KINE 1000 Lecture Notes - Lecture 18: Cdc25, Chek1, Eif4E
Mitoges Stiulate G1-Cdk & G1/S-cdk
Activities
• Mitogens control rate of cell division by acting in G1 phase
• Mitogens release brakes on cdk during G1 to allow entry into new cell cycle
• Mitogens interact w/cell-surface receptors to trigger intracellular signalling
pathways
- Mitogens interact w/monomeric GTPase Ras→ leads to activation of
mitogen-activated protein kinase (MAP kinase) cascade. Leads to
production of transcription regulatory proteins including Myc
- Myc promotes cell-cycle entry by increasing expression of genes incoding
G1-cyclins which increases G1-cdk activity. Also stimulates transcription of
genes that increase cell growth
• G1-Cdk Complexes activate regulatory factors called E2F proteins→ binds to DNA
sequences in promotors of genes that are required for entry into S-phase →
includes G1/S-cyclins, S-cyclins & proteins involved in DNA synthesis &
chromosome duplication
• In absence of mitogenic stimulation, E2F-dependent gene expression is inhibited
- Interaction of E2F & RB inhibits activity
• When cells stimulated to divide by mitogens, active G1-cdk accumulates &
phosphorylates rb family reducing their binding to E2F. Liberated E2F proteins
then activate expression of target genes
- E2F proteins increase transcription of own genes
- E3F-dependent transcription of G1/S-cyclins & S-cyclin genes leads to
increase in G1/S-cdk activities which increases Rb protein phosphorylation
& promotes further increase in E2F release
DNA Damage Blocks Cell Division: DNA damage Response
• Rate of cell proliferation is controlled by extracellular mitogens & other
extracellular & intracellular signals
• Cycle control detects DNA damage & arrests cycle at two transition
- One at start & entry into S-phase
- Or at G2/M transition
• DNA damage intitates signalling pathway by activating protein kinase called ATM
& ATR which associates w/site of damage & phosphorylates target proteins
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