Continued cell proliferation Flashcards
cyclins
proteins control progression of cells through the cell cycle
cyclins in G1
cyclin D
bind to CDK4 and CDKGH
cyclins in late G1
cyclin E
bind to CDK2
cyclins in S phase
cyclin A
bind to CDK2
cyclins in G2
cyclin A
bind to CDK1
cyclins in M
cyclin B
bind to CDK1
what does CDK mean
cyclin dependent kinases
they phosphorylate serine and threonine residues on target proteins
members of cyclin D
D1-3
members of cyclin E
E1 and E2
members of cyclin A
A1 and A2
members of cyclin B
B1-3
what is occurring in the image
CDK is inactive
T loop obscures the active site
no ATP binding
what is occurring in the image
binding of cyclin changes the T loop conformation
partial CDK activation
what is occurring in this image
full CDK activation
by T loop phosphorylation by CDK activating kinase CAK
enables optimum ATP binding
how is active CDK inactivated
by Wee kinase
inhibitory phosphorylation
how is inhibitory phosphorylation on CDK reversed
by CDC25 family of phosphatases
G1 to S transition mechanism
mitogen signalling activate Myc
Myc activates transcription of cyclin D
cyclin D binds and activates CDK4/6
CDK4/6 phosphorylates Rb which inactivates and causes it to release its inhibition on E2F1
E2F1 induces gene expression of cyclin E
cyclin E/CDK2 hyper phosphorylates Rb and completely inactivates it
E2F1 also induces expression of cyclin A required in S phase
S phase
activation of helices by CDK2/cyclin A starts DNA replication
components of preRC are phosphorylated preventing them rebinding to DNA and relicensing the replication complex
G2 phase
activating CDK1/cyclin B required for mitosis
1. CDK1/cyclin A activates CDC25 phosphatase, removes inhibitory phosphate on CDK1/cyclin B complex
2. Active CDK1/cyclin B: inactivates Wee1 via phosphorylation, activates CDC25 via phosphorylation (positive feedback)
M phase
CDK1/cyclin B phosphorylates and activates condensin, compacts DNA by folding and coiling
CDK1/cyclin B phosphorylates proteins of the nuclear envelope so they disassemble
CDK1/cyclin B activates centrosomes, move apart and increase microtubule length
what are the stimuli for cell cycle checkpoints (DNA damage)
microtubule spindle defects
unreplicated DNA
lack of growth factors
chromosomal deregulation
excessive mitogenic signalling
CDK inhibitor proteins
bind cyclin and CDK, distort CDK active site
CKI’s insert into the ATP binding site, inhibits CDK enzymatic activity
2 main groups called INK4A family and CIP/WIP family
members of INK4A family
p16^INK4A
p14^ARF
members of CIP/WIP family
p27^KIP1
p21^CIP1
proto-oncogenes
pro cell division
cyclins
CDKs
E2F1
CDC25
deregulation leads to oncogenes leads to cancer
tumour suppressor genes
anti cell division
p16^INK4A
p14^ARF
p27^KIP1
p21^CIP1
Rb
Wee1
deregulation leads to cancer
key activators of cell cycle checkpoints
ataxia telangiectasia mutated ATM, double strand break
ATM related ATR, single strand break
ATR process
phosphorylates CHK1 on serine 345 (p-S345)
CHK1 then undergoes auto-phosphorylation on serine 296 (p-S296)
CHK1 is an opposing regulator of Wee1 and CDC25A
