-CDK DNA 4 G 1 S G 2 M 3 (check points) G 1 DNA G 2 /M DNA DNA DNA 2 CDK CDK cylcin-dependent kinase 34 kda, Ser/Thr [ ] (Cyclin)5060 kda [ ] 1. (Rao & Johnson, 1970 ) a) M M b) S S G 2 /M S c) M S DNA 2. (maturation-promoting factor: MPF) (, 1970 ) MPF M M (M-phase promoting factor) 3. (Hartwell, 1970 ) cdc * CDC28 cdc2 cdc2 (Nurse 1987 )Cdc2 CDK1 *cell division cycle 4. (Hunt & Ruderman, 1980 ) A B M
1986 DNA mrna 5. MPF (Lohka & Maller, 1988 ) MPF 34kDa 46 kda Ser/Thr Cdc2 Cdc13( B) MPF Cdc2 B -CDK Cdc2 CDK1 A B CDK CDK- 3 CDK CDK 1. M Cdc2 CDC28 B[M ] G G C, D, E, F, G, H, I, T 20 A1, A2, B1, B2, C, D1, D2, D3, E1, E2, F, G1, G2, H, I, K, T1, T2a, T2b -CDK9 RNA (CTD) 2. CDK cdc CDC28 1 Cdc2 9 3. CDK two-hybrid -CDK CDK (CDK inhibitor, CKI) (1990 ) 2 G 1 Ink4 p15 Ink4b, p16 Ink4a, p18 Ink4c, p19 Ink4d D-CDK4 CDK Cip/Kip p21 Cip1, p27 Kip1, p57 Kip2 CDK E-CDK2 CDK p21 Cip1 PCNA 4. -CDK G 1 D-CDK4 S E-CDK2 S A-CDK2 G 2 A-CDK1(Cdc2) M B-CDK1(Cdc2) -CDK H-CDK7 CAK CDK CKI
(Hartwell, 1989 ). G 1 S G 1 G 1 S D-CDK4 E-CDK2 D CDK4 CAK Rb Rb E2F E S DNA E CDK2 Rb p27 Kip1 CKI 1 S CKI S S E - * b G 1 S * -CDK CKI G 1 /S p27 Kip1 E3 SCF Skp1-Cul1-F-box F-box Rb (retinoblastoma) RB Rb 928 (110 kda) 200 kb 27 G 1 S E2F 13 Rb E2F E2F S E2F TTTCGCGC DP1/2 E2F-16 Rb G 1 S G 2 M G 1 2. M G 2 /M M MPF Cdc2 B Cdc2(CDK1) Thr14, Tyr15, Thr161 Thr161 3
B S Cdc2 MPF Cdc2 MPF Cdc2 3 Myt1 Thr14 Wee1 Tyr15 CAK Thr161 Cdc2 B-Cdc2 G 2 G 2 Cdc25 25A, 25B, 25C Cdc2 Thr14, Tyr15 MPF Cdc25C Myt1 Wee1 MPF Cdc25 PP2A S G 2 M G 1 M M M E3 APC/C (anaphase- promoting complex cyclosome) (Ser/Thr) (protein phosphatases, PP) PP1, PP2A, PP2B, PP2C PP2A α β2 C A B B(PR55), B (B56), B (PR72) B α, β, γ3 3. cohesion (cohesin) Smc1/Smc3 Scc1/Scc3 separin securin Cdc20 APC/C Scc1/3 CENP-E Bub1 Mad2 Mad2 Cdc20 APC/C
DNA kb 1 ( ) 6 (Orc-16) post-rc (post-replicative complex ) M Cdc6 6 Mcm (minichromosome maintenance) (Mcm27) Mcm Orc-16 M pre-rc G 1 -CDK1 Cdc6 S Cdc7/Dbf4 Mcm Mcm4, 6, 7 Cdc45 2 DNA S DNA Cdc7/Dbf4 Dbf4 Orc-16 Mcm DNA post-rc S 1 DNA pre-rc M 1 Orc1-6: ORC Orc1: Cde18 Orc2: Cdc2 Cdc6: ATPase/GTPase Mcm : Mcm4/6/7 Cdc7: Ser/Thr Dbf4 Dbf4: Cdc7 Cdc45: DNA DNA
1. DNA DNA DNA PI3 ATM ATR ATM ATR Chk1 Chk2 G 1 ATM p53 Ser15 ATM Chk2 MDM2 p53 E3 p53 p53 p53 p21 Clip1 p21 Clip1 E-CDK2 S DNA p53 S p21 Clip1 PCNA DNA DNA DNA BRCA1 G 2 ATR ATM Chk1 Chk2 Cdc25C Ser216 Cdc25 B-Cdc2 Chk1/2 Wee1 B-Cdc2 p53 14-3-3σ Cdc25C Ser216 Cdc25C G 2 G 1 arrest σ δ G 2 arrest p53 --- (guardian of the genome)--- p53 SV40 T Lane, Levine, 1979 1988-1989 50% p53 CDK p21 Waf1 p53 1 (Vogelstein, 1993 ) p53 G 1 /S G 2 M 1 p53 17p13 11 11 p53 393 390 3 p53 p53 4 MDM2 p53 E3 20 ATM ATR Ser15 p19 ARF MDM2 p53 MDM2