Cell biology

The plasma membrane

• Fluid mosaic model: a phospholipid bilayer with cholesterol, integral and peripheral proteins, and a carbohydrate coat (glycocalyx).
• Phospholipids are amphipathic: a hydrophilic phosphate head and two hydrophobic fatty acid tails. In water they self-assemble into a bilayer whose oily core is a barrier to water-soluble substances. Cholesterol stabilises fluidity.
• Main function: a selectively permeable barrier that controls what enters and leaves, and carries receptors, transporters and adhesion molecules.
• Permeability across the bare bilayer depends on lipid solubility and size, not charge alone:

• Na⁺/K⁺-ATPase pumps 3 Na⁺ out and 2 K⁺ in per ATP. Digoxin blocks it in cardiac myocytes; intracellular Na⁺ rises, so the Na⁺/Ca²⁺ exchanger removes less calcium, more Ca²⁺ is stored in the sarcoplasmic reticulum and contractility increases.

Organelles

• Mitochondria multiply by growth and fission of existing mitochondria (they are never made from scratch), driven by endurance training and thyroid hormone. They are most numerous in high-energy cells: cardiac muscle, slow-twitch (type I, red) skeletal fibres, renal tubules, hepatocytes. Large flocculent densities in mitochondria are a sign of irreversible cell injury.

Cytoskeleton

• Intermediate filament markers tell the origin of an undifferentiated tumour: cytokeratin = epithelium (carcinoma); vimentin = mesenchyme (sarcoma); desmin = muscle; GFAP = astrocytes (glioma); neurofilaments = neurons; lamins line the nucleus.
• Microtubule drugs: colchicine, vinca alkaloids (stop polymerisation), taxanes (stabilise), griseofulvin, mebendazole.
• Primary ciliary dyskinesia (Kartagener): dynein arm defect causing bronchiectasis, sinusitis, situs inversus and infertility.

Exam trap Strong cytokeratin staining means an epithelial tumour (carcinoma), even when it looks undifferentiated.

Cell junctions

• Tight junctions (claudins, occludin) seal epithelia; adherens junctions (cadherins; E-cadherin lost in invasive and diffuse gastric cancer); desmosomes (desmoglein; targeted in pemphigus vulgaris); gap junctions (connexins; electrical coupling in heart and smooth muscle); hemidesmosomes (integrins to basement membrane; targeted in bullous pemphigoid).

Chromosomes, histones and telomeres

• DNA is wound around histone octamers (two each of H2A, H2B, H3, H4) to form nucleosomes; H1 links them. Histones are rich in lysine and arginine, whose positive charges bind the negatively charged phosphate backbone of DNA. Acetylation of lysine removes the charge, loosens chromatin and switches genes on.
• Telomeres are TTAGGG repeats at chromosome ends that shorten with every division, limiting cell lifespan. Telomerase (a reverse transcriptase carrying its own RNA template) maintains them in germ cells and stem cells and is reactivated in most cancers, giving immortality.
• The centromere normally splits longitudinally at anaphase. If it splits transversely, each daughter receives two copies of one arm and none of the other: an isochromosome (for example i(Xq) in some Turner syndrome).

Cell cycle

• G1 (growth; most variable length) then S (DNA synthesis) then G2 then M (prophase, metaphase, anaphase, telophase) then cytokinesis. G0 is the resting state.
• Driven by cyclins with cyclin-dependent kinases; brakes are CDK inhibitors (p21, p16, p27).
• G1/S checkpoint: Rb holds E2F; cyclin D–CDK4/6 phosphorylates Rb, freeing E2F to start S phase. Loss of Rb causes retinoblastoma and osteosarcoma.
• p53, the guardian of the genome, senses DNA damage and induces p21, stopping the cycle at G1/S until repair, or triggering apoptosis if repair fails. Loss of p53 lets damaged cells divide (Li–Fraumeni syndrome; most human cancers).
• Labile cells divide constantly (skin, gut mucosa, marrow); stable cells divide when stimulated (liver, kidney tubules, fibroblasts); permanent cells cannot (neurons, cardiac and skeletal muscle).
• Phase-specific drugs: S phase (methotrexate, 5-FU, cytarabine, hydroxycarbamide), M phase (vinca alkaloids, taxanes), G2 (bleomycin, etoposide).
• Mitosis gives two identical diploid cells; meiosis gives four haploid gametes with crossing over in prophase I. Nondisjunction, mostly in maternal meiosis I and rising with maternal age, causes trisomy.

Apoptosis versus necrosis

• Apoptotic cells are intensely eosinophilic: the cytoplasm condenses, and loss of basophilic RNA lets the pink proteins dominate. Examples: Councilman bodies in viral hepatitis and yellow fever.
• Intrinsic (mitochondrial) pathway, the central route: DNA damage or growth-factor withdrawal activates BAX and BAK, which make the outer mitochondrial membrane leaky; cytochrome c leaves and forms the apoptosome, activating caspase 9. BCL-2 and BCL-xL are anti-apoptotic, guarding the membrane. The mitochondrion is therefore the central organelle of apoptosis.
• Extrinsic pathway: Fas ligand binding Fas (CD95) or TNF receptor activates caspase 8. Cytotoxic T cells also use perforin and granzyme B.
• Both pathways converge on executioner caspases 3 and 7.
• Physiological examples: interdigital webs, endometrial shedding, thymic deletion of self-reactive T cells. In cancer, apoptosis is lost: BCL-2 overexpression from t(14;18) in follicular lymphoma, p53 loss; a Fas defect causes autoimmune lymphoproliferative syndrome.

Remember Shrinkage without inflammation is apoptosis; swelling with inflammation is necrosis.

How FCPS asks about this

• Molecule with highest membrane permeability: small lipid-soluble gases such as O₂ and CO₂; ions are least permeable.
• Organelle prominent in steroid-producing cells or tumours: smooth endoplasmic reticulum.
• Undifferentiated tumour positive for cytokeratin: epithelial origin (carcinoma).
• Why histones bind DNA: positive lysine and arginine bind negative phosphates.
• Enzyme keeping chromosome ends in stem cells and cancer: telomerase.
• Centromere splitting transversely: isochromosome.
• Anti-apoptotic protein overexpressed in follicular lymphoma: BCL-2 from t(14;18); p53 is the pro-apoptotic guardian of the genome.