L17: Cell Proliferation

Question 1

Describe cell cycle

Answer 1

• G1 —> S —> G2 —> M —> G1
• G0 for non-dividing cells
• Interphase: G1, S, G2
• Regulated by cyclin dependent kinase (cdks) which is activated by cyclin

S: DNA replication
M: nuclear division and cytokinesis

Question 2

Describe mitosis

Answer 2

1. Prophase: condensed chromosome
2. Prometaphase: break down of nuclear membrane, attachments of chromosome at kinetochore to spindle microtubules
3. Metaphase: Alignment at equatorial plane
4. Anaphase: Separation to two poles
5. Telophase: Chromatids separate from microtubules, reformation of nuclear membrane
6. Cytokinesis: Cleavage into two cells by aggregation of actin-myosin belt

Question 3

Intrinsic and Extrinsic cell cycle checkpoint

Answer 3

Intrinsic: Cell size, DNA replication, DNA damage, Alignment of chromosome
Extrinsic: Environmental signals

Question 4

G1, G2, Mitotic checkpoint

Answer 4

G1 checkpoint: cell size, DNA damage, favourable environment —> enter S

G2 checkpoint: cell size, DNA damage repaired?, ALL DNA replicated? —> enter M

Mitotic checkpoint: All chromosome properly attached to mitotic spindle? —> Mitosis

Question 5

What are Cdks

Answer 5

Cyclin-dependent protein kinases, require binding of cyclin to form Cyclin-Cdk complexes

Cyclically activated in a phase-specific manner
Function by phosphorylating different target proteins

Question 6

Target proteins of cyclin-Cdks

Answer 6

1. Retinoblastoma protein (Cyclin D-cdk4/6 —> phosphorylated Rb—> inactivated —> cyclin E transcription —> cyclin E-cdk2 —> further phosphylate Rb —> S phase entry)
2. Nuclear lamins (phosphorylated —> breakdown of nuclear membrane —> M phase entry)

Question 7

Regulation of Cdk activities

Answer 7

1. Synthesis (transcription) and degradation (proteolysis)
2. Phosphorylation and dephosphorylation by other kinases/phosphatases
3. Cdk inhibitors: CIP/KIP (p21) and INK4 protein (p16) (DNA damage-induced checkpoint control): DNA damage —> p53 activation —> p21 transcription —> stop cell cycle

CIP: CDK interacting protein
KIP: Kinase inhibitory protein
INK4: Inhibitor of Kinase 4

Question 8

Mutation of cell cycle regulators in cancer

Answer 8

1. Cyclin D1 over-expression (via gene amplification and translocation)
2. Amplification of Cdk4
3. Deletion of INK4/p16 gene
4. Inactivating mutation of Rb