Sustaining proliferative signals Flashcards
what is the cell cycle stimulated by?
extracellular signals inducing cell division
which extracellular signals induce cell division?
TK
tumour growth factor beta
intergrins
nutrient status
how many phases is the cell cycle divided into? name them
4 G1 S G2 M
how long does the G1 phase last?
6-12 hours
what happens in the G1 phase?
the cells growth and the chromosomes prepare for replication
where is the restriction point?
at the end of the G1 phase
what happens at the restriction point?
beyond this point the cells are committed to cell cycle progression
how long does the S phase last?
6-8 hours
what occurs in the S phase?
cells synthesise DNA
what happens in the G2 phase?
cells prepare for mitosis
how long does the G2 phase last?
3-4 hours
what is G0
non growing phase- called quiescent phase
order of mitosis phases?
prophase
prometaphase
metaphase
anaphase
what happens in prophase?
chromatin condenses and the process which separates the duplicated genetic material initiates
what occurs in pro metaphase
nuclear envelope breaks down
what occurs in metaphase
chromosomes align themselves in the centre of the cell
chromatids remain joined at the centromere
kinetochore microtubules pull the sister chromatids back and forth till they align along the centre
what are kinetochores and what do. they do?
protein filaments
extend from the poles of the cell and attach to the centromeres
what occurs in anaphase?
each pair of chromosomes are separated into 2 identical independent chromosomes
the sister chromatids are separated simultaneously at the centromeres and pulled to opposite ends of the cell
what separates chromosomes?
mitotic spindle
explain telophase?
separatess the duplicated genetic material into 2 separate cells
nuclear membrane forms around the chromosomes to separate them from the cytoplasm
chromosomes uncoil
what is cytokinesis
divides the cytoplasm of the cell
what type of proteins regulate cell cycle progression?
proteins which except kinase activity
what are the kinases which aid cell cycle progression?
cyclins
cyclin dependent kinases
what are cyclin dependent kinases and how do they contribute to the cell cycle?
family of serine/ threonine protein kinases triggered at specific points of the cell cycle, ensuring synchronised transition through the cell cycle
MOA: how do cyclin/ CKD complexes regulate cell cycle progression?
hint: restriction point and talk about the kinases at each phase of the cell cycle?
before the restriction point in early G1, extracellular mitogenic GFs activate cyclin D and cdk4/6 kinase.
AFTER the restriction point the cells activate the cyclin E and cdk2 kinases meaning the cell will progress to S phase.
in S phase: cyclin A
cdk2 and 3
cdc2
are all activated
in the G2 phase the cyclin B and cdc2 kinases ensure the progression of the cell cycle to mitosis.
before the restriction point which kinases are involved?
cyclin D and CDK4 and 6 kinases
after restriction point which kinases are involved?
cyclin E and cdk2
which ensure progression to S phase
S phase kinases involved?
cyclin A
cdk2 and 3
csc2
In. the G2 phase what kinases are involved? what do they do?
cyclin B
cdc2 kinases
ensure progression to mitosis
how are cyclin/ cdks regulated?
at the transcriptional level so specific transcription factors stimulate their expression at the right times
what happens to kinases after their role in the cell cycle is complete?
targeted by proteases and degraded
what occurs at cell cycle checkpoints?
DNA damage or defect in spindle formation are detected and this arrests the cycle
what happens in cell cycle arrest due to checkpoints?
time for the damage to be repaired
if beyond repair, the cell induces the programmed cell death pathway.
what happens if the cell cycle isn’t arrested and the cell can replicate with damage?
genome instability
which cyclins and cdks induce phosphorylation of pRb? effects what?
cyclin D
cdk4 or 6
dissociates from E2F and leads to E2F transcriptional activity
effect of p53 on cell cycle?
stimulates p21 expression which inhibits kinase activity of cdks and causes cell cycle arrest
what happens in the case that damage is not repairable?
p53 activates genes involved in apoptotic signalling= apoptosis
normal conditions at the G2/ M phase checkpoint?
the cdc25c is phosphorylated by ‘polo link kinase 1’ and dissociates and translocates to the nucleus
the nuclear cdc25c dephosphorylates the cdk1 cyclin B complex and activates signalling progression to mitosis
in normal conditions at the G2/M checkpoint:
what is the cdc25c phosphorylated by? what does it then do
polo like kinase 1
translocates to the nucleus
what does nuclear cdc25c dephosphorylate?
the cdk1 cyclin B complex
what does cdc25c dephosphorylation of the cdk1 cyclin B complex do?
activates signalling progression to mitosis
if these is DNA damage what happens at the G1/M checkpoint?
entry to M is prevented by maintaining cdk1 in its hyperphosphorylated inactive form in the nucleus.
how is the cdc25c removed from the nucleus in DNA damage at the G2/ M checkpoint?
activated Chk1 and chk2 phosphorylate the cdc25c which then translocates out of the nucleus
how does the translocation of cdc25c out of the nucleus stop G1/M transition?
can no longer dephosphorylate the cdk1-cyclinB complex so entry to M phase is blocked
regulatory control checkpoints are _____ in cancer. leading to?
defective
cell cycle progression of cells carrying mutations
5 small molecule inhibitors of CDKs? type 1
staurosporine flavopiridol butyrolactone roscovitine olomoucine
staurosporine moa
inhibition of protein kinases through the prevention of ATP binding to the kinase
flavopiridol MOA?
cdk inhibitor- strongest inhibitor
butyrolactone MOA
Selective inhibitor of the cdk;s
inhibits cell cycle progression of the G1/S and G12/M transitions
roscovitine MOA
inhibits enzyme targets including cdks (2,7,9) which alter growth phase within cell cycle.
olomoucine MOA
inhibits cdk 1 which promotes G2/M transition
3 ways to indirectly inhibit CDKs? (type 2)
mimic p21 activity
cyclin D antagonists
proteasome inhibitors
what do proteasome inhibitors do?
sensitive malignant cells and tumours to proapoptotic effects of chemotherapy and radiation.
