Oncogenes and Tumour Supressors Flashcards
Recap: What is a hallmark?
A characteristic a normal cell has to acquire in order to become a tumour cell
Which two hallmarks of cancer are linked to oncogenes and tumour supressors?
Sustaining proliferative signalling = oncogene
Evading growth suppression = tumour suppressor proteins
Summarise the major functional changes which occur in cancer
- Increased growth (loss of regulation, stimulation of environment promoting growth e.g angiogenesis)
- Failure to undergo programmed cell death apoptosis or senescence
- Loss of differentiation (including alterations in cell migration and cell to cell adhesion (forms hallmark for metastases)
- Failure to repair DNA damage (including chromosomal instability)
What is an oncogene? (Myc + Ras)
An oncogene is a mutant form of the normal gene (proto-oncogene) which can promote cell proliferation and are permanently active in cancer
They will normally encode for components of growth factor signalling pathways, when mutated they will produce products at a higher quantities or altered products will act in a dominant manner
(Oncogenes can be counteracted by tumour suppressor genes if they are strong enough)
Describe the historical perspective of oncogenes and their discovery
- Francis Peyton Rous used cell filtrate from a large tumour on chicken chest muscle to induce chicken sarcomas in healthy chickens .
- Found that the carcinogenic agent was small enough to pass through a filter (which excluded viruses)
- Concluded that a virus must be responsible
- Discovered that oncogenic transformation by this virus is caused by an extra gene which is contained in its genome called = oncogene (v-src)
- The Rous sarcoma viral gene is actually a host gene which has been kidnapped by the virus and transformed into an oncogene
Why does Rous sarcoma virus cause cancer (sarcoma)?
The virus contains a proto-oncogene (c-src) which acquires fragments of genes from host integration sites, resulting in the creation of a viral oncogene (v-src).
This causes _oncogenic transformation a_nd abnormal grwoth in host cells.
What is v-src?
An oncogene coding for 60kDa intracellular tyrosine kinase which can phosphorylate cellular proteins and affect growth.
(c-src proto-oncogene will acquire fragments of genes from host integration sites = viral oncogene v-src)
How do DNA viruses cause oncogenesis?
DNA viruses will cause lytic infection leading to death of the cellular host or replicate their DNA along with that of the host promoting neoplastic formation
DNA viruses will encode various proteins along with environmental factors which can initiate and maintain tumours
How can RNA viruses cause oncogenesis?
Integrate RNA copies of their genome into the genome of the host cell and as these contain transforming oncogenes they induce cancerous formation of the host
E.g EBV will produce its own oncogene called latant membrane protein (LMP-1) causing Burkitts Lymphoma, B-cell Lymphoma, Nasopharyngeal carcinoma
How can oncogenes be activated?
Oncogenes become activated due to alterations in the proto-oncogene sequence
- Mutations
- Insertions
- Amplification
- Translocation
These alterations can cause a loss of response to growth regulatory factors (only one allele needs to be altered)
What do proto-oncogenes encode?
They are normal signal transduction pathways encoding components of the growth factor signal transduction pathway
What are the products of oncogenes?
Proteins involved in the transduction of growth signals
- Growth factors (EGF)
- Growth factor receptors (ErbB)
- Intracellular signal transducers (Ras and Raf)
- Nuclear transcription factors
What can oncogenic proteins act as?
The oncoproteins produced by oncogenes will function as elements of the signalling pathways which regulate cell proliferation and survival (in response to growth factor stimulation)
Oncogene proteins will act as:
- Growth factors e.g EGF
- Growth factor receptors e.g ErbB
- Intracellular signalling molecules e.g Raf and Ras
What pathway do Ras and Raf activate?
Ras and Raf will activate the ERK/MAP kinase pathway leading to induction of additional genes (e.g fos) that encode potentially oncogenic transcription of regulatory proteins
Describe the discovery of the Ras oncogene family
Ras genes were identified from two cancer causing viruses -
- Harvey Sarcoma and Kirsten sarcoma
- They were originally discovered in rats hence called Rat sarcoma
What are Ras proteins?
Small GTPases which are bound to GDP in their inactive state
-
How can mutated Ras proteins cause oncogenesis?
- Ras proteins become mutated through point mutations
- In codon 12, 13, 61
- CONSEQUENCE = loss of GTPase activity required to return active Ras to inactive Ras GDP = hyperactive Ras (constitutive activation)
What occurs as a consequence of codon 12 point mutation in Ras?
Glycine to Valine = bladder carcinoma
Glycine to Cysteine = lung cancer
Describe the normal RAS mechanism
- Binding of extracellular growth factor signal
- Promote recruitment of Ras proteins to receptor complex
- Recruitment promotes Ras to exchange GDP (inactive Ras) with GTP (active Ras)
- Activated Ras then initiates the remainder of the signalling cascade (protein kinases phosphorylation)
- These kinases will phosphorylate targets (e.g TRANSCRIPTION FACTORS)
- This will promote the expression of genes important for cell growth and survival
Ras will normally hydrolyse GTP to GDP fairly quickly (turning itself off) however in mutated form it is hyperactive
How does Myc perform its role?
Encodes a helix-loop-helix transcription factor which dimerizes with its partner protein Max, to transactivate gene expression
What is the link between burkitts lymphoma and Myc?
- Burkitts lymphoma is associated with Epstein Barr Virus
- Myc is commonly activated in Burkitt’s Lymphoma
- All the BL cases carry one of the three characteristic chromosomal translocations
- Myc gene is under foreign regulation of the Ig heavy chain
- This causes c-myc expression to be deregulated
- Myc gene is under foreign regulation of the Ig heavy chain
- In all three translocations a region from one of these chromosomes is fused to a section of chromosome 8, switching MYC on
What does the eye of someone with retinoblastoma appear like?
- An eye which contains a tumour will reflect light back in a white colour
- This is often called cats eye appearance (technical term leukocoria)
Where is the hereditary mutation for retinoblastoma?
The hereditary mutation is on chromosome 13 (13q14), the retinoblastoma 1 gene
How does Rb support Alfred Knudson’s 2 hit hypothesis?
Most patients will have an inherited mutation (1st Hit) and then acquire a second mutation in the remaining functional copy of the tumour suppressor gene (2nd Hit)
In the sporadic form there is no inheritance, the patient had to acquire two separate hits one in each allele resulting in disease presentation at a later age
What does loss of heterozygosity mean?
Term used to describe the process which leads to inactivation of the second copy of the tumour supressor gene
A heterozygous cell will recieve a second hit in its remaining funcitonal copy of the tumour supressor gene = homozygous for mutated patient
Explain how retinoblastoma protein activity is regulated?
