Cell Cycle Control
• Cell cycle phases: G1 (growth phase, DNA replication proteins formed, G1 checkpoint: Cycling arrested if DNA damaged) → S (DNA synthesis, cell doubles DNA) → G2 (2nd growth period, G2 checkpoint: Arrest if DNA damaged/improperly replicated) → M (mitosis, aurora kinases regulate, M checkpoint: Chromosomal segregation arrest if spindles misaligned) (Nat Rev Cancer 2009;9:153)
• CDKs, phosphorylate proteins involved in cell cycling
• Cyclins: Proteins that bind to & positively regulate CDKs; CCND1 is overexpressed in mantle cell lymphoma via t(11:14)
• CDK inhibitors such as CIP/KIP family (inhibit cdk2) or INK family (proteins such as CDKN2A inhibit cdk4 & cdk6); inactivating germline CDKN2A (P16INK4A) Mt in familial atypical multiple mole melanoma or familial atypical multiple mole melanoma syndrome (FAMMM), Pt predisposed to develop multiple moles, melanomas, & pancreatic CA
• RB1: Plays major role in inhibiting G1-S phase progression, hypophosphorylated RB1 sequesters E2F/DP thus repressing transcription → in the presence of growth factors, Cyclin D-cdk4/6 & Cyclin E-cdk2 sequentially phosphorylate RB1 → results in transcription of E2F target genes → cell cycle proceeds
• Sporadic & germline Mt in RB1 lead to predisposition to develop retinoblastomas, familial form served as basis for Knudson two-hit model(Proc Natl Acad Sci USA 1971;68:820) → germline Mt in one allele inherited by child, ↑ likelihood of acquiring 2nd somatic Mt resulting in full phenotype; Mt also acquired sporadically in several other tumors
Figure 4-5 Cell cycle progression: Cyclin-CDK complexes regulate progression through various phases of the cell cycle; CDK inhibitors such as members of the INK & CIP/KIP families interact with specific cyclin-CDK complexes to block kinase activity.