question 10

What is telomerase?

Answer 10

= resynthesises telomeres to counterbalance the shortening effect

= normally only expressed in germ cells and stem cells

= most cancer cells become immortal by expressing TERT (the telomerase gene)

= expression of telomerase (in cancer cells) is associated with poor prognosis

Question 11

What is the Warburg effect? (Deregulation of cellular energetics)

Answer 11

Normal cells
= divert most pyruvate to Krebs cycle (efficient ATP production)
= oxidative phosphorylation
= BUT = requires oxygen, leaves little for biosynthetic pathways

Cancer cells
= 80% of cancers rely on aerobic glycolysis for energy instead
= due to hypoxic environment (but still occurs in presence of oxygen) , source of biosynthetic building blocks

= explains why PET imaging used with fluorescent glucose

(Extra Reading)
= Otto Warburg, 1920s
= noticed cancer cells consumed large amounts of glucose and produced lactic acid (even in the presence of oxygen)
= is a possible treatment target - the metabolic pathways that are altered in cancer cells