Oncogenes + Tumour Suppressor Genes

Question 1

Describe homeostasis

Answer 1

Interplay between +tive and -tive growth regulators

Question 2

What can a loss of growth control result from

Answer 2

Activation of +tive regulators
Inactivation of -tive regulators

Question 3

What can cause an increased or prolonged growth signal

Answer 3

RAS mutation where it is no longer recognised by GAP proteins
Deletion/mutation of GAP genes

Question 4

How is Ras activated

Answer 4

Displacement reaction from GTP -> GDP

Question 5

What is the role of GTPase in RAS

Answer 5

Intrinsic activity that brings RAS to ground state
Accelerated by GAP proteins

Question 6

What can a loss of GAP proteins cuase

Answer 6

Constitutively active RAS pathway

Question 7

What is evidence of tumour suppressor genes

Answer 7

Cell hybrid studies
Familial cancers
Non-random chromosome losses in tumours

Question 8

What is the concept of cell hybrid studies

Answer 8

Normal cells can suppress the transformed and tumourigenic phenotype
Cells that revert to a transformed phenotype show loss of specific chromosomes

Question 9

What does the fusion of different tumour cell limes imply

Answer 9

Can produce normal cell hybrids
= different tumour cells have different recessive mutations

Question 10

Describe the Knudson 2-hit hypothesis

Answer 10

Inheritance of a single mutated allele from one parent
Second ,auction in the normal allele during development
= tumour

Question 11

Describe of the characteristics of the RB gene and product

Answer 11

Accosted with DNA but not directly bound
Expressed abundantly in most normal tissues

Question 12

What is the function of the RB protein in transcriptional regulation

Answer 12

Binds and regulation TFs and cell cycle control proteins

Question 13

What is the function of the RB protein in cell cycle control

Answer 13

G0/G1: RB hypo-phosphorylated when bound to E2F -> E2F= inactive
Progression: RB phosphorylation = dissociation of the E2F/RB complex -> releases E2Fs TF activity

Question 14

What is the role of TF E2F

Answer 14

Drives expression of genes required into S-phase
E.g enzymes required for synthesis of DNA and precursors

Question 15

What is the relationship between RB and patients with non-occular tumours

Answer 15

Shows an increased risk
Particularly in osteosarcomas and soft-tissue sarcomas
Structural abnormalities of RB gene found

Question 16

What is the relationship between RB protein expression and prognosis in breast and bladder cancers

Answer 16

Low levels of RB = invasive lesions and poor prognosis

Question 17

Describe the karyotype in sporadic tumours

Answer 17

Unstable
Gains, losses and rearrangements = not random
17p deletions are common

Question 18

What is the critical region of chromosomal deletions in colorectal cancer

Answer 18

17p12-17p13.3

Question 19

What gene is also mapped to the 17p12-12p13.3 regions

Answer 19

TP53
Gene for p53

Question 20

Describe the TP53 mutation

Answer 20

Missense mutation in 1 allele
Coupled with loss of second allele

Question 21

Describe TP53 gene

Answer 21

Deleted in a wide range of common cancers
Compromises of 11 exons
Exons 2-10 code for p53 protein

Question 22

Describe the p53 nuclear phosphoprotein structure

Answer 22

N-terminal: acidic transcription transactivation domain
Central region: DNA biding domain
C-terminal: basic and binds to other p53 to form oligomers

Question 23

Where in the p53 protein do the mutations occur

Answer 23

Within central binding domain
+tively charged arginine residues
Critical for structure and binding to DNA

Question 24

Where is the MDM2 binding domain on p53

Answer 24

N-terminal domain
Heavily phosphorylated

Question 25

Describe Li-Fraumeni syndrome

Answer 25

High susceptibility to a range of malignant tumours
Rare hereditary disorder

Question 26

Describe how p53 levels can be detected

Answer 26

Some mutant forms of p53 can be detected via IHC staining
= mutant forms are stabilised and not degraded

Question 27

Can IHC staining be used to assess TP53 mutational status

Answer 27

No - insufficient data

Question 28

How can p53 act as a non-specific txn regulator

Answer 28

Suppresses a variety of promoters containing TATA elements

Question 29

How can p53 act as a specific txn regulator

Answer 29

Binds directly to specific promoter elements consisting of 20bp consensus

Question 30

What is the role of p53 in response to DNA damage

Answer 30

Induce:
-Cell cycle arrest
-Apoptosis

Question 31

Describe MDM2

Answer 31

E3 ubiquitin ligase that binds to p53 and blocks its txn activity
Targets p53 for degradation

Question 32

What 2 genes are induced by p53 in response to DNA damage

Answer 32

MDM2 and WAF1 (CDKN1A)

Question 33

Describe WAF1

Answer 33

Cyclin dependent kinase inhibitor
Stops RB being phosphorylated
= cell cycle arrest