Regulation of the cell cycle

Regulation of the cell cycle

1. Cyclin D + CDK 4/6

   • G1 phase up to restriction point

2. Cyclin E + CDK 2

   • Past G1 restriction point to beginning of S phase

3. Cyclin A + CDK 2

   • First half of S phase

4. Cyclin A + CDK 1

   • Second half of S phase to end of G2

5. Cyclin B + CDK1

   • M phase

6. Cyclin/CDK complexes are activated by the addition of 1 phosphate group by CAK

7. Cyclin/CDK complexes are inhibited by the addition of a second phosphate group by Wee1 kinase

   • Phosphorylation can be activating or inhibitory

8. The inhibitory second phosphate group can be removed by Cdc25 phosphatase

9. CDK inhibitors (CKI's) are proteins that bind to and inhibit Cyclin/CDK complexes (inhibit cell cycle)

   • E.g. P27 = suppresses G1/S CDK activity. P21 = suppresses CDK activity after DNA damage. P16 = stops Cyclin D/CDK 4/6 activity

10. Cyclins A + B contain a destruction box. Cyclins D + E contain a PEST sequnce (P - proline, E = glutamic acid, S - serine, T - threonine)

    • These are protein sequences that allow the cyclins to undergo ubiquitination and be marked for destruction by ubiquitin ligase complexes

11. Rb is usually bound to the transcriptional factor E2F. Cyclin D/CDK 4 complex phosphorylates Rb causing it to release the E2F protein which go on to activate genes required for cell replication and thus push the cell past the G1 restriction point

12. p53 is usually bound to Mdm2 that marks it for ubiquitination. DNA damage causes activating phosphorylation of p53 which then binds to the regulatory region of the p21 gene and causes its transcription. p21 then inhibits the cell cycle