STEPTRACKERBIOCHEMISTRY + PATHOLOGY + PHARMACOLOGY | CELL BIOLOGY | HIGH-YIELD REVIEW

Cell Cycle

G1 → S → G2 → M, gated by cyclin–CDK pairs and two guardians — Rb and p53 — whose loss lets cells divide unchecked.

FOCUS ON

CDKs are always present; cyclins rise and fall to activate them. The G1 → S checkpoint is the key one: Rb holds E2F until cyclin D–CDK4/6 phosphorylates it. p53 senses DNA damage → p21 → blocks CDKs → arrest or apoptosis. G1 is the variable-length phase. Labile cells never rest; stable cells sit in G0; permanent cells have left the cycle.

COMPONENT

ROLE

WHEN LOST OR OVERACTIVE

CLUE · DRUG

G1 phase

Growth, protein synthesis; length varies most between cell types

—

G0 = quiescent exit from G1

S phase

DNA replication (2n → 4n DNA content)

—

Antimetabolites act here (MTX, 5-FU, 6-MP, hydroxyurea, cytarabine)

G2 phase

Prepares for mitosis; checks replicated DNA

—

Bleomycin, etoposide (G2/S)

M phase

Prophase → metaphase → anaphase → telophase → cytokinesis

—

Microtubule drugs: vincristine/vinblastine, paclitaxel

Cyclins & CDKs

Cyclin binds and activates its CDK; cyclin degraded after its phase

Overexpressed cyclin D (t(11;14) mantle cell) → G1 escape

Palbociclib, ribociclib: CDK4/6 inhibitors (breast cancer)

Rb (retinoblastoma protein)

tumor suppressor

Hypophosphorylated Rb binds E2F → no S-phase genes; CDK4/6 phosphorylation releases E2F

Loss → free E2F → uncontrolled G1 → S

Retinoblastoma, osteosarcoma · HPV E7 binds Rb

p53

"guardian of the genome"

DNA damage → p53 ↑ → p21 (CDK inhibitor) → G1 arrest; triggers BAX → apoptosis if unrepairable

Loss → damaged cells keep dividing

Li-Fraumeni (germline TP53) · HPV E6 degrades p53 · most common mutated gene in cancer

CDK inhibitors

p21, p27 (and p16 for CDK4/6) brake the cycle

Loss of p16 (CDKN2A) → melanoma, pancreatic cancer

—

Labile cells

Always cycling

First to suffer with chemo (mucositis, marrow, hair)

Marrow, gut epithelium, skin, hair follicles, germ cells

Stable cells

Rest in G0, re-enter when stimulated

Regenerate after injury

Hepatocytes, proximal tubule, endothelium

Permanent cells

Cannot divide; G0 forever

Injury heals by scar

Neurons, cardiac and skeletal muscle, RBCs

Picture it — cycle and checkpoints

The cell cycleG1 is the longest and most variable phase; ◆ marks the G1/S and G2/M checkpoints; resting cells exit to G0.

The G1/S switchCyclin D–CDK4/6 phosphorylates Rb to free E2F; DNA damage raises p53 → p21, which blocks the CDKs.

Schematic diagrams, not to scale.

Mechanism — the G1/S checkpoint

Growth factor

→

Cyclin D–CDK4/6

→

Rb phosphorylatedReleases E2F

→

S-phase genes onReplication

DNA damage

→

p53 ↑ → p21

→

CDKs blockedRb stays bound

→

Arrest → repair or apoptosis

Chemotherapy by phase

PHASE

DRUGS

MECHANISM

Methotrexate, 5-FU, 6-MP, cytarabine, hydroxyurea

Antimetabolites

Bleomycin

Free-radical DNA breaks

S/G2

Etoposide, irinotecan

Topoisomerase inhibition

Vinca alkaloids, taxanes

Microtubule disruption

Nonspecific

Alkylators, platinums, anthracyclines

Damage DNA in any phase

How it's tested

COMMON CONFUSIONRb is a brake that phosphorylation releases — "phosphorylated Rb = active cycling". p53 acts upstream through p21.

THE TRAPHPV E6 targets p53 and E7 targets Rb — not the other way round ("E6 → p53, E7 → Rb": 6 before 7, 53 before b).

YOUR APPROACHIdentify the phase → the controlling cyclin–CDK → the brake (Rb, p53, p21, p16) → disease or drug acting there.

If you see… think…

Child with retinoblastoma, later osteosarcoma → germline RB1 loss

Family with sarcoma, breast cancer, brain tumors young → Li-Fraumeni (TP53)

HPV oncoprotein degrading p53 → E6

HPV oncoprotein inactivating Rb → E7

Breast cancer drug blocking CDK4/6 → palbociclib

Mantle cell lymphoma t(11;14) → cyclin D1 overexpression

Phase most variable in length → G1

Tissue healing by scar after infarct → permanent cells

Liver regrows after partial resection → stable cells re-entering from G0

Mucositis and hair loss with chemo → labile cells