Cell Cycle

Why is mitosis (controlled cell division) necessary?

Necessary for:

• Gametogenesis

• Developmental growth

• Maintenance of tissue and organ functions

• Repair of damaged tissues

• Immune cell proliferation

What happens with uncontrolled cell growth?

It becomes unsustainable — exponential cell divisions lead to unmanageable growth

What determines whether the cell cycle proceeds or is halted?

Checkpoints

Where are the major checkpoints located?

G1/S, G2/M, and M phases

What is the key to success in cell cycle control?

Proper checkpoint control

What do checkpoints monitor for?

Errors in replication, growth, and division

What are the molecular components of cell cycle checkpoints?

• Kinases

• Cyclins

• External signals

What do kinases do?

• They phosphorylate molecules

• Their amount does not fluctuate

What are Cyclin-dependent kinases (CDKs)?

Kinases that are inactive until cyclins are present

What are cyclins?

• Proteins whose concentration fluctuates

• They bind to kinases and act as checkpoints

• Cyclin–CDK complexes promote progression to the next stage of the cycle

What role do external signals play in the cell cycle?

They regulate progression through growth factors and physical factors

What does the G1/S checkpoint control?

Passage from G1 into S phase

What does the G1/S checkpoint check?

• The cell size is correct and the environment is suitable

• External agents also regulate progression

How do nutrients affect the G1/S checkpoint?

Lack of nutrients inhibits cell division

What specific growth factor is needed for cell division in wound healing?

Platelet-derived Growth Factor (PDGF)

How is PDGF clinically relevant?

It is a major stimulus in airway remodeling in chronic asthma

What is Triptolide and what does it do?

• A compound from the Chinese herb “Thunder God Vine.”

• It inhibits PDGF-induced airway smooth muscle cells via G0/G1 arrest

What is density-dependent inhibition?

Cells stop dividing when they contact each other (contact inhibition)

What is anchorage-dependent inhibition?

• Cells must attach to a substratum to divide

• Anchorage signals are transmitted through membrane proteins and the cytoskeleton

What protein plays a key role at the G1/S checkpoint?

Retinoblastoma protein (Rb)

How is Rb function regulated?

By phosphorylation status

What phosphorylates Rb?

S-phase Cyclin–CDK complexes

How does the CDK4/6–Cyclin D1 complex promote S-phase entry?

• It phosphorylates Rb, dissociating it from the Rb–E2F complex

• Free E2F binds DNA and upregulates transcription of S-phase genes

How is CDK4/6 clinically relevant?

It is a therapeutic target for breast cancer treatment

What does the G2/M checkpoint do?

Prevents the cell from entering mitosis if the genome is damaged

Is this checkpoint internally or externally controlled?

Almost exclusively internally

What is MPF?

M-phase Promoting Factor, a complex of CDK1 (CDC2) and Cyclin B

What does MPF do?

Triggers progression to M phase by phosphorylating proteins, e.g. those that degrade the nuclear membrane

How is MPF formed?

CDC2 binds Cyclin B during S and G2

How is CDC2 activated?

CDK-activating kinase phosphorylates CDC2 at threonine-161, stabilizing its binding with Cyclin B

What keeps MPF initially inactive?

Phosphorylation at tyrosine-15 and threonine-14 (inhibitory sites)

How is MPF finally activated?

Dephosphorylation of tyrosine-15 and threonine-14

How is MPF switched off?

Cyclin B is degraded and threonine-161 is dephosphorylated

How does meiosis differ between spermatocytes and oocytes?

Spermatocytes proceed uninterrupted, while oocytes arrest at specific stages

What is oocyte maturation?

The transition from prophase I to metaphase I, involving nuclear envelope breakdown, cortical cytoskeleton rearrangement, and meiotic spindle assembly

Why is oocyte maturation essential?

For meiosis progression and preparing the oocyte for fertilisation

What is the MPF status at prophase I arrest (GV stage)?

Low MPF; oocyte arrested with intact nucleus

What happens at Germinal Vesicle Breakdown (GVBD)?

MPF rises; nuclear envelope breaks down and meiosis I resumes

What happens at metaphase I → anaphase I?

High MPF; chromosomes align and segregate

What is MPF status at metaphase II arrest (secondary oocyte)?

High MPF; the oocyte waits for fertilisation

What happens to MPF after fertilisation?

MPF falls, meiosis II completes

What is GVBD?

Germinal Vesicle Breakdown — the breakdown of the nuclear envelope in a prophase I oocyte, marking resumption of meiosis I

What does MPF induce in oocytes?

• Exit from prophase I arrest

• Continuation of meiosis I

• Homologous chromosome extrusion

• Re-arrest at metaphase II

Why is MPF decrease at end of meiosis I necessary?

For homologous chromosome segregation

What maintains metaphase II arrest in oocytes?

Cytostatic factor (CSF)

How does CSF work?

By inhibiting the anaphase-promoting complex (APC)

What ends CSF-induced metaphase II arrest?

A sperm-derived Ca²⁺ signal that removes APC inhibition