cancer Flashcards
What are proto-oncogenes
Proto-oncogenes
- found in normal cells
- codes for a protein;
- involved in normal cell division
when mutated they are know as oncogenes
How does mutation of proto-oncogenes lead to uncontrolled cell division?
(a) increase the amount of proto-oncogene’s protein product
(i) - (iv)
(b) increase the intrinsic activity of the proto-oncogene protein product/ code for hyperactive protein
a)increase the amount** of proto-oncogene’s protein product
(i) by a point mutation* in base sequences of regulatory elements* (e.g. stronger promoter created)
- -> This can lead to increased frequency of transcription, and excess production of the proto-oncogene protein product (e.g.growth factor) and can lead to ➔uncontrolled *cell division
(ii) gene amplification, where the number of copies of a proto-oncogene in a cell is increased due to a mistake made during DNA replication
- -> This can lead to excessive production of proto-oncogene protein product (e.g.growth factor) and can lead to ➔uncontrolled cell division
(iii) chromosomal translocation* such that the proto-oncogene ends up under the control of an enhancer*
- -> This can lead to excessive production of proto-oncogene protein product (e.g. growth factor) and can lead to ➔uncontrolled* cell division
(iv) by retroviral integration*
1) can inactivate a silencer* of a proto-oncogene
2) can result in the insertion of a viral enhancer* that upregulates expression of a proto-oncogene
3) can insert a viral homologue of proto-oncogene*
All 3 events can lead to excessive production of proto-oncogene protein product(e.g. growth factor) and can lead to ➔uncontrolled cell division
(b) increase the intrinsic activity of the proto-oncogene protein product / code for hyperactive proteins
(i) by a point mutation within the proto-oncogene
This changes the amino acid sequence* of the
proto-oncogene protein (e.g. growth factor) which can then become hyperactive* or more resistant to degradation* and can lead to
➔uncontrolled cell divison
3.e.g. ras gene: mutation in the ras gene results in a constitutively active Ras protein that irreversibly binds to GTP and increases cell division even in the absence of growth factors
State 2 environmental causes of cancer
- Ultraviolet light/ radioactivity/ ionizing radiations
2. Carcinogens such as tar in cigarette smoke, asbestos,benzene, formaldehyde, ethidium bromide, etc.
Qn6 (tutorial) : Explain how this mutation (fig shows a point mutation) may change the structure and function of ras protein? [4m]
- Single base substitution GGC –> GTC** changes 1 amino acid gly –> valine**
- Different R groups affecting the type and location of bonds* formed (e.g.H bond, ionic bond, disulfide bond,,etc)
- hence altering the 3D conformation* of Ras protein**
4(!!!!). Binding site of mutated ras protein no longer complementary in shape* and cannot bind to target DNA sequences* to influence gene expression and hence cannot act as transcription factor*
What is the function of tumour suppressor genes
Outline the role of e.g p53 gene
it codes for protein products that inhibit cell division and prevent uncontrolled cell division or by activating cell cycle arrest, DNA repair and/or apoptosis
p53 gene: codes for a specific transcription factor(an activator) that can activate genes involved in:
- cell cycle arrest –> gives the cell enough time to repair damaged DNA and prevent formation of mutant daughter cells
- DNA repair –> prevents mutations that may lead to the formation of oncogenes or inactivated tumour suppressor genes
- initiating apoptosis when damaged DNA is beyond repair –>which will thus remove cells with damaged DNA with the potential to cause cancer
Outline the role of tumour suppressor genes in the development of cancer. [3m]
- Loss-of-function mutation** of tumour suppressor genes causes no functional gene products to form
As a result,
- unable to stop cell cycle to* allow repair of any damaged DNA
- unable to activate DNA repair mechanism* to repair damaged DNA thus accumulation of mutations occur
- Unable to initiate/ promote apoptosis* thus cell with potential to cause cancer is not removed
Describe gain-in-function mutation
(e.g when a proto-oncogene i.e. ras protein mutated to form an oncogene)
- mutation in just one copy ** of the allele results in uncontrolled cell division due to the increased synthesis/ activity of a functional product due to mutation
- -> dominant mutation
Describe loss-in function mutation
(e.g mutations in tumour suppressor gene, p53 gene)
- mutations in both copies** of the allele necessary for the loss-of-function phenotype to be observed
- even when one copy is mutated, the non-mutant copy still produces a functional gene product
Thus the non-mutant copy will mask the effect of the mutant copy and hence the mutation is said to be recessive**
Describe the 2 different types of tumour
- benign tumour
- mutations in several genes that are involved in the regulation of cell growth, division and cell death –> can result in a big mass of cells that keeps on dividing and growing and does not die off readily
- tumour is localised and does not spread to other regions. –> benign tumour , non-cancerous**
- malignant tumour
- benign tumour can transform into a cancerous one (i.e. malignant tumour)
- a malignant tumour results when more mutations accumulate** from the continual cell divisions* to allow the tumour to acquire 2 related traits:
- invasiveness**
- ability to undergo metastasis** (can spread to other parts of the body) :
tumour originate from a single aberrant cell that proliferates to give rise to primary tumour* whose cells eventually metastasise to other parts of the body to form secondary tumours*
Why is development of cancer a multi-step process?
▪The development of cancer requires the accumulation of mutations** in the genes which control regulatory checkpoints of the cell cycle in a single cell*
▪This will disrupt* the normal cell cycle,* thus causing the cell to undergo excessive cell proliferation*
▪A gain-in-function mutation is a dominant* mutation where mutation in just one allele* of a proto-oncogene* will result in its overexpression* which will result in the production of excessive amounts* of growth factors or hyperactive/degradation resistant growth factors* leading to excessive cell proliferation
▪Loss-of-function mutation** is a recessive** mutation where mutations in both alleles** of a tumour suppressor gene** will result in the non-functional/missing protein which will disrupt** their ability to inhibit cell cycle, enable DNA repair and promote apoptosis*
▪Activation* of the genes coding for telomerase* result in telomeres being lengthened allowing the cell to dividing indefinitely8 as the chromosomes are prevented from shortening with each DNA replication cycle.
( ➔A single cell that is immortal and continues to divide will accumulate more and more mutations)
▪Loss of contact inhibition* will enable the cells to grow into a benign tumour* (mass of cells).
▪Angiogenesis** occur within the tumour so that the blood vessels* formed can transport oxygen* and nutrients* for its growth.
▪The presence of blood vessels can result in the formation of a malignant tumour capable of metastasizing to other parts of the body via the bloodstream to form secondary tumours
▪As it takes years to accumulate these mutations, the chances of developing cancer increases with age.
State what you understand about the term oncogene [2m]
- mutated form of proto-oncogene* such that
- there is an excessive production of the protein or oncogene codes for a protein with increase activity/ more resistant to degradation, leading to;
- uncontrolled cell divison
link to concept: how mutation of proto-oncogene lead to uncontrolled cell division
qn: explain how the Myc proto-oncogene becomes an oncogene in burkitt’s lymphoma?
(context of qn: chromosomal translocation)
- (Proto-oncogene are normal genes found in normal cells)
Myc gene in chromosome 8 is regulated by normal promoter - (mechanism of how proto-oncogene becomes oncogene)
translocation in a chromosomal mutation when Myc gene transferred from chromosome 8 to chromosome 14 to be under the influence of enhancer** of igH gene - (enhancement of gene expression):
resulting in high level of transcription of Myc gene to produce excessive amount of myc protein* ; - gain in function mutation***
- excessive amount of Myc protein stimulates cell to undergo greater cell division
Describe and explain the potential consequences of the cell and individual person of methylation of the promoter region of the p53 tumour suppressor gene [4m]
- Methylation at promoter region of p53 tumour suppressor gene results in the condensation of chromatin in the promoter region*
- Hence general transcription factors* and RNA polymerase* cannot bind to the promoter, thus transcription initiation complex cannot be formed, hence cannot initiate transcription of the p53 gene
- p53 protein cannot function as a specific transcription factor and cannot activate genes that are involved in DNA repair, cell cycle arrest and stimulating damaged cell to undergo apoptosis
- Cell cycle continues without repairing DNA
- Results in uncontrolled cell division
