Cell Cycle Control And Cancer

Cell Cycle Control and Cancer

Cell Cycle • • • • • •

G1, S, G2, M Go CDK Cyclin p53 pRB

Checkpoint Controls • Go – S • G1 – S • G2 – M

CDK’s • • • • •

G1 – CDK4, CDK6, CDK2 S – CDK2 G2/M – CDK1 CDK7 + cyclin H = Cyclin Activating Kinase Stable levels during cell cycle

Cyclins • G1 – D1, D2, D3 (CDK4+6) E (CDK2) • S – A (CDK2) • G2/M – A (CDK1) • M – B (CDK1) • Periodic synthesis (not D – related to GF’s) • A+B contain destruction box • D+E contain PEST sequences (proline, glutamate, serine, threonine)

Regulation • Association with cyclin • Phosphorylation: CDK1 - P on threonine 172 by CAK • Induces conformational change – cyclin binding • Phosphorylation: CDK1 - P on tyrosine 15 by wee1 • Inactivates CDK1 • Phosphatase Cdc25 removes P-tyr15 • Inhibitors:

CDKI • 2 families INK4 Cip/Kip family • INK’s bind G1 CDK’s and prevent cyclin binding • Cip’s inactivate CDK/cyclin complexes (G1 and M) • Cip1 (p21) also binds PCNA to inactivate S-phase complexes • p53 responsive.

Localisation • Cyclin B is actively excluded from the nucleus until prophase • Cdc25 “held” in cytoplasm by 14-3-3 protein

G1 – S transition

G2 – M transition

Deregulation • p53 and pRb frequently mutated in cancer • CDK’s amplified in some tumours (melanoma, sarcoma, glioma) • Cyclin overexpression – D family. Translocations (Ig heavy chain) lymphoma Amplifications – breast, oesophageal, bladder, lung, squamous cell carcinoma • CAK – overexpressed in 32% of breast tumours • CDKI – p16 deletions, point mutations, hypermethylation

Therapeutic targets? • Target activity of CDK’s (direct approach) • Target regulators of CDK activity (indirect) • Indirect: overexpression of CDKI’s make peptides that mimic CDKI’s decrease cyclin levels modulate proteosome modulate phosphorylation status

Direct • Compete for ATP binding pocket:

CDK7

CDK2

CAK-Cyclin-dependent Activating Kinase: a key kinase in cell cycle control and a target for drugs? Lolli, G and Johnson, LN. Cell Cycle. 2005. 4:572-577.

Inhibitors • Phythormones (cytokinins) Dimethylaminopurine CDK1-cyclinB but non-specific kinase inhibitor • Led to synthesis of Olomoucine highly specific CDK inhibitor • Roscovitine 10x more potent on CDK1 In clinical trials • Purine and pyrimidine analogues..