Oncogenes And Tumour Suppressor Genes Flashcards
What are the major functional changes in cancer?
Increased growth
Failure to undergo apoptosis or senescence
Loss of differentiation
Failure to repair DNA damage
How does increased growth happen in cancer?
Loss of regulation and stimulation of environment promoting growth
What do oncogenes cause?
Gain of function- making cells divide
What are oncogenes?
Altered gene whos product can act in a dominant fashion to help make a cell cancerous
What is the normal version of oncogenes?
Protoconcogenes
What do tumour supressor genes cause?
Loss of function- normal activity prevents cancer formation
What is Rous’s protocol for inducing sarcoma in chickens?
Remove sarcoma and break up into small tissue chunks
Grind up with sand
Filter and collect filtrate through a fine-pore filter
Inject filtrate into young chickens
Observe sarcoma in injected chickens
How is c-src captured by retrovirus?
The virus can acquire fragments of genes from the host at integration sites
What is the c-src oncogene product?
60 kDa intracellular tyrosine kinase
What can the C-Src oncogene do?
Phosphorylate cellular proteins and affect growth
What are the ways to become an active oncogene?
Mutation/deletion
Gene duplication/amplification
Translocation
What do gene duplications/amplifications do for oncogenes?
Increase synthesis of encoded proteins
What are the four types of protein involved in the growth signal transduction pathway?
Growth factors
Growth factor receptors
Intracellular signal transducers
Nuclear transcription factors
What do the majority of oncogene proteins function as?
Elements of the signalling pathways that regulate cell proliferation and surivival in response to growth factor stimulation
What do the majority of oncogene proteins function as?
Growth factors, growth backer receptors and intracellular signalling molecules
What were RAS oncogenes identified from?
Studies of two cancer causing cell lines
What are RAS oncogenes?
Small GTPases that are normally bound to GDP in a neutral state
What proportion of oncogenic activation of RAS is seen in human cancer?
30%
What codons are the mutations in on RAS oncogenes?
12, 13 and 61
What do the point mutations lead to in RAS oncogenes?
Loss of GTPase acting on the RAS protein that is normally used to inactivate the RAS GDP
How do the RAS oncogene intracellular signal transducers work?
Binding of extracellular growth factor signal
- > Promotes recruitment of RAS proteins to the receptor complex
- > recruitment promotes RAS to exchange GDP for GTP (activates RAS)
- > activated RAS then initiates the remainder of the signalling cascade (mitogen activated protein kinases)
- > kinases ultimately phosphorylate targets such as transcription factor to promote expression of genes important for growth and survival
What does the MYC oncogene family consist of?
C-MYC
MYCN
MYCL
Where was the MYC oncogene family originally identified?
In avian myelocytomatosis virus
What are MYC oncoproteins?
Transcription factors
How much of the genome do the MYC oncogenes transcribe?
15%
What are the major downstream effectors of MYC?
Those involved in: Ribosome biogenesis Protein translocation Cell cycle progression and metabolism Cell proliferation, differentiation, survival and immune surveillance
What proportion of human cancers are affected by overexpression of MYC?
40%
What does MYC encode?
Helix-loop-helix leucine zipper transcription factor
How does MYC transactivate gene expression?
Dimerises with MAX (its partner protein)
When is MYC activated (generally)?
Comes under the control of foreign transcriptional promotors
What does activated MYC lead to?
Deregulation of the oncogene that drives proliferation as a result of chromosomal translocation
What is burkitts lymphoma?
High grade lymphoma
Who is affected by burkitts lymphoma?
Children aged 2-16
Where do the chromosomal translocations occur in the MYC gene?
Parts of chromosomes 2, 14 and 22 attach themselves to chromosome 8
Which accounts for 15-20% of leukaemia?
Chronic myelogenous leukaemia
What proportion of chronic myelogenous leukaemia patients carry the philadelphia chromosome?
95%
What is the result of the philadelphia chromosome generation?
Tyrosine kinase activity of the oncogene ABL leading to abnormal proliferation
What are tumour supressor genes usually regulators of?
Cell cycle checkpoints, differentiation or DNA repair
What does loss of tumour supressor gene function require?
Inactivation of both alleles of the gene
Are tumour supressor genes dominant or recessive?
Recessive
When do retinoblastomas occur?
When immature retinoblasts continue to grow very fast and do not turn into mature retinal cells
How can you see retinoblastomas?
Tumour will reflect light back in a white colour
What is leukocoria?
When the tumour reflects light back in a white colour
What are the two forms of retinoblastoma?
Familial
Sporadic
Where is the hereditary mutation in retinoblastoma?
chromosome 13
What does the Rb gene family include?
Three members collectively known as pocket proteins
How many binding partners does prb have?
Over 100
What is the main function of the RB protein?
Regulate the cell cycle by inhibiting G1-S phase transition
Which is the first cyclin to be synthesised?
Cyclin D
What does Cyclin D do?
Drives progression through G1 with CDK 4/6
What does the g1 checkpoint lead to if the DNA is damaged?
Arrest of the cell cycle
What is a key substrate for cyclin D?
RB protein
What is the main binding factor?
E2F transcription factor
What is Rb activity regulated by?
Phosphorylation
What happens when the Rb tumour suppressor is active?
Inhibits cell proliferation
What happens when RB is dephosphorylated?
Active and remains bound to E2F
What happens when RB is phosphorylated?
E2F is released and migrates to the nucleus to induce transcription
What can RB be inactivated by?
Phosphorylation, mutation or viral oncoprotein binding
How does viral inactivation in small DNA tumours mainly work?
Dirupting ELF binding or destabalisation of RB
What was the first tumour supressor gene to be identified?
P53
what is the prevelance of p53 mutation in cancers?
30-50%
What does frequent mutation of p53 in tumour cell genomes suggest?
Tumour cells try to eliminate p53 function before they can thrive
What are p53 levels kept low by?
MDM 2 protein
What is the MDM2 protein made from?
Oncogene-ubiquitin ligase
What happens in normal unstressed cells with MDM2 and p53?
Move between the nucleus and cytosol
What happens with MDM2 and p53 in the nucleus?
Bind to form a complex where MDM modifies the carboxyl terminus of p53 and targets it for degredation by the proteasome
What activates p53?
Stress signals
