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The control of cell cycle (Evidence 1: Rao and Johnson experiment…
The control of cell cycle
Evidence 1: Rao and Johnson experiment
Experiment I
G2 nucleus accelerates
the progress of the S nucleus towards mitosis
Experiment II
G1/S fusions resulted in S/S heterokaryons
Cell fusion experiments
identified the existence of a molecular cell cycle switch in cells
Experiment III, IV and V
G1/G2/S cell and M cell gave chromosome condense
Hypothesis
: The cell cycle appears to be driven by specific chemical signals present in the cytoplasm
the cell cycle appears to be driven by specific chemical signals present in the cytoplasm is proven and accepted
Evidence 2: MPF, Cdk & Cyclin discovery
maturation promoting factor (MPF)
two proteins (cyclin A/B and Cdks)
M-cyclin
: is a regulatory subunit required for catalytic
activity of the cdk
Cdk
: is a protein kinase that phosphorylates other proteins
activate MPF
Phosphorylation of Cdk at one site
inhibits MPF
Phosphorylation of Cdk at two sites
4 classes of cyclins
G1/ S phase(cyclin E)
cdk2
G2 phase(cyclin A)
cdk2
G1 phase(cyclin D)
cdk4 cdk6
Mitosis(cyclin B)
cdk1
STEPS
G1/S-cyclins bind Cdk-6
at the end of G1 and commit the cell to DNA replication
S-cyclins bind Cdk-2
during S phase and are required for the initiation of DNA replication
M-cyclins bind Cdk-1
and promote the events of mitosis
G1-cyclins bind Cdk-4
and are involved in progression through the checkpoint in late G1
How does M-Cdk drive entry to M phase?
Wee1
AND
Cak
inhibits M-Cdk by phosphorylation
Cdc25
activating M-Cdk by dephosphorylation
lead to
Chromosome condensation / Nuclear envelope
breakdown / Reorganization of Golgi apparatus and ER
What happens at the end of M phase?
Active APC promotes the completion of mitosis by:
Destruction of M-cyclin
APC is activated by cdc20 AND attaches to M-cyclin,
marking the protein for proteasomes
Degrading securin
APC causes the degradation of securin and it inhibits a protease by separase which cleaves Scc1p to allow sister chromatids to separate and initiating anaphase
How does S-Cdk drive entry to S phase?
Phosphorylate Cdc6 (cell division control) which causes Cdc6 degradation and associates with ORC initiates DNA replication
What happens if a cell has a damaged DNA?
The G2/M Checkpoint
checks the success of DNA replication from the S phase
The Metaphase/Anaphase Checkpoint
all chromosomes are properly attached to the spindle fibers
Failure to do so causes nondisjunction
The G1/S Checkpoint
p16 inhibits the formation of an active Cdk4/cyclin D1 and E2F inhibits by active Rb
DNA damage is too severe to be repaired,
p53
can induce the cell to undergo apoptosis
The arrest of the cell cycle in G1 gives the cell time to repair the damaged DNA
p21 protein binds to G1/S Cdk and S Cdk
preventing cell into S phase
p53 activates the
expression of p21
cancers
mutations in Rb
deletion or inactivation of the p16
p53 is missing or defective