Senescence Flashcards
When can senescence occur?
G1, G2
How does quiescence differ to senescence?
Quiescence is growth arrest in G0 due to starvation of growth factors or contact inhibition. It is reversible, unlike senescence.
What is antagonistic pleitrophy of senescence?
It is a beneficial, tumour suppressing function in early life. But it becomes procancerous in the elderly
What is the role of senescence in wound healing?
senescent cells will secrete PDGF-AA which induces myofibroblast differentiation leading to accelerated wound closure
What effect does removal of p16 positive senescent cells have on wound healing?
It delays the time for wound closure
What are SASP proteins?
senescence associated secretory phenotype proteins. These are pro-inflammatory cytokines, chemokines, growth factors and proteases
What is the effect of SASP protein autocrine Vs paracrine signalling?
Autocrine acts to reinforce senescence.
Paracrine has an effect on the microenvironment and neighbouring cells.
What SASP protein is secreted by senescent cells that aids in invasion and metastasis?
Matrix metalloproteases
Also VEGF
What is a good way to mark senescent cells in mice? How do these mice respond if these cells are lost?
p16INK4a positive cells
clearance of these cells delays ageing associated disorders
What procancerous traits do SASP proteins have
Degradation of the ECM facilitates invasion, induces EMT, angiogenic factors promote neo-angiogenesis.
SASP establishes immunosuppressive environment that promotes tumour growth.
Which cancer is associated with SASP proteins?
Hepatocellular carcinoma
What is SAB?
a marker for senescence: senescence associated B-galactosidase. At a pH of 6, it will turn the cells blue if they express B-galactosidase.
Is senescence a dominant or recessive trait?
Dominant
What is the effect of injecting polyA+ RNA from senescent human fibroblasts into proliferating cells? What does this suggest?
It inhibits the synthesis of DNA, the cell becomes quiescent suggesting that senescence is a dominant cellular trait./
What cell cycle inhibitor is required for the induction of senescence?
p21CIP1
What is shelterin?
a complex of six telomere specific proteins. They form a lariet like structure which tucks the ends of the telomeres.
What is the result of losing TTAGGG telomere repeat sequences?
Results in the loss of shelterin complex’s and activation of DNA damage response signal
Why do telomeres shorten over time?
The lagging strand requires primers before it can undergo 5’ to 3’ DNA synthesis. So at the end of the telomere on the lagging strand there will be an RNA primer. When this is removed there is no 3’ OH group to allow for the synthesis of DNA. So a small portion of the telomere is lost.
What are the two critical componenets of telomerase and what role do they have?
hTERT is the catalytic subunit - acts as a reverse transcriptase
hTR acts as a template RNA
how does telomerase maintain the length of telomeres
Telomerase recognises tip of telomeres. RNA template (hTR) within the enzyme used to elongate the parental strand in the 5’ to 3’ direction (requires hTERT reverse transcription). It adds additional repeats which is recognised by DNA pol alpha which creates an RNA primer for the lagging strand. DNA pol alpha can then fill the gap using the 3’OH group to begin DNA synthesis.
Do somatic cells have high or low telomerase activity?
Low/no telomerase activity. They lack hTERT, hTR is constitutive.
How do cancer cells maintain telomeres?
Reactivation of telomerase or ALT (recombinational mechanism)
How does a cell respond to shortening of telomeres?
Recognised as DNA damage which leads to the activation of ATM/ATR (p53 dependent damage response)
What is the result of introducing oncogenic Ras into fibroblast cell culture?
Induces cellular senescence (oncogene induced senescence)
What are some triggers of senescence?
Oncogenic signalling, ionizing radiation, oxidative stress, genotoxic stress, lack of nutrients,
What are the two major pathways that induce senescence?
1) activation of the p53 pathway which induces p21CIP1. This prevents cyclin/cdk complexes from phosphorylating pRB which activates the RB pathway.
2) RB activation independently of p53. Upregulation of p16INK4A inhibits cyclinD/cdk4/6 complex’s that would normally phosphorylate RB and inactivate it.
What is geroconversion?
The conversion of a reversible cell cycle arrest into cellular senescence. It requires mTOR activity in the context of activated p53. Sustained mTOR activity in the presence of active p53 results in geroconversion.
