Cellular Senescence Flashcards
What is the difference between growth between primary cells and transformed cells?
primary cells grow for a limited time in culture then will stop growing- don’t die just persist without dividing whereas transfromed cells continue to grow
How did Hayflick indicate senscence?
described that cells have a finite replicative capacity which despite adequte space; nutrient and growth factors fail to proliferate and remain viable
What was the first molecular explanation for senscence?
telomere shortening
What are the telomere repeats?
TTAGGG repeats
What is the function of telomeric cap ?
represses DNA damage repair pathway which would normally respond to the loss of TTAGGG repeats
What happens to the telomere cap with progressive telomere shortening?
there is not enough telomere for the cap to bind exposing DNA damage resulting in sustained DNA damage signalling
What are the two results of sustained DNA damage signalling?
apoptosis or cellular senscence
What is the function of cellular senescence in the context of telomere shortening?
cell must stop dividing or will start getting DNA damage in the genome, not telomeres and risk of transformation
How is senescence related to iPS reprogramming?
the majority of cells undergo sensecence as recognise the factors provided as oncogenic which provides a significant challenge in the field
How is the effect of cytotoxic drugs induced senscence important?
in lymphomas this is one of the most important reasons for why cytotoxic drugs work as they induce senscence
What happens if you give a primary cell an oncogene?
will undergo lots of proliferation then will recognise this and undergo senescence?
What are the different factors leading to senescence?
telomere shortening; serial culture; cytotoxic drugs; oxidative stress; DNA damage; oncegene activation; iPS reprogramming
What is the overall function of cellular senescence?
maintain genomic stability
What is the first thing seen in response to a senscence stimulus?
develop lots of DNA damage response foci
Why is there upregulation of cylin-kinase dependent regulators in senescence?
to stop the cell cycle
What cyclin-kinase dependent regulators are upregulated in senescence?
p21; p53; p16
What happens to the DNA in cells undergoing senescence?
reorganise nuclear chromatin and nuclear lamina to change gene transcription
What do you see in senescent cells as a result of chromatin reorganisation?
SAHF- senescence associated heterochomatin foci
What happens to the lysosomes in senscent cells?
increased lysosome activity
What is the marker of increased lysosome activity in senescence
SA b-Gal
How do you know SA b-Gal isn’t a driver of senescence?
if knock it out, still get senescence- not a driver but a marker
What is the result of the altered protein metabolism in senescence?
releas of SASP- senescence associated secretory phenotype; also see altered mitochondrial function which is needed to produce lots more proteins
What are SASPs?
collection of things that can cross membrane- paracrine activity which can force other cells to senesce; activate inflammation programs; give GF to other cells to promote transformation
What was the first indication that SASP can promote transformation?
if culture pre-neoplastic prostate cells with senescent cells there is increased transformation
