Cell Senescence and Cancer Flashcards
1
Q
What is cell senescence?
A
- a form of permanent arrest of cell proliferation
- major defence against cancer
- contributes to mechanisms of ageing
2
Q
When is cell senescence activated?
A
- Extended proliferation - replicative senescence
- Activation of an oncogene - oncogene-induced senescence (OIC)
- Other genotoxic (DNA damaging stresses
3
Q
What are molecular properties/markers of senescent cells?
A
- expression of effectors (cell cycle inhibitors) eg p16, p53
- DNA damage signalling
- increased lysosomal content
4
Q
What is SASP?
A
- “senescence associated secretory phenotype”
- senescent sells secrete many inflammatory factors:
1. Cytokines and their receptors (IL6, IL8 etc)
2. Proteases (MMPs)
3. Angiogenic factors (VEGF)
4. Other growth factor (IGF2 etc)
5
Q
What is the DNA end replication problem?
A
- the section of DNA at the 3’ end of each strand can’t be replicated by DNA polymerase
- therefore a small stretch of DNA at the 3’ end can’t be replicated normally
6
Q
How do telomeres solve the DNA end replication problem?q
A
- telomeres are DNA structures at the ends of chromosomes
- made of repeats of DNA hexamer TTAGGG
- enzyme telomerase (protein RNA complex) can replicate telomeric DNA in 5-phase by reverse transcribing the DNA hexamer from its own RNA sequence
- it joins these onto the 3’ end to allow the strand to maintain its length
- telomerase activity is highest in germ cells
7
Q
What are the 2 main subunits of telomerase?
A
- TERT = telomerase reverse transcriptase (protein part)
- TERC = telomerase RNA component (RNA part)
8
Q
What happens when telomeres get too short?
A
- most somatic cells lack telomerase activity so telomeres shorten as they divide
- replicative senescence is trigged in normal cells when the telomeres get quite short so the population arrests
9
Q
How are telomeres protected?
A
- normal telomeres end in loops and bind a protective protein cap of shelterin complexes
- this cap conceals the chromosome end from DNA damage signalling and repair systems
10
Q
What happens to the cap on telomeres when they shorten?
A
- when the telomeres shorten the cap destabilises and breaks off
- the exposed end is now recognised as a DNA break which sets up stable DNA damage signalling but not repair
- p53 is recruited and activated by kinases and signals growth arrest
- DNA damage signalling (without repair) seems to be the core trigger of cell senescence
11
Q
What happens when DNA damage signalling doesn’t work?
A
- if the telomeres are too short and p53 is activated, if the senescence signalling does not work, the cells can proliferate and turn into cancer cells
- This can lead to cancer such as melanoma cancer
12
Q
What happens to mice that have cells that express p16 removed?
A
- median lifespan of mice increased by 25%
- delayed deterioration in organs including heart, kidneys, fat
- delayed tumourigenesis
- extended healthspan
13
Q
Which cells are naturally immortal?
A
- Germ line cells and embryonic/pluripotent stem cells express TERC and TERT therefore they have telomerase activity and maintain full length telomeres
- whereas most somatic cells express TERC but only a little/no TERT so telomeres shorten at division
14
Q
Do adult stem cells have telomerase?
A
- somatic/adult stem cells are stem cells still present after birth
- cells in the basal epidermis and bone marrow have some telomerase activity though not enough to make them immortal
- they still shorten but a low slower than other somatic cells so are said to gradually senescence
15
Q
Why do we need cell senescence to act as a tumour suppressor?
A
- p53 and p16 are products of the two genes most commonly defective in advanced human cancers
- cell senescence is the only established function of p16 and an important one of p53
- reactivated telomerase activity is reported in 90% of human cancer cell lines
- p16 and p53 defects and telomerase activity are required to immortalise cells
- immortalisation is a hallmark of cancer and is necessary to produce an advanced cancer
