Cell cycle

The phases of the cell cycle

•    G0

•    G1

•    S

•    G2

•    M

Cyclin Dependent Kinase

•    Cyclin Dependent Kinases allow for the progression of the cell through various phases of the cell cycle by activating cyclin dependent kinases (CDKs)

•    Cyclins are synthesized during certain phases of the cell cycle, phosphorylate constitutively produced CDKs to activate them and their levels subsequently decline

•    Activated CDKs phosphorylate target proteins required for the progression of the cell to the next phase of the cell cycle
c) Desribe the role of RB protein

•    RB prevents the cell from entering S phase until certain cellular signals are met

•    Hypophosphorylated RB is bound to E2F (a transcription factor) and prevents its activity since RB recruits histone deacetylase, causing compaction of chromatin and inhibiting transcription

•    Growth factors cause the concentrations of cyclins D and E to go up, thereby activating cyclin D-CDK4 and cyclin E-CDK2, which then phosphorylate RB

•    Phosphorylation of RB releases it from its complex with E2F, allowing E2F to transcribe key cell cycle proteins such as thymidine kinase, DNA polymerases, cyclin E and dihydrofolate reductase, allowing the cell to transition from G1 to S phase

•    During the M phase, RB is converted to its hypophosphorylated form by cellular phosphatases

Cell Cycle Gene Mutations and Cancer

•    Mutations that activate oncogenes (eg. Her2-neu, EGFR, KIT, BRAF, β-catenin, RAS, MYC, RET, Cyclin D1)

•    Mutations that inactivate tumour suppressor genes (eg. RB, p53, BRCA1, BRCA2, E-cadherin, NF-1, NF-2, APC/ β-catenin, WT-1, p16/INK4)

•    Mutations of DNA repair genes (hMLH1, hMSH2, PMS1, PMS2, ATM)

•    Alterations of genes involved in apoptosis (eg. BCL-2, p53, MYC)