Cell Determination & Cell Senescence Flashcards
what is cell determination?
process whereby cell fate becomes stable and is followed by cell differentiation
what is a master gene regulator?
a transcription factor that regulates many or all of the genes specifically expressed in a cell type.
what is cell determination caused by?
- by inductive signals from neighbouring cells
- one group of cells influences the development of other cells
- pioneer factors/master regulators & cofactors play important role in cell-fate decision making
what is cell senescence?
the irreversible cell-cycle arrest mechanism where cells cease to divide
why does cellular senescence occur?
- as a response to excessive extra/intracellular stress
- strongly implicated in symptoms of ageing but also important defence against cancer
what is the hayflick limit?
the maximum number of times a cell can divide before reaching senescence
-all cells have except for cancer cells
what types of changes does senescence apply to cells
-morphological, biochemical, chromatin changes in cell
what are the morphological changes that occur in a cell?
- larger flat cells
- prominent nuclei
- nuclear lamina degradation
- vacuolised
- chromatin reorganisation
what are the 2 molecular markers of the cell
β-galactosidase and protein p16
what are the products of biochemical and molecular changes associated with?
inflammation, proliferation and changes to the intracellular matrix
what is the p53 pathway?
the main way to control senescence
what are the main factors of senescence?
telomere attribution
what are telomeres?
regions at the end of the chromosomes composed of the TTTAGG DNA sequence
unstable chromosomes are due to what?
loss of telomeres and risk resulting in flanking genes
when is replicative senescence triggered?
when the telomeres get short, 1-5 telomeres
what is telomerase?
an enzyme that replicates telomeric DNA by reverse transcription
how does telomerase work?
they reverse transcribe telomeric headers from RNA using RNA (TERC) and it’s protein component (TERT)
what are TERT and TERC
- TERT: telomerase reverse transcriptase (the protein part, = catalytic subunit).
- TERC (or TR): telomerase RNA component
how does p53 work?
the ATM proteins scan the DNA for damage and activate the p53 which activates p21 which codes for proteins that arrest cell division at G1
what are the 2 stages in which telomerase elongates telomeric DNA?
1) synthesis
2) translocation
explain the process of how telomerase elongates telomeric DNA
- telomeric DNA w overhanging 3’ end
- newly synthesised lagging strand binds to telomerase RNA
- 3’ end of the leading strand elongated by one repeat unit as an extension of the leading strand
- the RNA primer is removed
- telomeric DNA extended
what are the mechanisms of cell senescence?
- the telomeres shorten
- the DNA damage signal phosphorylates p53 (a tumour suppressor), activating it
- the p53 stimulates the expression of p21 (a growth inhibitor)
- P21 inhibits CDK 1/2/4/6
- that means that there is no phosphorylation of pRB, meaning that it remains bound to E2F, blocking transcription, thus effectively arresting cell division.
- radiation, oxidative stress or DNA damage occurs.
- this activates p53 (and that continues down the same path as before) and p16
- P16inhibits CDK 4/6
- that also continues down the same path as before.
why are germ line cells immortal?
they express TERT so they maintain full length telomeres
what is the relationship between cancer and telomeres?
cancer cells activate telomeres which leads to the uncontrollable replication
- 90% of all cancer cells express TERT = infinite divisions
- advanced cancer cells surpass senescence
what are some abnormalities that lead to defective senescence and immortality of the cell?
- expression of TERT
- p53 defects
- p16 defects
what is the relationship between telomeres and ageing?
shortening of telomeres cause old age
what is the evidence that telomere shortening is the cause of old age?
- p16 and associated proteins expressed increasingly in ageing tissues (leading to senescence)
- telomere length varies between people but genetically linked to age at death
- defective genes for telomerase subunits give symptoms w premature ageing and death
- p16 locus genetically linked w human senile defects like TII diabetes, cardiovascular diseases and cancer
do embryonic stem cells express TERT?
yes, this means they are immortal
do telomeres in somatic stem cells shorten?
yes, but they shorten less than in somatic cells
