Oncogenesis and tumour suppressor genes Flashcards
What are the major functional changes in cancer?
- Increased growth
• Loss of growth regulation, stimulation of environment promoting growth e.g. angiogenesis) - Failure to undergo apoptosis/senescence
- Loss of differentiation
○ Including alterations in cell migration and adhesion - Failure to repair DNA damage
-Including chromosomal instability
What are oncogenes normally components of?
Many oncogenes are normally components of growth factor signalling pathways
What happens when oncogenes are mutated?
When mutated produce products in higher quantities or whose altered products have increased activity and therefore act in a dominant manner
What do tumour suppressor gene products act as?
Many tumour suppressor gene products act as a stop signal to uncontrolled growth, may inhibit the cell cycle or trigger apoptosis
What is the normal job of oncogenes?
• Normal job: make cells divide, driving cell division forward
What happens in cancer to oncogenes?
In cancer:Pick up mutations that mean they are permanently active
What does a mutation cause to oncogenes?
Mutation causes gain of function
What has to occur in order to completely knock out tumour suppressor function?
In order to completely knock out tumour suppressor function, must have mutations in both alleles – two hit hypothesis
What does a mutation cause to tumour suppressor gene?
Mutation causes loss of function
How can viral oncogene be transmitted?
Viral oncogenes can be transmitted by either DNA or RNA viruses
What can DNA viruses cause?
• DNA viruses can cause lytic infection leading to the death of the cellular host or can replicate their DNA along with that of the host and promote neoplastic transformation
What do DNA viruses encode?
○ Encode various proteins along with environmental factors can initiate and maintain tumours
What do RNA viruses integrate and induce?
○ Integrate DNA copies of their genomes into the genome of the host cell and as these contain transforming oncogenesthey induce cancerous transformation of the host
What causes activation of oncogenes?
○ Mutations
○ Insertion
○ Amplifications
○ Translocations
What does activation of oncogenes do?
○ Loss of response to growth regulatory factors
○ One allele needs to be altered
What are the 4 types of proteins involved in the transduction of growth signals?
- Growth factors
- Growth factor receptors
- Intracellular signal transducers
- Nuclear transcription factors
What do the majority of oncogene proteins function as?
○ The majority of oncogene proteins function as elements of the signalling pathways that regulate cell proliferation and survival in response to growth factor stimulation
What do oncogene proteins act as?
Oncogene proteins act as growth factors (e.g.EGF), growth factor receptors (e.g. ErbB) and intracellular signalling molecules (Ras and Raf)
What pathway do Ras and Raf activate and what does this lead to?
Ras and Raf activate the ERK MAP kinase pathway, leading to the induction of additional genes (e.g. fos) that encode potentially oncogenic transcriptional regulatory proteins
What are RAS proteins?
○ RAS proteins are small GTPases that are normally bound to GDP in a neutral state
What percentage of cancers is oncogenic activation of Ras seen in?
○ Oncogenic activation of ras is seen in about 30% of human cancer
What is the most commonly mutated oncogene?
Ras gene
Where do the point mutations for Ras occur?
In codons12, 13, 61
What does a mutation from glycine to valine in Ras cause?
Glycine to valine - bladder carcinoma
What does a mutation from glycine to cysteine in Ras cause?
Glycine to cysteine - lung cancer
What are the steps involved in activating Ras and what do these activated Ras do?
- Binding of extracellular growth factor signal
- Promotes recruitment of RAS proteins to the receptor complex
- Recruitment promotes Ras to exchange GDP (inactive Ras) with GTP (active Ras)
- Activated Ras then initiates the remainder of the signalling cascade (mitogen activated protein kinases)
- These kinases ultimately phosphorylate targets, such as transcription factor to promote expression of genes important for growth and survival
How is Ras inactivated?
- Ras hydrolyzes GTP to GDP fairly quickly, turning itself “off”
What does mutations in the codons of Ras result in?
• Mutation in codons results in hyperactive Ras protein
○ Always switched on
Cells are continually dividing
– leads to tumorigenesis
What does the MYC oncogene family consist of and what do they encode?
○ The MYC oncogene family consists of 3 members, C-MYC, MYCN, and MYCL, which encode c-Myc, N-Myc, and L-Myc, respectively
What family does the MYC oncoproteins belong to?
○ The MYC oncoproteins belong to a family of transcription factors that regulate the transcription of at least 15% of the entire genome
What are the main downstream effectors of MYC include?
○ Major downstream effectors of MYC include those involved in:
§ ribosome biogenesis
§ Protein translation
§ Cell-cycle progression and metabolism
§Orchestrating a broad range of biological functions
In what is MYC oncogene overexpressed?
○ The MYC oncogene is overexpressed in the majority of human cancers and contributes to the cause of at least 40% of tumours
What does MYC oncogene encode and what does it dimerize?
○ It encodes a helix-loop-helix leucine zipper transcription factor that dimerizes with its partner protein, Max, to transactivate gene expression
When is MYC generally activated and what does this lead to?
○ Generally MYC is activated when it comes under the control of foreign transcriptional promoters. This leads to a deregulation of the oncogene that drives relentless proliferation.
What is activation of MYC a result of?
○ Such activation is a result of chromosomal translocation
What virus is associated with Burkitt’s lymphoma?
Epstein Barr virus is associated with Burkitt’s lymphoma
What is burkitt’s lymphoma?
• BL is a high grade lymphoma that can effect children from the age of 2 to 16 years
When does EBV infection usually happen and what happens if this infection is delayed to teenage years?
• Usually this infection happens in childhood but if it is delayed to teenage years, you get infection mononucleosis or glandular fever