regulation of the 3rd checkpoint Flashcards
3rd checkpoint
- name
- enters into?
metaphase-to-anaphase transition
re-entry into G1
3rd checkpoint
- role
detects chromatin attachment problems
normal timing of anaphase
.:. can block cell cycle
APC/C
- means
- function
- type of enzyme
anaphase promoting complex
targets cyclins for degradation
an E3 ubiquitin ligase
how is APC/C activity controlled?
upstream regulation
activation:
M-Cdk phosphorylates APC/C
-> then can Cdc20 bind
inactivation:
Mad2 binds to Cdc20
- prevents activation
APC/C triggers entry into anaphase
M-Cdk phosphorylates APC/C
->
APC/C triggers entry into anaphase
M-Cdk + Cdc20 activate APC/C
- > ubiqutination of securin
- > degraded
- > separase released
- > cleaves cohesion
- > sister chromatids pulled apart by spindle fibres
Mad2 checkpoint break
blocks anaphase entry via APC/C inhibition
- until every chromatid is attached to a spindle
Mad2
- recruited
- sequestered
to unattached kinetochore
sequesters + inhibits Cdc20
mitotic exit
- requires
reversal of early mitotic events induced by M-Cdk
nuclear envelope formation
requires destruction of M-cyclins
-> M-Cdk cannot induce degradation of nuclear pore complex + nuclear lamina
APC/C targets M and S-cyclins for destruction
active APC/C + E1 + E2 add ubiquitin molecules onto cyclin of M-Cdk + S-Cdk
-> target for degradation
drastic decrease in active M-Cdk
- ve feedback loop established
- > active APC/C decreased due to decrease in active M-Cdk (normally phosphorylated APC/C)
when are S-cyclins + M-cylins degraded?
S
= start of mitosis
M
= metaphase to anaphase transition
actin-myosin ring drives cytokinesis
begins in anaphase
completed in telophase
regulators of metaphase-anaphase transition
Cdc20
- regulatory protein binds to APC/C
- promotes
APC/C
- ubiquitin ligase
- promotes
Securin
- inhibitory protein binds separase
- blocks
Separase
- protease
- promotes
Mad2
- regulatory protein binds Cdc20
- blocks
re-entry into G1 depends on APC/C activation by Cdh1
M-Cdk inhibits formation of Cdh1-APC/C complex
by phosphorylating Cdh1
destruction of M-cyclin via ubiquitination
-> Cdh1 is dephosphorylated
-> binds to APC/C
= active
p27
a CKI
binds + inactive cyclin-Cdks
p27 contributes to G1 stability
- mechanism
- effects
acts in G1
- blocks G1/S-Cdk and S-Cdk activity
> maintains G1
prevents cell cycle progression
levels elevated in mitogen-starved cells
how is p27 inactivated in order to pass Start checkpoint?
G1-Cdks remove p27 from G1/S-Cdks
p27 then phosphorylated by Cdks
-> SCF ubiquitin ligase tags for degradation in proteasome
-> p27 can no longer act as block on S-Cdk either
G0
- entry into G0 process
INK4 proteins contribute to cell entering G0
absence of mitogens
- > INK4 proteins act as CKIs
- > block G1-Cdk function
- > high levels of Rb
- > cell enter resting phase
ALSO:
G1-Cdk cannot enter nucleus to phosphorylate its targets needed for cell cycle progression
G0
- presence of mitogens
e.g. Myc
directly lowers expression of INK4 proteins
-> G1-Cdk is active
-> cell cycle progression
