2. Oncogenes and Tumour Suppressors Flashcards
Describe the cancer cell phenotype
- Disregard of signals to stop proliferating
- Disregard for signals to differentiate
- Capacity for sustained proliferation
- Evasion of apoptosis
- Ability to invade
- Ability to promote angiogenesis
Describe the stages of the cell cycle.
G0 - the cell is in a quiescent phase - it is not replicating
G1 - the cell makes sure that it has enough nutrients, nucleotides etc. to replicate
At the end of G1, the cell has a checkpoint where you get growth arrest to ensure the genetic fidelity of the cell
Specific proteins accumulate/are destryed during the cycle e.g. cyclin, Cdks, Cdk inhibitors
Permanent activation of a cyclin can drive a cell through a checkpoint
What is the function of proto-oncogenes? What would mutations do?
- Proto-oncogenes code for essential proteins involved in maintenance of cell growth, division and differentiation
- Mutation can convert a proto-oncogene into and oncogene, whose protein product no longer responds to control influences
- Oncogenes can be aberrantly expressed, over-expressed or aberrantly active
- e.g. Myc, Ras, ERB, Sis
- A proto-oncogene an be converted to an oncogene by a single mutation
Describe the activation of an oncogene.
Oncogene activation can occur during:
-
Gene Amplification (production of multiple gene copies)
- It can occur due to problems with a polymerase protein
- Having multiple copies of a gene will lead to overproduction of the gene product
-
Chimeric genes are genes that are formed by combinations of portions of one or more coding sequences to produce new genes (e.g. the swapping of tips of chromosomes)
- This can be a problem if one of the pieces of translocated DNA is a promoter, leading to upregulation of the other gene portion (this occurs in Burkitt’s Lymphoma)
- This can also be a problem if the fusion gene formed produces an abnormal protein (e.g. Philadelphia chromosomes in CML)
Explain the formation of the philadelphia chromsome
- The philadelphia chromosomes is formed by the translocation of chromosome segments from chromosome 9 + 22
- The two key areas that are translocated are:
- ABL - chromosome 9
- BCR - chromosome 22
- The resulting BCR-ABL fusion gene leads to the development of cancer
- Single event that can lead to cancer
Describe signal transduction pathways.
- Proteins that are involved in signal transduction pathwaysare potentially critical gene targets (proto-oncogenes)
- Activation of proto-oncogenes to oncogenes can disrupt normal activity
- It can lead to downstream activation of signalling pathways such that they no longer respond to the upstream stimuli
What is the function of RAS? What would happen if it has been mutated?
- Normallu, upon binding to GTP, Ras become active and activates the kinase cascade leading to the production of gene regulatory proteins
- Dephosphorylation of the GTP to GDP switches Ras off
- A mutant Ras will fail to dephosphorylate GTP, meaning that the GTP persists so Ras remains active
- The Ras pathway is part of a much more complicates signalling cascade called the mitogen-activated protein kinase cascade (MAPK)
- Summary:
- Ligand binds to receptor
- Leads to internal signalling
- Activates RAS and RAF
- When GTP is released (converted to GDP), RAF is released (regulatory)
- If there is a mutation, RAF and RAS are permanently bound and there is no regulation
Give examples of Oncogenes and their tumours with the aid of this table.
Damage of a single proto-oncogene will lead to the generation of a oncogene which drives cancer
Ras codes for a family of proteins such as Ki-Ras and Ha-Ras, which are membrane bound GTPases that are important in the stimulation of cell proliferation
What is the function of tumour supressor genes?
- Typically proteins whose function is to regulate cellular proliferation and maintain cell integrity (e.g. retinoblastoma)
- Each cell had two copies of each tumour supressor gene
- Mutation or deletion of just one gene copy is usually insufficient to promote cancer
- Mutation or loss of both copies means loss of control.
What are you more likely to have if you have an inherited cancer susceptibility?
- Family history of related cancers
- Unusually early onset
- Bilateral tumours in paired organs
- Synchronous or successive tumours
- Tumours in different organ systems in same individual e.g. mutation in p53
- Mutation inherited through the germline – inheritance of faulty gene
Retinoblastomas are examples of inherited cancer. How does it develop?
- Retinoblastomas are malignant cancer of developing retinal cells
- Sporadic diseases usually involves one eye
- Hereditary causes can be unilateral or bilateral or multifocal
- It is caused by a mutation of the RB1 tumour supressor gene on the chromosome 13q14
- RB1 encodes a nuclear protein that is involved in regulation of the cell cycle
What are the functional classes of tumour supressor genes?
- Regulate cell proliferation
- Maintain cellular integrity
- Regulate cell growth
- Regulate the cell cycle
- Nuclear transcription factors
- DNA repair proteins
- Cell adhesion molecules
- Cell death regulators
OVERALL: They supress the neoplastic phenotype
Name the tumour suppressor genes and their associated human tumours with the aid of the table.
What is the function of p53?
- When p53 is bound to MDM2 it is inactive
- p53 is important in a wide range of activities including regulation of p53 target genes and protein-protein interactions
- p53 can be activated by many different types of cellular stresses
- Although p53 is a tumour supressor gene, mutants of p53 act in a DOMINANT manner and mutation of a single copy is sufficient to get dysregulation of activity
- Phosphorylation of p53 destabilises it so that it isn’t degraded so quickly and can exert its effects
- Phosphorylation is triggered by cellular stress
Describe Familial Adenomatous Polyposis Coli (APC)
- Due to deletion in 5q21 resulting in loss of APC gene (tumour supressor gene)
- It is involved in cell adhesion and cell signalling
- Peopl woth APC mutation and develop multiple benign adenomatous polyps in the colon –> not cancer
- there is 90% risk of developing colon cancer - cells are susceptible to mutations due to their rate of growth
- Treatment: Remove the colon - effective at preventing cancer
What is the function of the tumour supressor gene APC?
The tumour suppressor gene APC participates in the WNT signalling pathway.
APC protein helps control the activity of b-catenin and thereby preventing uncontrolled growth.
Mutation of APC is a frequent event in colon cancer.
Tumour suppressor – red
Proto-oncogene – green
What will cause cancer?
Describe the differences in oncogenes and tumour supressor genes.
