CDK 1 Cyclin B active CDK 1 Cyclin B ubiquitinated uuuu APC Cdc20 APC active inactive APC Hct1 APC Hct1 + CDK 1

S M G2 G1 CDK4 Cyclin D CDK2 Cyclin A CDK2 Cyclin E INCOMING SIGNAL CDK 1 Cyclin B

APC Hct1 APC Hct1 + S M G2 G1 CDK4 Cyclin D INCOMING SIGNAL E2F RB E2F RB cyclin E E2F Myc

S M G2 G1 CDK4 Cyclin D E2F RB E2F RB cyclin E E2F CDK2 Cyclin E P53 G1 Checkpoint cell size nutrient levels DNA damage DNA DAMAGE Apoptosis p21

CDK4 Cyclin D E2F RB E2F RB cyclin E E2F P53 DNA DAMAGE Apoptosis p21 P53 MDM2 +

Apoptosis – Programmed Cell Death

Cell ProliferationCell GrowthCell Death Organism size and Organ size are dependent on... mitogensgrowth factorsIntrinsic or external signals

Lack of mitogens in medium new mitogens present in the medium (from serum) Cells need mitogen signals to divide... unless they are transformed or immortalized!

NIH 3T3 Fibroblast Cells Grown in Tissue Culture Plates Confluent, normal growthTransformed foci

Such as a lack of ____integrin______ binding to extracellular proteins, thereby failing to recruit FAK (focal adhesion kinase) for docking of Src. Excessive mitogens leads to excessive __Myc____ protein, which activates the __p19 ARF_ protein that then activates p53. Example of a ___positive______ feedback loop In mammalian cells is Cyclin __E_____ In mammalian cells is Cyclin ___A ____ This is sensed by the protein _Mad2_____. APC regulates this process by ubiquitinating _Securin__ to release _Separase which then degrades _cohesion to allow sister chromatids to separate