Biology and molecular biology of cancer II Flashcards
What is an oncogene?
An oncogene is a gene that has the potential to cause cancer
An overactivity mutation of one gene creates an oncogene
What is a tumour suppressor gene?
is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer.
2 inactivating mutations functionally eliminates the tumour suppressor gene promoting cell transformation
Which type of mutation leads to an oncogene being formed?
An overactivity mutation
What is an overactivity mutation?
A function is gained
Which type of mutation leads to a tumour suppressor gene being formed being formed?
An under activity mutation
What is an under activity mutation?
Loss of a function
Define oncogenesis
The process of activation of photo oncogenes to oncogenes
What can oncogenesis include?
- Retroviral integration
- Point mutations
- Insertion mutations
- Gene amplification
- Chromosomal translocation
- Protein-protein interactions
What are proto oncogenes?
They are a group of geese that cause notable cells to become cancerous when they are mutated
Are Proto-oncogene mutations usually dominant or recessive?
Typically dominant
What is the mutated version of a Proto-oncogene called?
An oncogene
What do Proto-oncogenes encode?
They encode proteins that function to stimulate cell division, inhibit cell differentiation and halt cell death
Why are photo oncogenes important
They code proteins that function to stimulate cdll division, inhibit cell differentiation and halt cell health which are all important processes to maintain tissues and organs
What do oncogenes code for?
They encode for the same proteins as proto-oncogenes but the production of these proteins is at an increased rate
This leads to increased cell division, decreased cell differentiation and inhibition cell death
How many men are estimated to develop cancer inter lifetime ?
Approx 1 out of every 2 men
How many women are estimated to develop cancer inter lifetime?
Approx 1 out of 3 women
Out of the current list of known cancer genes how many are associated with germlinemutations?
70 genes
Out of the current list of known cancer genes how many are associated with somatic mutations?
342
What are germline mutations?
Inherited mutations
What are somatic mutations?
Spontaneous mutations
Generally speaking name the 2 basic classes of genes that if mutated can lead to cancer?
- proto-oncogenes
2. tumour suppressor genes-
Who discovered the first tumour causing virus?
Peyton Rous
Name the first tumour causing virus
The rous sarcoma virus
What was the road sarcoma viral gene responsible fro and how did it lead to cancer?
Caused cancer as the host cell proto-oncogene (c-src) was hijacked by the viruses viral oncogene (v-src)
So following infection the v-src oncogene was depressed at high levels in the host cells leading to uncontrolled host cell growth
What does the c-src gene code for?
A protein that is involved in the positive regulation of cell growth and cell division
What functions to PROTO-oncogenes have within the cell?
- Growth factors
- Protein kinases
- Membrane associated G-protein
- Nuclear DNA- binding/ transcription factors
What role do oncogenes have in the cell?
- Growth factors
- Protein kinases
- Receptors
- Transcription factors
How are cell activities and interaction regulated?
They are tightly regulated via cell signalling
In cancer what happens to cell signalling?
Cell signalling is disrupted at several points
Describe how cell signalling is disrupted in cancerous cells
- The growth facto receptor is amplified or mutated
- So the signalling molecule is locked in its active configuration
- Deletion or methylation induced silencing of genes occurs due to negate regulators
- As the signalling molecule is locked in its active configuration the transcription factor gene is amplified
- So the target gene is activated when it shouldn’t be or inactivated when it should be
What does the c-sis gene encode for?
Encodes the PDGF beta chain (the platelet derived growth factor)
What is the PDGF beta chain?
the platelet derived growth factor
Where is the v-sis gene found?
In the simian sarcoma virus
What does the int-2 gene encode for?
An FGF- related growth factor
What does the KFG gene encode for?
An FGF- related growth factor
What is another name for the KGF gene?
Hst
What has the KGF (hst) gene also been identified in ?
Gastric carcinoma and kaposis sarcoma cells
What is the FGFR gene?
The fibroblast growth factor receptor
What has the FGFR been been associated with?
Many types of cancer
What have ERBB2 mutations been linked with?
Lung and gastric cancers
What is RAS?
RAS is a GTPase
What is RAF?
A serine/threonine kinase
What doe KRAS and BRAF have a role in?
Colo-rectal cancer
What does the RAS-MAPK signalling pathway lead to?
Expression of genes involved in proliferation, differentiation and survival
What is the CDK4 gene?
It is a cyclin dependent kinase
What is CDK4 associated with?
Associated with melanoma but also breast cancer and myeloma
What does the CDK4 protein help with?
Helps to control cell division
What happens when the CDK4 gene is mutated?
It makes an abnormal CDK4 protein that is too active
This abnormal protein makes cells divide abnormally fast which could lead to tour formation
What has a disrupted c-myc gene found to be involved in?
Involved in numerous haematopoietic neoplasias
What happens if the c-myc gene is disrupted?
Show to result in retroviral integration and transduction as well as chromosomal rearrangements
Where was the Myc gene originally identified?
In the avian myelctomatosis
What is the Fos gene identified as?
As the feline osteosarcoma virus
What does the fos protein interact with?
The protein interacts with a second proto-oncogenic protein, Jun to form a transcriptional regulatory complex (Fos-Jun).
What was the p53 gene originally identified as?
Asa major nuclear antigen in transformed cells
Name the most identified mutant protein in human tumours?
The p53 gene
What do mutant forms of the p53 gene interact with?
Interfere with cell growth suppressor effects of wild type p53 indicating that the p53 gene product is actually a tumour suppressor.
How were tumour suppressor genes first identified?
By making cell hybrids between tumour and normal cells
Name some tumour suppressor genes tat have been identified
- Retinoblastoma susceptibility gene (RB1),
- Wilms’ tumours (WT1),
- neurofibromatosis type-1 (NF1),
- Familial adenomatosis polyposis coli (APC or FAP),
- p53 which was originally thought to be a proto-oncogene
How does the tumour suppressor P53 gene arise?
Due to a loss of of heterozygosity at the short arm of chromosome
What has analysis of several murine leukemia cell lines shown?
That the p53 locus was lost by either insertion or deletion on both alleles
Mutations at the p53 locus occur in which cancers?
- Colon
- Breast
- Liver
- Lungs
What can lead to damage/ mutation of a stable p53 gene?
- Hyperproliferative signals
- DNA damage
- Telomere shortening
- Hypoxia
What can damage/mutation to the p53 gene lead to?
- Cell cycle arrest
- Senscence
- Apoptosis
What does the p53 gene do?
It regulated cell division and prevents cells dividing too fast
Also prevents damaged cells from dividing
How does our body protect cells that have been exposed to lethal mutations due to environmental carcinogens?
Cells have the ability to repair DNA defects which prevents cancer
Name some hereditary cancers
- Hereditary nonpolypbosis colorectal cancer (Colon, ovaries)
- Xeroderma pigmentosum (skin carcinomas, melanomas)
- Blooms syndrome (Carcinomas, leukaemia, lymphomas)
- Fanconi anemia (acute myeloid leukaemia. squamous cell carcinomas)
- Hereditary breast cancer (breast and ovarian caner)
How can tumour cells arise due to infections?
Tumor cells also can arise through the actions of specific tumor viruses
Name the 2 distinct types of tumour viruses?
- DNA genomes
2. RNA genomes (termed retroviruses)
What are RNA tumour viruses common in?
Chickens, mice an cats but RARE in humans
Name the only known human retroviruses
- The human T-cell leukemia viruses (HTLVs)
2. the human immunodeficiency virus (HIV).
Cellular transformation to cancer by DNA tumor viruses has been shown to be the result of what?
Protein protein interactions
What are tumour antigens?
Proteins encoded by the DNA tumour viruses
What can t antigens interact with?
Can interact with cellular proteins
What can interactions between cellular proteins and T antigens lead to?
Can effectively sequester the cellular proteins away from their normal functional locations within the cell
Name the predominant types of proteins that are sequestered by viral T antigens
Tumour suppressors
What causes the cellular transformation of tumour suppressors?
It is the loss of their normal suppressor functions
What happens when a retrovirus infects a cell?
- When a retrovirus infects a cell its RNA genome is converted into DNA by an RNA-dependent DNA polymerase (reverse transcriptase)
- The DNA then integrates into the genome of the host cell where it can remain being copied as the host genome is duplicated during the process of cellular division.
What type of oncogenes do Retroviruses contain?
Retroviruses can carry viral versions of cellular proto-oncogenes (v-onc).
What type of oncogenes do Retroviruses contain?
Retroviruses can carry viral versions of cellular proto-oncogenes (v-onc).
What is located at the ends of retroviral genomes?
There are powerful transcriptional promoter sequences termed long terminal repeats (LTRs)
What can promoter sequences termed long terminal repeats (LTRs) activate?
They can activate host genes near to the site of integration.
Name the 3 distance pathways by which most people come to oral cancer
- Tobacco and alcohol use
- Exposure to the HPV-16 virus
- Under 7% of people can get get oral cancers from no currently identified cause thought to be some genetic predisposition.
