7 - Oncogenes and Tumour Suppressor Genes Flashcards
Name 4 Major Functional Changes in Cancer 4
- Increased growth (loss of growth 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 adhesion)
- Failure to repair DNA damage (including chromosomal instability)
Define Oncogenes 1
An altered gene whose product can act in a dominant fashion to help make a cell cancerous.
Oncogene is a mutant form of a normal gene (a “proto-oncogene”) involved in the control of cell growth or division.
Many oncogenes are normally components of growth factor signalling pathways that when mutated produce products in higher quantities or whose altered products have increased activity and therefore act in a dominant manner.
Their normal job is to make cells divide, driving cell division forward
In cancer, they pick up mutations that mean they are permanently active.
Oncogene: “Gain of function”
If you activate an oncogene you are speeding up the growth
Define Tumour suppressor gene 1
Many tumour suppressor gene products act as a stop signal to uncontrolled growth, may inhibit the cell cycle or trigger apoptosis.
Even if you have a mutation in an oncogene that pushes cell division forward, if your tumour suppressor genes are strong enough, they should still be able to counteract the oncogene
A gene whose normal activity prevents formation of a cancer.
Both genes for the tumour suppressor must be mutated
Loss of this function by mutation enhances the likelihood that a cell can become cancerous (a normal process to maintain control of cell division is lost).
In cancer, pick up mutations that switch the gene off.
Tumour Suppressor gene: “Loss of function”
Tumour suppressor act normally as a counteracted to oncogenes
Function of a normal oncogene 3
Oncogene is a mutant form of a normal gene (a “proto-oncogene”) involved in the control of cell growth or division.
Their normal job is to make cells divide, driving cell division forward
In cancer, they pick up mutations that mean they are permanently active.
If you activate an oncogene you are speeding up the growth
Function of a mutated oncogene 3
An altered gene whose product can act in a dominant fashion to help make a cell cancerous.
Many oncogenes are normally components of growth factor signalling pathways that when mutated produce products in higher quantities or whose altered products have increased activity and therefore act in a dominant manner.
In cancer, they pick up mutations that mean they are permanently active.
Function of a normal TSG 3
Many tumour suppressor gene products act as a stop signal to uncontrolled growth, may inhibit the cell cycle or trigger apoptosis.
Even if you have a mutation in an oncogene that pushes cell division forward, if your tumour suppressor genes are strong enough, they should still be able to counteract the oncogene
A gene whose normal activity prevents formation of a cancer.
Function of a mutated TSG 3
Both genes for the tumour suppressor must be mutated
Loss of this function by mutation enhances the likelihood that a cell can become cancerous (a normal process to maintain control of cell division is lost).
In cancer, pick up mutations that switch the gene off.
Tumour Suppressor gene: “Loss of function”
What is the Knudson hypothesis? 4
Knudson hypothesis, also known as the two-hit hypothesis.
Is the hypothesis that most tumour suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change.
Two separate mutations in each allele are required to knockout the function of a tumour suppressor
A mutation in one of those alleles this behaviour in a dominant manner and gene is activated –> cell proliferation. Loss of function.
First mutation in one allele is not enough to have a functional effect on that protein, two mutations one in each allele is required to change function and make that tumour suppressor inactive.
There are many pathways affected by oncogenes and tumour suppressor proteins
There are many pathways affected by oncogenes and tumour suppressor proteins
RAS – part of normal cell growth signalling pathways
Myc – important oncogene
Tumour suppressor gene – Rb and P53 (guardian of the genome)
Oncogenes - A Historical Perspective - Landmark experiments
Frances Peyton Rous began his work in 1910 that lead to the discovery of Rous sarcoma virus (RSV).
50 years later he received the Nobel Prize in Medicine in 1986
In 1911 when a farmer brought Rous a prized Plymouth Rock hen that had a large tumour growing in the chest muscle, he used the cell free filtrate from the chicken sarcoma and was able to induce sarcomas in healthy chickens
He was brought a chicken which had a massive tumour in the chest wall (sarcoma) –> chicken sarcoma
Although some human cancers are thought to be transmissible through viruses, most are confined to other animals.
The idea that cancer was transmissible was already circulating as early as 1840 when an Italian scientist
Domenico Rigoni-Stern observed that nuns in Verona rarely developed cervical cancer. Papilloma virus was not identified until 1983
He took the chicken and removed the sarcoma and broke it into small chunks and then ground them with sand and filtered it
He took the filtrate and injected it into young healthy chickens
Why are retroviruses important experimentally 5
Retroviruses were important experimentally:
- technological advances
- funding
- improved tissue culture techniques
- the discovery of reverse transcriptase, RNA
- genome, replicates via DNA intermediate and that they are enveloped.
c-scr definition 1
c-src, cellular oncogene
C-src is a cellular oncogene that is acquired by the virus.
v-src defintion 1
v-src proto-oncogene altered form transduced by retroviruses
V-src is a proto-oncogene, an altered form of c-src transduced by retroviruses.
Following infections, the v-src oncogene was expressed at high level in the host cell, causing uncontrolled cell growth and division and cancer.
How did Frances Peyton Rous induce sarcoma in healthy chickens 1
cell free filtrate from the chicken sarcoma and was able to induce sarcomas in healthy chickens
Oncogenic transformations by RSV were found to be caused by? 1
Decades later oncogenic transformation by this virus was found to be caused by an extra gene contained in its genome an ‘oncogene’ called v-src
Oncogenic transformations by RSV were found to be caused by? 1
Rous’s protocol for inducing sarcoma in chickens
- Bacteria was too small so must’ve been a virus
- Tumours developed weeks later
- Taking the new sarcoma, filtrates produced could also induce tumours in other chickens
- The cycles could be repeated indefinitely. Also the carcinogenic agent was small enough to pass through a filter
- Although the filter used excluded bacteria it was not small enough to exclude viruses
- Rous concluded that a virus must be responsible for the induction of tumour formation
- Discovery that this sarcoma was transmissible through viruses- Rous Sarcoma Virus.
Harold Varmus and J. Michael Bishop research on RSV 7
- Upon finding there was a gene homologous sequence to v-src in uninfected chickens, in 1989 Harold Varmus and J. Michael Bishop received the noble prize for laying down the foundation of mutations in carcinogenesis
- Discovered that some genes of cancer-causing viruses were mutated forms of the cellular gene not viral genes
- They concluded that the RSV gene was in fact a host gene that had been ‘kidnapped’ by the virus (and ‘transformed’ into an oncogene)
- An oncogene is any cellular gene that upon activation can transform a cell. Viral SRC was a mutated cellular gene.
- Used hybridisation experiments, and they found that the c-src gene was present in the genome of many species.
- They then showed that the host cell c-src gene was normally involved in the positive regulation of cell growth and cell division.
- Following infection, however, the v-src oncogene was expressed at high levels in the host cell, leading to uncontrolled host cell growth, unrestricted host cell division, and cancer.
Harold Varmus and J. Michael Bishop concluded that RSV is? 1
They concluded that the RSV gene was in fact a host gene that had been ‘kidnapped’ by the virus (and ‘transformed’ into an oncogene)
What did Harold Varmus and J. Michael Bishop find from their hybridisation experiments? 3
Used hybridisation experiments, and they found that the c-src gene was present in the genome of many species.
They then showed that the host cell c-src gene was normally involved in the positive regulation of cell growth and cell division.
Following infection, however, the v-src oncogene was expressed at high levels in the host cell, leading to uncontrolled host cell growth, unrestricted host cell division, and cancer.
When proto-oncogenes are activated what do they become> 1
Proto oncogenes have to be activated to become active oncogenes
Function of SRC 1
SRC was usually involved in cell growth but when mutated you lose that function
Capture of c-src by retrovirus 6
- During evolution, the virus can acquire fragments of genes from the host at integration sites and this process results in the creation of oncogenes.
- This results in the creation of oncogenes.
- The oncogene product was characterised as a 60kDa intracellular tyrosine kinase
- Can phosphorylate cellular proteins and affect growth
- The provirus is accidentally integrated next to the host cellular SRC sequence –> you get this fusion which then gets packaged into a capsid.
- End up with an RSV with a viral-src.
Following infections what oncogene is expressed? 1
What does it cause? 1
Following infections, the v-src oncogene was expressed at high level in the host cell, causing uncontrolled cell growth and division and cancer.
Viral Oncogenesis 3
Approximately 15%-20% of all human cancers are caused by oncoviruses
Viral oncogenes can be transmitted by either DNA or RNA viruses.
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
How many human cancers are caused by oncoviruses 1
Approximately 15%-20% of all human cancers are caused by oncoviruses
How can Viral oncogenes be transmitted? 2
Viral oncogenes can be transmitted by either DNA or RNA viruses.
How can DNA viruses cause a lytic infection? 1
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
Viral Oncogenesis - DNA Viruses 1
Encode various proteins along with environmental factors can initiate and maintain tumours
Viral Oncogenesis - RNA Viruses
Integrate DNA copies of their genomes into the genome of the host cell and as these contain transforming oncogenes they induce cancerous transformation of the host
Examples of human oncogenic viruses - table
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Selected oncogenes, their mode of activation and associated human tumours - table
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How can you activate an oncogene? 3
- Mutation
- Amplification/duplication
- Translocation
Ways to become an active oncogene and can INCREASE synthesis of protein
How to become a bad oncogene - diagram
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What do protooncogenes do in the growth factor signal transduction pathway 1
Proto-oncogenes encode components of the growth factor signal transduction pathway
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 4 types of proteins are involved in the transduction of growth signals 4
4 types of proteins are involved in the transduction of growth signals
Growth factors
Growth factor receptors
Intracellular signal transducers
Nuclear transcription factors
What do oncogene proteins act as 3
Oncogene proteins act as
- growth factors (e.g. EGF)
- growth factor receptors (e.g. ErbB)
- intracellular signalling molecules (Ras and Raf).
What are the oncogene pathways that are intracellular signalling molecules 2
What pathway do they activate 1
What does this pathway lead to 1
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 studies was RAS discovered in 2
ras genes were identified from studies of two cancer-causing viruses the
- HARVEY SARCOMA VIRUS
- KIRSTEN SARCOMA VIRUS
These viruses were discovered originally in rats hence the name Rat sarcoma
What are RAS proteins 1
What are they normally bound to 1
RAS proteins are small GTPases
Normally bound to GDP in a neutral state
How is RAS activated 1
What % in oncogenic cancer 1
Activated by point mutations
Oncogenic activation of ras is seen in about 30% of human cancer
Name 3 most commonly mutated oncogenes 3
Most commonly mutated oncogene
Point mutations in codons 12, 13 and 61
Glycine to valine - bladder carcinoma
Glycine to cysteine - lung cancer
Intracellular Signal Transducers - Activation of Ras - steps 5
- Binding of extracellular growth factor signal
- Promotes recruitment of RAS (GTPase) 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
- Ras hydrolyses GTP to GDP fairly quickly, turning itself “off”
- Consequence of each of these mutations is a loss of GTPase activity of the RAS protein normally required to return active RAS to the inactive RAS GDP
What can a mutation in Ras cause 1,2
Mutation in RAS means it’s always switched on, hyperactivation
Continually get progression through the cell cycle, they can’t stop and so that leads to tumour genesis, don’t go through checkpoints.
How can a mutation in Ras lead to hyperactive Ras, what mutation occurs 1
Consequence of each of these mutations is a loss of GTPase activity of the RAS protein normally required to return active RAS to the inactive RAS GDP
What is the MYC Oncogene Family 1
Transcription Factors
The MYC oncoproteins belong to a family of transcription factors that regulate the transcription of at least 15% of the entire genome
Name 3 members of the MYC oncogene family 3
What do they encode for 3
The MYC oncogene family consists of 3 members,
- C-MYC
- MYCN
- MYCL
which encode c-Myc, N-Myc, and L-Myc, respectively
Where was the MYC oncoproteins originally identified 1
Originally identified in avian myelocytomatosis virus (AMV)
Name downstream effects of MYC oncoproteins 4
- ribosome biogenesis
- protein translation
- cell-cycle progression and metabolism
- orchestrating a broad range of biological functions
- cell proliferation, differentiation, survival, and immune surveillance
Is the MYC oncoproteins over or underexpressed in the majority of human cancers? 1
What % contributes to human tumours? 1
The MYC oncogene is overexpressed in the majority of human cancers
Contributes to the cause of at least 40% of tumours
What does the MYC oncogene code for? 1
What does this dimerise with? 1
A helix-loop-helix leucine zipper transcription factor that dimerizes with its partner protein, Max, to transactivate gene expression.
What does a helix-loop-helix leucine zipper and its partner protein, Max do? 1
A helix-loop-helix leucine zipper transcription factor that dimerizes with its partner protein, Max, to transactivate gene expression.
Activation of MYC oncogenes is a result of what? 1
Such activation is a result of chromosomal translocation
This leads to a deregulation of the oncogene that drives relentless proliferation.
Activation of MYC oncogenes by chromosomal translocation is a characteristic of what type of tumour? 1
Which you get if you are infected by? 1
Activation via chromosomal translocation very much characteristic of Burkitt lymphoma –> tumour type that you get if you have been infected with Epstein Barr virus (EBV).
What is Burkitt’s lymphoma (BL) 2
BL is a high-grade lymphoma
can affect children from the age of 2 to 16 years
In central Africa, children with chronic malaria infections have a reduced resistance to the virus. This is known as classical African or endemic BL In Africa it is found in the jawbone.
In central Africa why do children have a reduced resistance to the virus? 1
What is this known as? 1
Where is this found? 1
In central Africa, children with chronic malaria infections have a reduced resistance to the virus.
This is known as classical African or endemic BL
In Africa it is found in the jawbone.
The MYC gene is under regulation by what chain? 1
What happens here? 1
MYC gene under the regulation of the Ig heavy chain
chromosomal translocations
All BL cases carry one of three characteristic chromosomal translocations, what chromosomes do they occur in 3
In BL three distinct, alternative chromosomal translocations involving chromosomes 2, 14 and 22.
In all three translocations a region from one of these three chromosomes is fused to a section of chromosome.
What happens in the chromosome translocations in BL? 1
In all three translocations a region from one of these three chromosomes is fused to a section of chromosome.
What effect do the chromosomal locations in BL have on Myc gene? 2
- Lose control of Myc so you get lots of proliferation
- Mutation of Myc gene so now under control of immunoglobin heavy chain. So from chromosome 2,14,22 to chromosome 8 and Myc is switched on all the time
Name another disease caused by the activation of oncogenes due to chromosomal translocation 1
Chronic myelogenous leukaemia (CML) accounts for 15-20% of all leukaemia’s
What % of leukaemia does CML account for 1
Chronic myelogenous leukaemia (CML) accounts for 15-20% of all leukaemia’s
What number of CML patients carry a different type of chromosome? 1
What is this chromosome called? 1
95% of CML patients carry the Philadelphia chromosome, that is the product of the chromosomal translocation t(9;22)(q34;q11) generating the BCR-ABL fusion protein
The Philadelphia chromosome is a product of what chromosomal translocation 1
What does this generate 1
Philadelphia chromosome, that is the product of the chromosomal translocation t(9;22)(q34;q11) generating the BCR-ABL fusion protein
What is the result chromosomal translocation done by the Philadelphia chromosome? 1
95% of CML patients carry the Philadelphia chromosome, that is the product of the chromosomal translocation t(9;22)(q34;q11) generating the BCR-ABL fusion protein
As a result of this translocation the tyrosine kinase activity of the oncogene ABL is constitutive leading to abnormal proliferation
Name a therapeutic strategies for CML? 1
What is its function? 1
Therapeutic strategies for CML include Imatinib (Gleevac) a tyrosine kinase inhibitor-96% remission in early-stage patients
The Logic of Tumour Suppressor Genes
The Logic of Tumour Suppressor Genes
Like other well-designed control systems biological systems follow a similar logic-component promoting a process must be counterbalanced by others that oppose the process-tumour suppressor genes.
What do tumour suppressor gene products act as 3
Tumour suppressor gene products act as stop signs to uncontrolled growth, promote differentiation or trigger apoptosis
What are tumour suppressor genes regulators of 3
Therefore they are usually regulators of
- cell cycle checkpoints (e.g. RB1)
- differentiation (e.g. APC)
- DNA repair (e.g. BRCA1)
How can a loss of tumour suppressor gene come about 1
What is it a result of 2
Loss of tumour suppressor gene function requires inactivation of both alleles of the gene
Inactivation can be a result of mutation or deletion
What type of genes are tumour suppressor genes 2
Tumour suppressor genes are defined as recessive genes
Sometimes referred to as ‘anti-oncogenes’
Name 3 functions of Tumour suppressor genes and examples 3,3
regulators of cell cycle checkpoints (e.g. RB1),
differentiation (e.g. APC)
DNA repair (e.g. BRCA1)
Tumour suppressor and cancer - table
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How does Retinoblastoma develop 1
Develops when immature retinoblasts continue to grow very fast and do not turn into mature retinal cells.
Retinoblastoma is a rare childhood cancer (1 in 20,000)
If an eye contains a tumour what colour light will reflect back 1
What is the technical term for this 1
An eye that contains a tumour will reflect light back in a white colour.
Often called a “cat’s eye appearance,” the technical term for this is leukocoria.
What are the 2 forms of the Retinoblastoma disease 2
Two forms of the disease
- familial (40%)
- sporadic (60%)
Where is the mutation found for retinoblastoma 1
The hereditary mutation is on chromosome 13 (13q14), the retinoblastoma 1 (Rb1) gene
What is ‘Loss of heterozygosity’ 1
“Loss of heterozygosity“ often used to describe the process that leads to the inactivation of the second copy of a tumour suppressor gene a heterozygous cell receives a second hit in its remaining functional copy of the tumour suppressor gene, thereby becoming homozygous for the mutated gene.
Mutations that inactivate tumour suppressor genes can also be called 1
What are these caused by 2
Mutations that inactivate tumour suppressor genes, called loss-of-function mutations
Often point mutations or small deletions that disrupt the function of the protein that is encoded by the gene.
Hereditary tumours vs Sporadic tumours 2
One set of patients which had the inherited form of the disease, and in these patients the first mutations in one of the alleles was inherited, and then second is acquired.
Sporadic people developed tumour much later on, not inheritance, patient had to acquire two separate hits/mutations, and patients presented at a much later age.
How many members are in the Rb gene family 3
Name them 3
What are they collectively known as 1
The Rb gene family includes three members:
- Rb/(p105/110)
- p107
- Rb2/p130
-collectively known as pocket proteins
