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25 ( 1013)

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mRNA
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.
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,

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3.

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(replication origin).


septum .
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.

.
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()
10-20


.
G1, S G2


.


G0 (
quiescent state)

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().
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24
,

G0
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S G2


DNA

.



G1 (2n)

DNA
.

G2 (4n) G1,
(2n)
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S

4n.
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-
.

,



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(2n)


:
()
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G1

(Fluorescent Activated Cell
Sorter; FACS)

G2 DNA.
S
DNA

DNA .
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.
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DNA
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.
~ 2.000 Volt

.

.
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G1 S G2 M 1/10 X 24 = 2.4

16 24

G1 S G2 M 3/10 X 24 = 7.2

8
36
4 3/20 X 36
G1 S G2 M = 5.4
2

0 8 16 24


(1/1024, 2.4 ).
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DNA ( 3 10)
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(check points)
DNA .
,

.
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DNA (G1S) (G2M).

G1 (
R) ' '
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 (check points)
DNA?
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() (check points)
:

MPF
.


DNA
(G2) M




G2 G1
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DNA
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DNA
(S)

.
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 (
)

(
-Cdk)
()

Cdk-Cyc (-Cyc) (-Cyc)
(-
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(
) .
Cdk Cdk
Cycs
Cyc.
,

( Cyc-Cdk )
. Cyc
Cdk Cyc
Cyc .

APC

NH2 COOH

NH2 COOH

MPF



MPF

G1 S G2 M

,
G1 - S G2 - .

Cdk Cyc.
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1

.

.


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X
G1 G2 M

G1

Cdc2+

Cdc2-

Cdc2D
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cerevisiae) (check points)
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(START, R)
G1. START Cdk Cyc
G1 G2 Cdk
Cyc. Cyc
.

Cdk-Cyc
G1S (APC).

(
) MPF.

O APC
,
.

APC Cdk-Cyc G1.

Sic1
S-. S Sic1
SCF.
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(MPF) Cdk-CycAs /

APC
DNA
/
MPF
M
G2
G1

Cdk-CycEs
-
( )
G1
START
S

(
Cd
k-

DNA

Cy Cdk-CycB
cD
s
)
.
Cyc A,
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B, C .
()

CycCs,
Sic1 CycDs
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Cyc Cdk

.
Cdk .

MPF (maturation promoting factor phase kinase)
( Cdk Cyc).

Cdk (Cyc)
MPF. Cyc Cdk MPF

(Weel, CAK) (cdc25) Wee1 cdc25
cdk .

Wee1 Cdc25
Cdk-Cyc (MPF).
(
S )
(
Cdk-APC Cdk-SCF).


cdk (cdc2
Cdc28),
Cyc Cdks
.

Cyc-cdk
Cyc-Cdk

Cdks 1, 2, 3 . Cdk1
cdc2, Cdk2 cdc28.
Cyc Cdks ()
G0.
G0
.
( ).


- .

c-fos c-jun
.
30
.

15
c-fos
c-myc
10

30 60 90 2 4 6 8 10

.
START DNA.


DNA

E2F, D, Cyc-E
Cdks 2-, 4- 6-. O Cdks4, 6 D Cyc-
Cdk2. G1 D-
Cdk4 Cdk6.
D G1
Cdk2 Cdk2-CycE Cdk2-CycA.

Cdk1-Cycs ,B

-
()

G2 M G0
1 hr (
3-4 hrs

Cdks 4, 6- (5?) G0
6-12 hrs
Cycs D1,2,3
6-8 hrs

G1 ).
S
()
E2F4,5

Cdk-Cyc

Cdk2-CycA .
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E2F

Cdk2-Cyc E2F1,2,3 Cdk-Cyc .


TGF

RII RI RII RI

Smad4
Smad3

 R
(restriction point)
E2F.
Cyc-,-
Cdk2-, E2F
().

E2F
(pRb)
p107 p130.
 S
Rb CycD-Cdk4 CycD-Cdk6 o
G1 ( ).
E2F
pRb-E2F. E2F CycE Cdk2 ( )
Cyc-Cdk2 pRb ( ).

R G1S. .
Rb S, G2 M Cdk2-, Cdk1-
Cyc A, B, E2F M pRb
PP-1 ( ). pRb E2F (
)
.

DNA CycA CycA

DNA. CycA
G1S
. o
Sic1 (
S) CycA-Cdk2.


G1S
- CycD-Cdk4,
CycD-Cdk6 Cyc-Cdk2

PP-1 pRb

- pRb E2F ( p107,
E2F p130
G0 E2F )
pRb
p107, p130
E2F
M E2F


(),
G2 G1 Rb E2F -

D pRb

Cdk4/6
DNA

S E
G1S. E2F

Cdk2
( PP-1)

E2F

(
pRb ).
E2F
 Cdk G2 Cdk1
MPF CycA-Cdk1 CycB-Cdk1.
Cyc
. MPF
- .
-
Cdk1-CycA Cdk1-Cyc (
Cdk2). H Cdk1 Cyc, (Wee1, CAK)
(Cdc25) G2
CycA Cdk1 Thr161

.

APC ( ) -
Cyc Cyc ( Cyc
, Cyc)
MPF .
Cyc-A Cyc Cdk M
G1 ( G0) pRb.
(, )
Cdk1
.

.


(MPK MPF)

( CycA B-Cdk1)

CAK

(
MFP

Thr161
Tyr15

Cdc25
)
- (

Cdk1 Cdk1 Cdk1
Wee1, CAK)

Cyc-A,B Cyc-A,B Cyc-A,B
( Cdc25)
- Cdk1

,
.

Wee1

Rb APC
Cdk1 Cdk1 Cdk1
.
Cyc-A,B
Cyc-A,B Cdk2 Tyr15 Thr161.
-

Cyc-A,B
.
 Cyc-Cdk ( )


() Cdk (CdkI, Cdk Inhibitors).

Cdk
( Cyc),
ATP Cyc-Cdk.

CdkIs
, DNA
.
. G1S
G2M
( G1)
( G2)
( ). DNA
G1-S ,
.


Cyc-Cdk.




Cdk (CdkI, Cdk
Inhibitors).

A Cdk Cdk
(CdkI) (

Cyc),

ATP
Cyc-Cdk.
 CdkIs :

(1) 4 (inhibitors of kinase 4)

p16Ink4a, p15Ink4b, p18Ink4c p19Ink4d. ( p14ARF
) CycD-Cdk4, CycD-Cdk6.

(2) Cip/Kip . p21Cip1, p27Kip1

p57Kip2. Cdk2-CycE Cdk2-CycA
CycD-Cdk
Cip/Kip
Cip/Kip
Cdk4-6/CycD.

CdkIs

.
DNA

ATM

p53

Cyclin G

p53
GADD45

IGF-BP3
M2
Bax MD
p21
PCNA
DNA

Cdk-Cyc, PCNA

p14ARF ATM

p53
( )
 p53

DNA DNA
-

I II III IV V C

E6, E1b
MDM2

SV40T

p53
Mdm2 p21




(
)

.

,





()

.
(
)


- .
-
,
-





.




( )

,

- (post-mitotic)
-
-

( ).

(, ,
)

-




.





 Early passage Late passage
(young) (senescent)

Human fibroblasts

B-gal (-) B-gal (+)

In vitro

 HPV E6/E7
Smooth muscle cells

pd 16
pd 30

pd 60
pd 88
pd 46
kb

Telomeres: (TTAGGG)n Loss of telomeric ands

Human somatic cells:
Loss of ~100bp/cell division

Senescent cell
Senescent cell

In Vitro: Replicative Senescence in Normal Cells

Short telomeres correlate with

replicative senescence


 ()
, (
) ( )
.

,


,
,
,
/ DNA


DNA .

p53



.

in vitro
(2) SA--
galactosidase pH 6.0.