F3: Tumour suppressor genes Flashcards
Tumour suppressor genes
- Normal cellular genes, present in all cells in the body.
includes cell cycle proteins, transcription factors, cell surface proteins, DNA repair proteins, apoptosis related proteins. - Control critical checkpoints in the cell cycle
- Induce the transcription of regulatory inhibitory genes
- in general, proteins encoded by these genes control cell growth NEGATIVELY.
Tumour suppressor genes prevent rapid cell cycling and thereby rapid cell division and cell growth
What do tumour suppressor genes encode for and what happens when these genes are mutated in cancers?
- Some tumour suppressor genes code for cell adhesion/recognition proteins. In cancer, mutations of these genes cause cells to lose adhesion to their neighbours and spread.
- Some tumour suppressor genes code for enzymes involved in DNA repair.
In cancer, mutant proteins no longer repair DNA and mutations accumulate. - Some tumour suppressor genes inhibit cell division by stopping the cell cycle in G1.
In cancer, mutant proteins no longer block cell division.
How can tumour suppressor genes be mutated to predispose to cancer?
- loss of function (i.e inactivating mutations) can lead to cancer
- loss of function requires both copies of the gene to be lost for cancer to develop (i.e “two hit hypothesis”)
- loss of one copy of a tumour suppressor gene –> slight cell cycle progression advantage
- loss of both copies is (complete inactivation) –> significant growth advantage predisposes to cancer.
- when an individual is born with only one functioning copy they may then lose the second copy and be predisposed to a life long cancer predisposition.
Tumour suppressor genes: Role in cell cycle
- Function is to prevent cells from progressing through the cell cycle - this allows time for the repair of damaged DNA.
- When the tumour suppressor gene is lost the cell cycle proceeds unchecked and hence cells will divide at abnormal rates.
- requires loss of function of both copies of the gene
Characterised by inactivating mutations whether inherited or acquired
Classical examples p53 and retinablastoma gene product.
Retinoblastoma: a model for cancer resulting from tumour suppressor gene inactivation
Retinoblastoma
rare childhood tumour in the retina, neural precursor cells of the retina
1/20 000 children are affected
- Hereditary retinoblastoma
- Develops at a very young age
- Tumour in both eyes
- Mutant Rb allele on chromosome 13 in every cell of the body (but they will also have one healthy copy of Rb left) - Non-Hereditary retinoblastoma (very rare)
- One tumour in one eye
- Develops at a later age
- Chromosomal changes only in tumour cells
Retinoblastoma: Although rare this syndrome is a model for tumour suppressor genes.
explain the hereditary form and the non-hereditary form - what events happen that predispose to development of cancer
- Hereditary form: All body cells lack one normal copy of Rb gene –> slight growth advantage.
Additional acquired somatic mutation in remaining functional copy —> loss of both copies of Rb.
Now the cell has no functional copies of the gene and is now strongly predisposed to develop cancer. (tumour is likely to develop @ a very young age) - Non-hereditary form: requires two somatic acquired mutations in a single retinal cell to destroy both copies of the gene. this is a very rare event
Retinoblastoma gene.
what is its function and why is it so important in cell cycle progression?
- Rb - widely expressed gene found in every cell in the body. (in conjugation with p53, won’t let the cell enter into the S-phase until the cell is ready to do so)
- Acts as a regulator of cell cycle progression.
- prevents the transcriptional activation of genes that are required for the onset of S-phase.
- Plays a role in regulating other cellular processes including differentiation, DNA replication and apoptosis.
The Rb gene is also implicated in what other cancers?
The Rb gene is also mutated in many other cancers - including breast, lung and bladder tumours.
In these cases the tumours arise from a complex series of genetic events in which the loss of the functional Rb genes is one of many genetic events leading to cancer. as well as a gain in function of other oncogenes. It will be a step-wise process with the accumulation of the genetic mutation.
How do we inactivate tumour suppressor genes. so how do we inactivate our one functional copy of Rb left and give this cell a huge growth advantage.
6 possible ways of eliminating normal Rb gene.
- nondisjunction (chromosome loss)
- nondisjunction and duplication
- Mitotic recombination
- Gene conversion
- Deletion
- point mutation
Tumour suppressor p53:
- Cancer cells survive because they have developed the molecular mechanisms to evade cell death (apoptosis)
- one of the most common mutations is in the tumour suppressor gene p53 (50% of all tumours show mutations and loss of function of p53)
- Cancer cell acquisition of p53 mutation allows the tumour to evade the apoptotic cell death pathway and thereby promote proliferation.
Functions of p53
- P53 induces specific cell responses including:
Cell cycle arrest, senescence, cell differentiation, apoptosis. - p53 contributes to DNA repair following DNA damage
- If cell DNA damage is severe, p53 will induce cell death, thus preventing replication of damaged or mutated DNA.
- p53 induced cell death, depends on the ability of p53 to induce gene expression, with selective activation of p53 target genes.
In general the effect of p53 activation is to inhibit cell growth, either through CELL-CYCLE ARREST or INDUCTION OF APOPTOSIS, thereby preventing tumour development.
What can cells defective in functional p53 do?
cancer cells
- escape apoptosis
- DNA damage is no repaired
- No halt to the cell cycle at the checkpoints to repair damaged DNA
- cells may survive and proliferate with a mutated genome
- common result is that chromosomes become fragmented, and incorrectly rejoined creating successive rounds of cell division an increasingly mutated genome
What is an example of human cancer where p53 is lost early in cancer development
squamous cell carcinoma (SCC)
these type of mutations are UV-light induced, they cause a single point mutation in p53 and they inactivate it.
causes the cells to start growing more quickly than the normal cells.
vast majority of squamous cell carcinoma induced by sun exposure.
At least one copy of p53 lost early in sun damaged skin.
Loss pf p53 in skin cancer
- p53 gene is mutated in up to 90% of squamous cell carcinoma and have the hallmark of UV light induced mutation (C-T substitution)
- Even loss of one copy of p53 confers growth advantage probably as a result of decreased apoptosis following UV light exposure.
- P53 mutations relevant but not sufficient to cause skin cancer on its own - accumulation of mutations including Ras oncogene.
How many mismatch repair genes are their in humans and name 3 of them.
8 MMR - mismatch repair genes.
MSH MLH PMS
