Oncogenes and Tumour Suppressor Genes Flashcards
What have tumour cells lost their ability to do?
Tumour cells have lost their ability to control proliferation so they don’t respond to growth signals in the same way. You cannot supress the growth of tumour cells.
What major functional changes occur in cancer?
- 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)
What do oncogenes do normally and what changes in cancer?
Oncogenes are like a car’s accelerator pedal.
Their normal job is to make cells divide, driving cell division forward
In cancer, pick up mutations that mean they are permanently active – a bit like putting a brick on the accelerator. The car approaches the red light and can’t stop
Oncogene: The mutation is a “Gain of function”
Oncogene:
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.
a single mutation in one of the alleles of an oncogene is usually enough to activate that oncogene so you end up with cells proliferating abnormally
What is the role of tumour suppressor genes and how does this change in cancer?
Tumour suppressor genes are like the car’s brakes.
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
In cancer, pick up mutations that switch the gene off. This is like cutting the brakes in a car. Even if there is no oncogenic brick on the accelerator, without breaks the car definitely can’t stop
Tumour Suppressor gene: the mutation is a “Loss of function”
With tumour suppressors, you have to have a mutation in BOTH alleles - not just a mutation in one allele like oncogenes. Then cells proliferate abnormally as a result.
Tumour Suppressor gene:
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).
What is a sarcoma?
How was this investigated initially?
a malignant tumour of connective or other non-epithelial tissue
A rare type of cancer that grow in connective tissue like bones, nerves, muscles, tendons, cartilage and blood vessels of the arms and legs
There was a scientist - Rous and he was bought a chicken with sarcoma tumour and the scientist cut the tumour and split it into small pieces and filtered it etc and injected into young chickens who also developed sarcoma. But he got rid of all bacteria etc so discovered that this sarcoma was transmissible through viruses-
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
By 1976, homologous sequences were found in uninfected chickens and other organisms-
fruit flies to humans
Fundamental principle: Oncogenes are alerted forms of normal genes or proto-oncogenes
c-src, cellular oncogene
v-src proto oncogene altered form transduced by retroviruses
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 the some genes of cancer causing viruses were mutated forms of the cellular gene not viral genes
They concluded that the Rous sarcoma viral 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 cells
During evolution, the virus can acquire fragments of genes from the host at integration sites and this process results in the
creation of oncogenes
The oncogene product was characterised as a 60kDa intracellular tyrosine kinase
Can phosphorylate cellular proteins and effect growth
So this is an exception- you go from RNA to DNA rather than the usual other way around. You end up with a RSV virion carrying src sequences.
What did Bishop and Varmus continue to discover about oncogenes etc?
Bishop and Varmus used different strains of Rous sarcoma virus in their research, they:
Identified the v-src oncogene as responsible for causing cancer.
Used hybridization 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.
Proto oncogenes are normal genes that can control growth
Various agents, including radiation, chemical carcinogens, and, perhaps, exogenously added viruses, may transform cells by “switching on” the endogenous oncogenic information.
It’s only when the proto oncogenes become mutated, we then refer to them as oncogenes/
What 2 types of viruses can viral oncogenes be transmitted by?
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
DNA Viruses
Encode various proteins along with
environmental factors can initiate
and maintain tumours
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
How many oncogenes have been identified to date?
To date-over 100 identified oncogenes
There are examples of oncogenes for every type of protein involved in a growth factor signal transduction pathway
These genes captured by animal retroviruses are altered in human cancer, activation can involve
mutations, insertions, amplifications and translocations.
this leads to a Loss of response to growth regulatory factors
just One allele needs to be altered
What are 4 types of proteins are involved in the transduction of growth signals?
give an e.g.
Normally Growth factors Growth factor receptors Intracellular signal transducers Nuclear transcription factors
Growth factors, signal transduction and cancer
The majority of oncogene proteins function as elements of the signalling
pathways that regulate cell proliferation and survival in response to growth
factor stimulation
Oncogene proteins act as growth factors (e.g.EGF),
growth factor receptors (e.g. ErbB) and intracellular signalling molecules (Ras and Raf).
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 do we know about the Ras Oncogene family?
RAS Oncogene Family
ras genes were identified from studies of two cancer-causing viruses the Harvey sarcoma virus and Kirsten sarcoma virus, These viruses were discovered originally in rats hence the name Rat sarcoma
RAS proteins are small GTPases that are normally bound to GDP in a neutral state
Oncogenic activation of ras is seen in about 30% of human cancer
Most commonly mutated oncogene
Point mutations in codons 12, 13 and 61
e.g. Glycine to valine - bladder carcinoma
Glycine to cysteine - lung cancer
What is the normal function of the RAS Oncogene Family?
- 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)
4. 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 hydrolyzes GTP to GDP fairly quickly, turning itself “off”
what happens when there is a Point mutation in codons 12, 13 and 61? How does it affect Ras?
you get hyperactive Ras
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
There’s no stop to the cell cycle- cells are continuously dividing!
What do we know about the transcription factor MYC? and the MYC oncogene?
The MYC oncogene family consists of 3 members,
C-MYC, MYCN, and MYCL, which encode c-Myc, N-Myc,
and L-Myc, respectively
Originally identified in avian myelocytomatosis virus (AMV)
The MYC oncoproteins belong to a family of transcription factors that regulate the transcription of at least 15% of the entire genome
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, such as cell proliferation, differentiation, survival, and immune surveillance
The MYC oncogene is overexpressed in the majority of human cancers and contributes to the cause of at least 40% of tumours
It encodes a helix-loop-helix leucine zipper transcription factor that dimerizes with its partner protein, Max, to transactivate gene expression
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.
Such activation of MYC is a result of chromosomal translocation- NOT a mutation
What do we know about the activation of MYC in Burkitt’s Lymphoma?
Epstein Barr virus is associated with Burkitt’s lymphoma (BL)
BL is a high grade lymphoma that can effect 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
All BL cases carry one of three characteristic chromosomal translocations that place the MYC gene under the regulation of the Ig heavy chain. Therefore c-myc expression is deregulated
In BL three distinct, alternative chromosomal translocations involving chromosomes 2, 14 and 22
In all three translocations a region form one of these three chromosomes is fused to a section of chromosome 8
What do we know about the Philadelphia chromosome?
Chronic myelogenous leukaemia (CML) accounts for 15-20%
of all leukaemias
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
Therapeutic strategies for CML include Imatinib (Gleevac) a tyrosine kinase inhibitor-96% remission in early-stage patients
