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MOLECULAR CELL BIOLOGY
SIXTH EDITION
CHAPTER 20
Regulating the Eukaryotic
Cell Cycle
Copyright 2008 © W. H. Freeman and Company
V. Replication at Each Origin is Initiated Only Once
during the Cell Cycle
*1 Multiple replication origin
*2 Only once initiation
•
Yeast Replication origin
a. 11-base-pair conserved core sequence
b. Origin recognition complex (ORC)
c. Initiation factors
d. Prereplicatiom complex
(2) Regulation of prereplication complexs
a. Phosphorylated initiation factor
b. S-phase cyclin-CDK and DDK
c. B-type cyclin-CDK
d. Cdc14
20.6 Cell-Cycle Control in Mammalian Cells
•
•
•
Extracellular signal
Signal transduction
Intracellular cues
I. Mammalian Restriction Point
(1)
(2)
Growth factors (mitogen)
Restriction point
II. Mammalian CDKs and Cyclins
(1) Cyclin-dependent kinase (CDK)
a. 적어도 4개가 확인
b. 각 phase마다 작동하는 CDKs가 다름:
* G1; CDK4, 6
* mid G1 to S; CDK2
* G2 to M; CDK1
(2) Cyclins ( Two major group : G1 cyclins & B type )
a. Ability to complement yeast mutant로 확인
b. Mid- G1 : D
c. Late- G1 : E
d. S-phase : A
e. Mitotic : B, A
f. Destruction box
(3) Cyclin D is essential for passage
a. Anti-Cyclin D Ab microinjection
b. Before 14 h
c. After 14h
(4) G0 cells
III. Regulated Expression of Two Classes of Genes
Return G0 mammalian cells to the cell cycle
(1) Early-response genes
a. Activation of preexisting TF
b. Induction of gene expression : c-Jun, C-Fos
(2) Delayed-response genes
a. Early gene product 에 의한 gene expression이 조절됨
b. Mid-G1 cyclin, Late-G1 cyclins , CDKs, E2F factors
c. Growth factor를 restriction point passage 직전에 제거 시
d. Cyclin D mRNA의 translation 조절
IV. Passage though the Restriction Point
(1) E2F factors : Activation of cyclin E, A expression
(2) RB protein : Tumor-suppressor
(3) Regulation of Rb and E2F activity
V. Cyclin A: for DNA synthesis
CDK1: for Mitosis Entry
(1) Cyclin A-CDK2 complex (S-phase complex)
(2) CDK inhibitory proteins (CKIs): p27KIP1, p57KIP2, p21CIP
a. Sic1과 기능이 유사
b. p27KIP1
(3) Cyclin-CDK2 function의 조절( MPF 와 유사)
a. Cdc25A phosphtase
b. G1 to S transition
c. Activation in late G1
(4) Initiation of DNA replication
a. Phosphorylation of preinitiation complex : IFs
b. Geminin
c. Cdc14 phosphatase
(5) CDK1: G2 & Mitosis에서 주된 역할
a. Cyclin A & B 와 association
b. Cdc25C Phosphatase
(6) Cyclin B
a. Synthesis
b. Cyclin B shuttles between the cytosol and nucleus
c. Removal by APC/C-Cdh1
VI. Two Types of Cyclin-CDK inhibitors
(1) CKI type : S- phase 로 entry전에 제거
a. Inhibition of CDK2
b. p21CIP : DNA Damage 시 작동
c. p27KIP1 knockouts
d. p57KIP2 knockouts
(2) INK4 type
a. Binding to CDK4 & CDK6
b. Tumor suppressor
20.7 Checkpoints in Cell-Cycle Regulation
*1 Fundamental processes in the eukaryotic cell cycle
a.
b.
c.
d.
e.
f.
g.
h.
i.
DNA prereplication complexs assemble at origin
G1 cyclin-CDK inactivate Cdh1
G1 C-C activates expression of S-phase C-C component
G1 C-C phosphorylates S-phase inhibitor
SCF/proteasome degrades phosphorylated S-phase C-C inhibitor
S cyclin-CDK activates prereplication complex
Cdc25 phosphatase activates Mitotic cyclin-CDKs
APC/C-Cdc20 degrade securin
Cdc14 phosphatase activates Cdh1
*2 Checkpoints in Cell-Cycle Regulation
I.
II.
III.
IV.
Intra S phase checkpoint : Inhibition of Cdc25C
Spindle-assembly checkpoint : Inhibition of Cdc20
Spindle-position checkpoint : Prevention of Cdc14
DNA-damage checkpoint : Inhibition of Cdc25A
I . Intra S phase checkpoint
a.
b.
c.
d.
Association of ATR with replication fork
Chk1 kinase
Cdc25 phosphatase
Checkpoint controller
II. Spindle-assembly checkpoint
(1)
(2)
Mad2 (Mitotic arrest defective 2)
p31comet
III. Proper Segregation checkpoint
(1) The spindle-position checkpoint
(2) Mitotic exit network
a. Tem1 : GTPase superfamily
b. Releasing of Cdc14
(3) Checkpoint인 이유
a. Telophase initiation
b. Kin4 kinase
IV. DNA-damage checkpoint
(1) DNA를 damage 시키는 요인들
a. Chemical agents
b. Irradiation
c. G1 arrest or G2 arrest
(2)
a.
b.
c.
Tumor-suppressor gene products, ATM & Chk2
ATM or Chk2 mutation
Encode protein kinase
Inactivation of Cdc25A
(3) p53 protein (Tumor-suppressor)
a. DNA damage
b. Transcription factor
c. Degradation by Mdm2
d. ATM & ATR
e. Activation of p21CIP
f. p53 induced apoptosis
20.8 Meiosis
I. Key Features Distinguish Meiosis from Mitosis
(1)
(2)
(3)
Meiosis
Comparison of mitosis and meiosis
Chiasmata
II. Repression of G1 Cyclins and a Meiosis-specific
Protein Kinase Promote Premeiotic S phase
(1)
S. cerevisiae and S. pombe 의 meiosis
a.
b.
Nitrogen and Carbon source 부족 시
Ime2 의 Induction
(2)
a.
b.
c.
d.
Meiosis I 과 II 사이에 DNA replication의 suppression
MPF activity
2nd rise in MPF activity
Cdc20 activity is increased
Separase is activated
III. Two Physical links: Recombination
Meiosis-specific cohesin subunit
(1)
(2)
(3)
(4)
Homologous chromosome사이에 physical links
Recombination
Cohesin function during mitosis and meiosis
Meiotic chromosome 와 cohesin
IV. Rec 8 Stability
(1) Meiosis I
(2) Meiosis II
V. The Monopolin Complex Co-orient Sister
Kinetochores in Meiosis I
(1) MAMI
(2) Monopolin complex
VI. Tension on Spindle Microtubles Contributes to
Proper Spindle Attachment
(1) Mitosis 에서
(2) Meiosis I 에서