Lecture 7/8: Cell cycle control

Lecture 7/8: Cell cycle control

1. G1

   • S
     • G2
       • Mitosis
         • G1
       • cdc2 (CDK)
         • MPF (heterodimer)
           • Mitosis
             • Spindle Assembly Checkpoint
           • Regulation
             • Wee1 (kinase)
               • Phosphorylates tyrosine, repressing MPF activity (G2)
             • cdc25 (phosphatase)
               • Removes PO4 from tyrosine, increasing MPF activity (start of M)
             • CAK (kinase)
               • Phosphorylates threonine, increasing MPF activity (late G2)
             • APC/C (ubiquitin ligase)
               • In anaphase, tags Cyclin "destruction box" with polyubiquitin
       • Mitotic cyclin
       • DNA Damage Checkpoint
     • S cyclin
       • Regulation: same as G1/S
     • DNA Damage, Replication Checkpoints
   • G1 cyclin
     • Regulation: same as G1/S
   • G1/S cyclin
     • SPF
       • Regulation
         • Phosphorylation of inhibitor
         • SCF (ubiquitin ligase)
           • At end G1, tags phosphorylated inhibitor with polyubiquitin
   • CDK
   • Inhibitor
   • DNA Damage, Environmental Checkpoints
     • DNA Damage phosphorylates and activates p53
       • Activates p21
         • Inhibits all cyclin-CDK complexes
           • Stops cell cycle. DNA either repaired or cell undergoes apoptosis
         • A CDK inhibitor protein (CKI)
       • Mutation in many cancers

2. S. cerevisiae

   • Budding yeast
     • New cell buds off the original at end of G1 and grows
   • Long G1 phase
   • cdc28 (CDK)
     • Mutation arrests cells without buds

3. S. pombe

   • Fission yeast
     • Cell elongates and splits
   • Long G2/M phase
   • cdc2 (CDK)
     • Mutation keeps cell in G2 - keeps elongating

4. Kinases

   • Enzyme that adds PO4
     • CDKs
       • Expression level constant

5. Phosphatases

   • Enzyme that removes PO4

6. Cyclins

   • Protein
     • Expression "cycles" throughout cell cycle
   • Bind to form factors that control cell cycle (ie. MPF)
     • Degraded by Proteasome once tagged by Ubiquitin ligase
       • polyubiquitinates target protein
     • Activity regulated

7. E2F Transcription factor complex

   • Promoter of G1/S cyclin gene
     • Bound Rb (Retinoblastoma) prevents transcription (repressor)
       • Phosphorylating Rb releases it from E2F, transcription starts
       • Inactivated in many cancers