Premed · Premed · Cell Biology

Lecture 28: Course Review

Cell Biology

Learning Objectives

By the end of this lecture, students will be able to:

1. Integrate concepts across all major topics covered in this course
2. Identify connections between cellular structures, signaling pathways, and disease mechanisms
3. Apply cell biology principles to solve multi-step problems
4. Prepare effectively for the final examination by understanding key themes and high-yield topics

Lecture Content

I. Cell Structure and Compartmentalization (Lectures 1-3)

Cells are the fundamental unit of life; all cells share common features (plasma membrane, ribosomes, DNA genome) Prokaryotes vs. eukaryotes: eukaryotes have membrane-bound organelles that compartmentalize functions. Endomembrane system: ER, Golgi, lysosomes, endosomes, vesicles — interconnected by vesicular transport. Macromolecules: proteins, nucleic acids, carbohydrates, lipids — structure determines function. Key concept: compartmentalization allows simultaneous, incompatible biochemical reactions and increases efficiency.

II. Membranes and Transport (Lectures 4-6)

Fluid mosaic model: lipid bilayer with embedded and peripheral proteins. Membrane fluidity determined by: fatty acid saturation, chain length, cholesterol content, temperature. Asymmetry: different lipid and protein composition on each leaflet. Transport: Passive: simple diffusion, facilitated diffusion (channels, carriers) — down the electrochemical gradient; no energy required. Active: primary (ATP-driven pumps: Na+/K+-ATPase, Ca2+-ATPase, H+/K+-ATPase) and secondary (co-transporters using ion gradients, e.g., SGLT1) Na+/K+-ATPase: 3 Na+ out, 2 K+ in per ATP; establishes the Na+ and K+ gradients essential for membrane potential, secondary active transport, and cell volume regulation. Ion channels: selective, gated pores. Voltage-gated (Na+, K+, Ca2+ channels): action potentials. Ligand-gated: neurotransmitter receptors (nAChR) Mechanosensitive: Piezo1, Piezo2. Key diseases: cystic fibrosis (CFTR Cl- channel), channelopathies (long QT syndrome, epilepsy).

III. Cell Signaling (Lectures 7-9)

General principles: signal -> receptor -> intracellular transduction -> cellular response. Amplification, specificity, integration, adaptation/desensitization. GPCRs (7-TM receptors): largest receptor family. G-alpha-s -> adenylyl cyclase -> cAMP -> PKA. G-alpha-q -> PLC -> IP3 (Ca2+ release) + DAG (PKC activation) G-alpha-i -> inhibits adenylyl cyclase. Desensitization: GRK phosphorylation -> beta-arrestin binding -> internalization. RTKs: dimerization -> autophosphorylation -> recruitment of SH2-domain proteins. Ras-MAPK pathway (proliferation): RTK -> Grb2 -> SOS -> Ras-GTP -> Raf -> MEK -> ERK. PI3K-Akt pathway (survival): RTK -> PI3K -> PIP3 -> Akt (inhibited by PTEN) Both pathways are major oncogenic drivers when constitutively activated. Intracellular receptors: steroid/thyroid hormones cross the membrane; bind nuclear receptors -> transcription factor activation. Integration theme: the same pathways appear in multiple contexts (development, physiology, cancer).

<image>Integrated signaling overview. Panel A: Side-by-side comparison of the three major receptor types — GPCR (7-TM, heterotrimeric G protein, cAMP/Ca2+ second messengers), RTK (dimerization, autophosphorylation, Ras-MAPK and PI3K-Akt cascades), and nuclear receptor (ligand crosses membrane, binds intracellular receptor, receptor-ligand complex acts as transcription factor binding DNA response elements). Panel B: Convergence and crosstalk — arrows showing how GPCR signaling (via PKA/PKC) can modulate MAPK pathway activity, how Akt cross-talks with the cell cycle (inhibits p27, activates cyclin D/MDM2), and how these pathways converge on transcription factors (CREB, Myc, Fos/Jun) that regulate proliferation, survival, and differentiation.</image>

IV. Endomembrane System and Protein Trafficking (Lectures 10-15)

ER: protein synthesis (rough ER), lipid synthesis and detoxification (smooth ER) Signal hypothesis: signal peptide -> SRP -> SRP receptor -> translocon -> co-translational translocation. Protein folding: BiP, calnexin/calreticulin, PDI. Unfolded protein response (UPR): IRE1, PERK, ATF6 sensors. ER quality control: ERAD (misfolded proteins retrotranslocated and degraded by proteasome) Golgi: cis -> medial -> trans processing; glycosylation (N-linked modification, O-linked addition) Sorting at the TGN: signals direct proteins to lysosomes (M6P), plasma membrane (default), or secretory granules. Vesicular transport: COPII (ER to Golgi), COPI (Golgi to ER retrograde), clathrin (TGN to endosomes, PM to endosomes) Coat proteins, Rab GTPases (tethering), SNAREs (membrane fusion) Endocytosis: clathrin-mediated, caveolae, receptor-mediated (LDL receptor pathway) Lysosomes: acid hydrolases (pH ~4.5-5.0), autophagy (macroautophagy: phagophore -> autophagosome -> autolysosome) Lysosomal storage diseases: Tay-Sachs, Gaucher, I-cell disease. Mitochondria: oxidative phosphorylation, TCA cycle; double membrane; own DNA; maternal inheritance. Electron transport chain: complexes I-IV -> proton gradient -> ATP synthase (complex V) Peroxisomes: beta-oxidation of very long chain fatty acids; catalase (H2O2 detoxification) Zellweger syndrome: peroxisome biogenesis disorder.

V. The Cytoskeleton and Cell Motility (Lectures 16-19)

Three cytoskeletal systems:

Motor proteins: myosins (actin), kinesins (MT, mostly plus-end), dyneins (MT, minus-end) Muscle contraction: sarcomere, sliding filament model, Ca2+-troponin-tropomyosin regulation. Cell migration: protrusion (actin polymerization) -> adhesion (integrins) -> traction (myosin II contraction) -> retraction.

VI. Cell Cycle, Division, and Death (Lectures 20-22)

Cell cycle: G1 -> S -> G2 -> M; driven by cyclin-CDK complexes. Cyclin D-CDK4/6 (G1) -> Cyclin E-CDK2 (G1/S) -> Cyclin A-CDK2 (S) -> Cyclin B-CDK1 (G2/M) Restriction point: Rb phosphorylation releases E2F -> commitment to S phase. Checkpoints: G1/S (p53/p21), G2/M (Cdc25/Wee1), SAC (Mad2-APC/C) Mitosis: prophase -> prometaphase -> metaphase -> anaphase -> telophase. APC/C-Cdc20: ubiquitinates securin (freeing separase -> cohesin cleavage) and cyclin B (CDK1 inactivation) SAC prevents premature anaphase until all kinetochores are bi-oriented. Cytokinesis: RhoA -> contractile ring (actin + myosin II) -> furrow ingression -> ESCRT-III-mediated abscission. Apoptosis: Intrinsic: stress -> BH3-only proteins -> Bax/Bak -> MOMP -> cytochrome c -> apoptosome -> caspase-9 -> caspase-3. Extrinsic: death ligand -> death receptor -> DISC -> caspase-8 -> caspase-3. Regulated by Bcl-2 family (anti- vs. pro-apoptotic balance) and IAPs/Smac.

<image>Cell cycle and apoptosis integration. Panel A: Cell fate decision diagram — a cell receiving growth factor signals progresses through the cell cycle (G1->S->G2->M, with cyclin-CDK complexes driving each transition); DNA damage activates p53, which can either arrest the cycle (via p21 inhibiting CDKs) or induce apoptosis (via PUMA/NOXA activating the intrinsic mitochondrial pathway). Loss of growth factor signals can lead to apoptosis (Bad activation) or quiescence (G0). Panel B: Connections to cancer — oncogenic mutations that override each control point are indicated: cyclin D amplification or Rb loss (bypasses G1 restriction), p53 mutation (bypasses DNA damage arrest and apoptosis), Bcl-2 overexpression (blocks intrinsic apoptosis), SAC defects (causes aneuploidy). Panel C: Overview of the apoptosis pathways — extrinsic (Fas/FADD/caspase-8) and intrinsic (Bax/cytochrome c/apoptosome/caspase-9) converging on executioner caspases (caspase-3) leading to cell dismantling and phagocytic clearance.</image>

VII. Cell Adhesion, ECM, and Tissue Organization (Lectures 23-24)

Cell-cell junctions: tight junctions (barrier/fence), adherens junctions (E-cadherin-actin), desmosomes (desmosomal cadherins-IFs), gap junctions (connexins, direct communication) Cell-ECM adhesion: integrins (bidirectional signaling, focal adhesions) ECM components: collagen (tensile strength), proteoglycans/GAGs (compression resistance, hydration), laminin and fibronectin (adhesion, signaling) Basement membrane: type IV collagen + laminin + nidogen + perlecan. Mechanotransduction: cells sense ECM stiffness and respond (YAP/TAZ, FAK/Src) Clinical connections: epidermolysis bullosa (keratin/integrin mutations), pemphigus (anti-desmoglein antibodies), Alport syndrome (collagen IV), fibrosis (excessive ECM), cancer invasion (MMPs, EMT).

VIII. Stem Cells, Cancer, and Modern Methods (Lectures 25-27)

Stem cells: self-renewal + differentiation; niche regulates behavior. ESCs, iPSCs (Yamanaka factors: Oct4, Sox2, Klf4, c-Myc), adult stem cells. Wnt, Notch, BMP, Hedgehog: key niche signaling pathways. Cancer: accumulation of genetic/epigenetic alterations; hallmarks of cancer framework. Oncogenes (gain-of-function): Ras, Myc, HER2, BCR-ABL, cyclin D. Tumor suppressors (loss-of-function): p53, Rb, APC, BRCA1/2, PTEN. Metastatic cascade: invasion -> intravasation -> circulation -> extravasation -> colonization. Targeted therapy: imatinib, trastuzumab, PARP inhibitors, checkpoint inhibitors. CRISPR: Cas9 + sgRNA -> DSB -> NHEJ (knockout) or HDR (knockin) Advanced tools: base editing, prime editing, CRISPRi/a, genome-wide screens. Therapeutic: exa-cel for sickle cell disease (first approved CRISPR therapy) Single-cell technologies: scRNA-seq reveals cellular heterogeneity; spatial transcriptomics preserves tissue context. Perturb-seq: CRISPR + scRNA-seq for functional genomics.

IX. Exam Preparation: Key Themes and Integration

Recurring principles to master: Structure-function relationships at every level (protein, organelle, cell, tissue) Compartmentalization and sorting signals. GTPase switches (Ras, Rho, Rab, Ran, heterotrimeric G proteins): common regulatory logic. Phosphorylation cascades as signal amplifiers and integration points. Ubiquitin-proteasome system: targeted protein degradation drives irreversibility (cell cycle, signaling) Cytoskeletal dynamics: assembly/disassembly regulated by nucleotide hydrolysis and accessory proteins. From cell biology to disease: nearly every cellular pathway has a disease associated with its malfunction. High-yield clinical connections: cystic fibrosis, lysosomal storage diseases, Kartagener syndrome, epidermolysis bullosa, laminopathies, cancer (multiple oncogenes and tumor suppressors), immunodeficiencies, neurodegenerative diseases. Practice strategy: focus on understanding mechanisms (not just memorizing facts); draw pathway diagrams from memory; explain how a mutation in a specific gene would affect downstream events.

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