oncogenes and tumour suppressor genes

Question 1

major functional changes in cancer

Answer 1

1. increased growth
2. failure to undergo programmed cell death
3. loss of differentiation
4. failure to repair DNA damage

Question 2

what are the 2 major types of mutated gene contributing to cancer

Answer 2

oncogenes = speed up process

tumour suppressors = loss of function

Question 3

describe capture of c-src by retrovirus

Answer 3

virus can acquire fragments of genes from host at integration sites
results in creation of oncogenes. oncogene product characterised as 60kDa intracellular tyrosine kinase

Question 4

describe viral oncogenes

Answer 4

transmitted by either DNA/RNA viruses

Question 5

DNA virus

Answer 5

encode various proteins and environmental factors can initiate and maintain tumours

Question 6

RNA viruses

Answer 6

integrate DNA copies of their genome into genome of host cell and transform oncogenes and induce cancerous transformation of the host

Question 7

describe activation of oncogenes

Answer 7

mutation/amplification or duplication/translocation

Question 8

what is the signal transduction pathway

Answer 8

4 types of protein involved in transduction of growth signals

1. growth factor = oncogenes act as these
2. growth factor receptors
3. intracellular signal transducers
4. nuclear transcription factors

Question 9

describe RAS oncogene

Answer 9

small GTPases normally bound to GDP in neutral state

seen in 30% of cancers
most commonly mutated oncogene

Question 10

process of RAS - intracellular signal transducer

Answer 10

1. binding of extracellular growth factor signal
2. promotes recruitment of RAS protein to receptor
3. recruitment promotes RAS to exchange GDP with GTP
4. activated RAS initiates remainder of signalling cascade
5. these kinases phosphorylate targets e.g. TF to promote expression of genes important for growth and survival

Question 11

describe TFs

Answer 11

MYC oncogene family - 40% of tumours
3 members = C-MYC, MYCN, MYCL
regulate transcription at least 15% of entire genome
ribosomal biogenesis, protein translocation, cell-cell cycle progression and metabolism
encodes helix-loop-helix zipper TF and dimerises partner protein , MAX , to transactive gene expression

Question 12

describe MYC in burkitts lymphoma

Answer 12

BL = high grade lymphoma that can affect children from 2-16 years
in africa, children with malaria = decreased resistance to the virus
carry 1/3 chromosomal translocations that place MYC gene under regulation of Ig heavy chain

Question 13

describe chronic myelogenous leukaemia

Answer 13

15-20% of all leukaemia
95% of CML patients = carry philadelphia chromosome = generates BCR-ABL fusion protein = causes tyrosine kinase activity of oncogene ABL = leads to abnormal proliferation

therapeutic strategies for CML include imatinics = tyrosine kinase inhibitor

Question 14

describe retinoblastoma gene

Answer 14

rare childhood cancer which develops when immature retinoblasts grow v fast and do not turn into mature retinal cells
eye containing tumour reflects light back in white colour = cat eye appearance
hereditary mutation is on chromosome 13

Question 15

describe structure of retinoblastoma protein

Answer 15

Rb gene family = 3 members
Rb (105/110), p107, Rb 2/p130 = pocket proteins
pRb = over 100 binding partners
transcriptional cofactor can bind to TFs

Question 16

main function of Rb

Answer 16

regulate cell cycle by inhibiting G1-S phase transition

2 important proteins involved = cyclins and CDKs

Question 17

what is cyclin D

Answer 17

1st cyclin to be synthesised and drive progression through G1 with cdk4/6

G1 checkpoints lead to arrest of cell cycle in response to DNA damage
key substrate for cyclin D = RB protein
cyclin D + E + cdks phosphorylate RB

Question 18

inactivation of Rb - loss of function

Answer 18

by phosphorylation/mutation/viral oncoprotein binding

pRb inactivated by mutations/partial deletions

Question 19

describe p53 tumour suppressor gene

Answer 19

involved in sensing DNA damage and regulating cell death
p53 mutated in 30-50% of human cancers
prevents appearance of abnormal cells
MDM2 keeps p53 levels low, MDM2 binds p53 = complex in nucleus
MDM modifies carboxyl terminus of p53 and targets it for degradation by proteasome
stress signals can activate p53
signals sensed by kinases that phosphorylate p53
phosphorylation of p53 disturbs interactions with MDM2
so p53 regulates genes, involved in DNA damage repair and apoptosis and cell cycle repair

loss of function in p53 by mutation = cancer

Question 20

describe therapeutic strategies

Answer 20

gene therapy

use of inhibitors