Final Exam Study Guide PDF

**[Cell Junctions II]** - Cell junctions: multiprotein complexes between cells or between the cell and the ECM - Hemidesmosomes (IF mediated) - Actin-linked cell matrix junction (AF mediated) - ECM: collagen, proteoglycans, multi-adhesive matrix proteins - Cells-tissue...

**[Cell Junctions II]** - Cell junctions: multiprotein complexes between cells or between the cell and the ECM - Hemidesmosomes (IF mediated) - Actin-linked cell matrix junction (AF mediated) - ECM: collagen, proteoglycans, multi-adhesive matrix proteins - Cells-tissues-function - Migration - Signaling - Growth, expression, proliferation - 3D network of extracellular macromolecules - Basal laminae: epithelial cell layer - Muscle, adipose, peripheral nerves - Connective - Bone, tendon, cartilage - ECM components: - Proteoglycans (sulfates) cushion cells - Insoluble fibers (collagen, elastin) provide strength - Soluble, multi-adhesive ECM proteins (fibronectin, laminin) bind receptors and insoluble fibers - Proteoglycans: protein/carbohydrate constituents - Extremely hydrophilic - Long, unbranched glycosaminoglycan - Hydrate tissues - Collagen: main structural tissue - 25-35% of body content - Proline-hydroxyproline-glycine - Triple helix - Elastin: elasticity and resilience - Makes vessels stretchy/helps lungs expand and contract - Tropoelastin and fibrillin-1 - Fibrillin-1 coated with tropoelastin - Fibronectin: soluble, multi-adhesive ECM protein - Binds membrane-spanning receptor proteins (integrins) - 500-600 kDa - Can bind collagen, fibrin, heparan sulfate, etc. - Wound healing: - Fibrinogen converted by thrombin to fibrin - Interacts with fibronectin to form temporary matrix - Associates with heparan sulfate to build a scab - Plasma-fibronectin pseudo-matrix fills space in wound - Cells proliferate - Remodeling to break down enzymes to create scar - Degrading the ECM is required to heal, but may also associate with morphogenesis, angiogenesis, repair, cirrhosis, arthritis, metastasis, etc. - Marfan: FBN1 (needed for fibrillin-1) is limited - Flexible, tall, thin - Near sighted - Stretched skin - Flat feet - Low body fat - Shortness of breath - May enlarge heart or break vessels - Hemidesmosomes: basal epithelial cells to underlying basement membrane - Inner plaque, outer plaque, inner basal plate - Laminin/lamina - Lots of collagen (type 17) and lots of IF connections - Lots of cell transductions - Actin-linked/Focal adhesions: link to integrin and actin cytoskeleton - Facilitates movement - Alpha and beta integrins interact with actin - Leading end stretches out - Myosin pulls connection to move cell **[Cytoskeleton, Motors, Cell Motility]** - Cytoskeleton: microtubules, actin filaments, intermediate filaments - Microtubules: tubulin, bind GTP - Actin filaments: bind ATP - Intermediate filaments: no energy (ATP or GTP) - Function of ECM and cytoskeleton: - Support, position of organelles, movement, cell division - Actin: f-actin and microfilaments - 2 stranded structures - 2 grooves - May be branched, bundled (with actin binding proteins), ordered arrays - Barbed positive end where monomers added - Pointed negative end where monomers disassembled - Found in muscles - Bind ATP (hydrolyzing ATP grows chain) - Not stable when bound to ATP - Treadmilling: process that adds to the barbed end and takes away from pointed end to keep constant chain length - Control of the cytoskeleton with help with locomotion, shape, phagocytosis, cytokinesis, etc. - Myosin: motors used with actin - Move to barbed end - Have "motor" head - Site to bind actin, bind to ATP to drive - Tails are very different and create diversity - Conventional (type II) in muscle - Unconventional (type I) - Conventional (type II): muscle contraction - Move to barbed end - Split cells - Generate tension at focal adhesion - Cell migration - Turning growth cones - Globular heads with a catalytic site - Dimers - Pair of alpha helix and 2 light chain regions at head - Single rod tail with alpha helix and 2 heavy chain - Tail: forms filaments - Ends point to center, heads point away - Bipolar, so can pull actin apart - Unconventional myosins: - Dimers and polarized - Tail region binds cargo quickly - Bind vesicles and cargo - Localized to bend (such as hair and ear) - Sarcomeres: multinucleate skeletal muscle fiber - Myofibrils: cylindrical strands cause independent contraction - Repeating contractile unties make myofibrils of sarcomeres - Actin fiber + network of myosin - One z line to another z line - Densely staining myosin in the H zone - A band: actin and myosin - I band: myosin only - Contraction: sarcomere shortens - Actin and myosin slide over - Size of A band remains constant - H and I bands shorten and move inward - Z band pulls toward A band - Thin filaments: actin, tropomyosin, troponine - Actin: aligned with bared ends at the Z line - Tropomyosin: long molecule in grooves in 7 subunits - Only bound to actin - Troponine: 3 subunits in 40 nm connected to both actin and tropomyosin - Thick filaments: myosin II mainly - Opposing tail regions - Staggered - Titin: elastic, help sarcomere to not pull apart - Helps myosin position properly - Nebulin: "molecular ruler" - Helps position correct number and placement of actin monomers in assembly - Contraction: - Myosin head binds to actin - Undergoes conformational change to move actin - Continuous pulling from all sides - Energy comes from ATPase and a "power stroke" - ADP release creates gap for ATP - Requires a huge number of ATP - Neuromuscular junctions: contact between nerve and muscle - Excitation-contraction coupling: nerve impulse linked to sarcomere shortening - Propagated by transverse (T) tubules - Terminate at sarcoplasmic reticulum - [NEED CALCIUM TO TRIGGER SIGNAL ] - Calcium binding - Calcium binds troponine to create conformational change - Moves to tropomyosin - Exposes mysosin sites to bind actin - Actin-binding proteins: - Crosslink or branches of actin fibers - Organize actin - Can nucleate, build polymers, depolymerize, cross-link, sever filaments, bind to membranes, etc. - Cell motility: fibroblast flattens with broad frontal and "tail" end - Leading edge: extends out as broad, flattened, veil protrusion called lamellipodium - Attaches to substratum to anchor and pull cell forward - "feel around" by focal adhesions - Formins will add actin monomers to [linear chains] - Arp 2/3 complex bound by WASP/WAVE - Serves as sites for new filaments - Attach to sides of filaments - Sides start to [branch] and extend outward - Push edge out - "Tractions" forces grip substrates and contact integrins to create contact to surface - Edge disassembles as cell moves forward - Unconventional myosins push lagging edge forward - Growth cone: motile region elongates axon - Lamellipodia and filopodia respond to stimuli - Go towards attractive factors - Steering "directions" to get to target - Gastrulation: - Elongate microtubules parallel to cell axes - Constrict growth at one end - Curve inward to make spinal cord by actin rearrangement **[Bioenergetics, Enzymes, Metabolism:]** - Bioenergetics: study of energy transformation - Capacity to do work - Thermodynamics: study of energy changes due to the universe - 1^st^ law of thermodynamics: conservation of energy - Energy transduction, storage, transport - Exothermic vs. endothermic - 2^nd^ law of thermodynamics: universe tends to disorder - Free energy: free for work - \< 0: exergonic reaction, spontaneous - \> 0: endergonic reaction, nonspontaneous - = 0 at equilibrium - Standard states are only used for approximations - \[ADP\]/\[ATP\] is highly exergonic - There is significantly more ADP at equilibrium - Reactions are driven by energy input - Coupled to ATP hydrolysis - Products = reactants and vice versa - ATP hydrolysis: - Separate charge - Concentrate solute - Move filaments - Change properties of proteins - Steady state: concentration of reactants = concentration of products - Requires constant energy input, so NOT at equilibrium - Enzymes: catalysts of metabolism - Cofactors: inorganic conjugates - Coenzymes: organic conjugates - Small amounts per reaction - Catalytic - Affect rates of substrate reactions - Highly regulated - Metabolism: collection of reactions all coupled together - Pathways confined to specific locations - Metabolic intermediates facilitate the path of reaction **[Metabolism]** - Catabolism: break down large compounds into their monomers - Anabolism: build polymers from monomers - Steps of metabolism: - Stage one: macromolecules hydrolyzed into building blocks - Stage two: building block degraded into common metabolites - Stage three: small molecular weight metabolites degraded into ATP - Redox reactions: change electronic states of reactions - LEO-GER - Coupled redox of carbon sources - Reduced going to oxidized releases energy - Hydrogen atoms released can be used for ATP hydrolysis - Glycolysis: 1^st^ stage in catabolism of glucose in cytoplasm - Tricarboxylic acid (TCA) cycle: occurs in mitochondria - [KEY TO GLYCOLYSIS: Glucose makes pyruvate which makes 2 ATP] - Kinase: transports phosphate group to ATP - Substrate-level phosphorylation: ATP formed by kinase enzyme - NAD+ reduced to NADH - Dehydrogenase oxidizes and reduced cofactors - NAD+ oxidized and reduced in different places in the cycle - NADH donates electron into ETC - ATP formation is moderately endergonic - Transfer potential: molecules with higher transfer potential have less affinity for group transferred than lower on the transfer potential scale - Glycolysis: anaerobic process used to make pyruvate in cytoplasm - Makes 2 ATP - Can move pyruvate to aerobic or anaerobic pathway depending on environment - Fermentation: restores NAD+ from NADH with no oxygen - Pyruvate reduced to lactate or ethanol (in yeast) - 8% of glucose energy goes into making ATP, so very inefficient - Anabolism: needs electron source - NADPH donates electrons - Nonprotein cofactor - High reducing power - NADP+ = ATP + P + NAD+ - NADPH and NADH are partially convertible - NADPH: oxidized in anabolism - NAD+: reduced in catabolism - Transhydrogenase: transfer H+ between cofactors - NADPH: used when energy is abundant - NADH: used when energy is scarce - Cell regulation: control metabolic enzymes - Regulated by phosphorylation by protein kinases - Add P to specific tyrosine - Add P to specific serine or threonine - Allosteric modulation: mechanism inhibited/stimulated by compound bound to allosteric site - Feedback inhibition: shut down anabolic assembly - Enzyme inactivated with concentration of substrate at end of cycle reaches a certain level - Gluconeogenesis: catabolic/anabolic path leading to glucose synthesis - Plants: - Circadian oscillator: sense light from environment and links to light - Less vulnerable to changes in light, intensity - Makes proteins for photosynthesis - Warburg effect: increased rate of glycolysis in cancer cells - Detect tumors - Radioactive glucose analog tracer to map tumor cell concentration **[Aerobic Respiration and Mitochondrion]** - Anaerobes: use anaerobic path in oxygen-free environments - Aerobes: use oxygen to extract energy - Mitochondria: various structures depending on cell type - Typical: bean shape - May be round/thread like - Size and number show the cell requirements - Fatty acid containing drops to derive ATP oxidation material - Sites of synthesis of substances, amino acids, hemes - Vital role in calcium uptake and release - Regulate cell death - Mitochondrial fusion: two or more mitochondria combine - Mitochondrial fission: two or more mitochondria break - Contact with thin tubules from ER and encircle - Constrict and break into two - No actin use - Outer membrane - Outer cell membrane - Inner membrane - Inner boundary: rich in proteins for import of mitochondrial proteins - Outer boundary: series of invaginate cristae - Cristae: machinery of aerobic respiration and ATP formation - Matrix: interior of cristae - Intermembrane space: region between two cell membranes - Matrix: ribosomes and circular DNA to make RNA and mitochondrial proteins - mtDNA is a remnant of an ancient organism - Importance: use of the TCA cycle - Glycolysis makes pyruvate, 2 ATP, NADH - Moves into TCA - Oxidative metabolism: - Glycolysis 1^st^: pyruvate, NADH, 2 ATP - Pyruvate goes to intermembrane space goes to intermembrane and makes acetyl CoA - TCA: feeds pyruvate into cycle to oxidize - 2 carbon acetyl CoA condensed with 4 carbon oxaloacetate to form 6 carbon citrate - Two carbons converted to CO~2~ to make oxaloacetate - 4 reactions transfer pair of electron to NAD+ to make NADH or FADH~2~ - Contain high electron energy - Fed through cycle and ETC to make ATP - ATP formation: - Higher energy electrons from FADH~2~ pass to electron carriers in the ETC - H+ sent across inner membrane - Coupling H+ to ATP is called chemiosmosis - 3 molecules ATP from NADH, 2 from FADH~2~ - Mitochondria extract energy from organics to make electrical energy - Makes an ionic gradient - Uses gradient to drive energy-requiring activities like ATP synthesis - Via oxidative phosphorylation: energy from electron removed in oxidation - Electron-transfer potential - Oxidizers have high electron affinity - Reducers have low electron affinity - Adds to redox potential - Most metabolites have negative redox potentials to be able to move to NADH - Flavoproteins: bound to flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN) - Key: work with NADH dehydrogenase and succinate dehydrogenase to start 1^st^ electron transfer - Cytochromes: have Cu or Fe hemes - Reversible Fe(III) to Fe(II) transition via redox - 3 types (A, B, C) of cytochromes in ETC - 3 copper atoms: single protein with Cu(II) to Cu(III) transition - Get from diet - Ubiquinone: coenzyme Q - 5 C isoprenoid - Get from diet - Iron Sulfur proteins: use Fe for electron transport - All proteins pass electron down a positive redox potential "downhill" - Reduces oxygen to water at end - Found by inhibitors that block "tunneling pathway" - Travels through protein channels - Move protons into intermembrane space - Electron transport chain: series of four asymmetric complexes - Passing electrons creates proton gradient - Electron transfer creates free energy increase - Electron transport chain complexes transfer electron to FAD^+2^ or NAD^+^ - End product is proton gradient - Every molecule of oxygen reduced moves 8 protons - 4 for water, 4 into intermembrane space - Concentration of protons creates a pH gradient - Creates electric potential across the membrane - Making ATP uses proton-motive force - ATP synthase - Energy from proton motive force changes affinity for ATP - Conformational change - ATP made by physical rotation - Mitochondria uses proton motive force to "pull" calcium in for signaling - Peroxisomes: oxidize fatty acids to make plasmalogens - Uses products to make ATP **[Cell Signaling]** - Require: signal, receptor, transduction - Signaling: cells perceive and respond to environmental signaling - Errors may lead to variety of diseases like cancer - Ligand: primary hydrophilic - Need receptors either in or at surface of cell - Some small hydrophobic can pass through and have internal receptors - Endocrine: long distance - Paracrine: local distance - Neuronal: short distance - Contact-dependent: need actual contact between groups - Autocrine: send to act on self - Receptor types: - G protein coupled receptors - At membrane - Enzyme linked - Kinases for mainly tyrosine - Ion channel - Pass ions through - G-protein: relay many intracellular signals - Intracellular second messengers - Molecular switch - Trimeric complex coupled to GTP-binding proteins - Alpha, beta, gamma subunits - When alpha subunit is bound to ATP, the protein is active - Once GTP is hydrolyzed to GDP, the protein is inactive - Very particular structure - Seven pass transmembrane domains (serpentine structure( - C-terminus (intracellular) changes conformation when bound to signal, which then recruits G proteins - The identity of the alpha subunit determines the function - GDP bound to the trimeric unit is inactive - Once GTP binds, alpha breaks away and causes activity - Rate limiting step is release of GDP and amount of time it takes to hydrolyze GTP determines time of activity - G alpha: series of 16 genes - May stimulate or inhibit enzyme activity - G alpha S: adrenaline pathway - Signal: serotonin/adrenaline - Receptor: Beta adrenergic - G alpha S binds and activate adenylate cyclase - Increase cAMP - Effects PKA - G alpha Q: muscle pathway - Signal: acetylcholine - Activates G alpha Q - Activates phospholipase c which increases levels of calcium, DAG, and IP3 - Effects PKC and CaM kinase - CaM kinase: - Inactive when inhibitory domain is bound - Calcium and calmodulin binds leads to partial activation - If phosphate and calcium/calmodulin binds, leads to full activation - If you leave the phosphate and take off calcium/calmodulin, enzyme is partially inactive - take off phosphate is fully inactive - G alpha I: eyes - Signal: lights - Receptor: Rods/rhodopsin - Transducing (G alpha I) - Activates phosphodiesterase which decreases GMP - Na^+^ channel closes - Negative mechanism - RGS: regulators of G protein signaling - Act as GTPase activating proteins (GAPs) - Increase GTP hydrolysis - Cholera: no GTP hydrolysis - GTP pathways always on - Lose water and chlorine ions - Use GTP gammas S to prolong activation of GTP dependent proteins - Enzyme-linked (tyrosine kinase) receptors - Phosphorylate tyrosine in selected intracellular proteins - Activates GTP binding protein Ras - Discovery of NGF receptors: - Chick spinal ganglia in presence of tissue - Grew towards tumor like neurons - Showed NGF promotes survival and differentiation - Chemical labeling: vary the number of binding sites to see the binding affinity - High affinity: K~d~ = 10^-11^ M - Exponential decay - Low affinity: K~d~ = 10^-9^ M - Linear decrease - Low and high (two binding sites): exponential drop off then slow decay - Use PC-12 cells to treat with NGF - Turns into neuronal phenotype - Shooter: ran gel to find binding proteins - MW of 2 bands - 70 kD and 130 kD subsegments binding - Chao: took huge number of antibodies to see if he could block the NGF receptors - Both groups found p75 to be a ligand - Issues: bound with low affinity, did not constitute high affinity site in non-neuronal cells, no "known" signaling motifs (it is not a GTP or kinase) - Proto-oncogene: normal cell transduction - Oncogene: mutated proto-oncogene - Tyrosine kinase receptors - Src - Ras (monomeric G protein) - Raf (serine/threonine kinase) - TrkA: protein specifically expressed in neuronal cells - If you knockout, no nerve growth - Works with TrkA and p75 to bind to NGF - Signaling proteins: S6 kinase, MAPK, PKC - Grb2 and Grb1 bind the receptor - Ras and Raf - In drosophila, son of sevenless - Ras: monomeric GTP binding protein - Similar to G alpha - Active when bound to GTP - Promoted by GEF - Terminated by GAP - CORT: cloning of receptor target - Expression cloning technique - Tyrosine autophosphorylated C-terminus to probe a library - Grb1 and Grb2 found - Proteins bound directly to receptor only acted as coupling protein - Gain of function: overexpress protein to trigger signal without ligand - Loss of function: knockout protein and express ligand - Loses function of the gene - Son of sevenless (SOS): downstream of TKR acting as a GEF - NGF promotes differentiation while EGF promotes proliferation - Binds same receptor and same signals - Temporal regulation - NGF active for one hour - EGF active for thirty minutes - MAPK: Ras-dependent signal initiated at plasma membrane by tyrosine phosphorylation of receptor - TrkA-SHC-Grb2-SOS-Ras-Raf-MAPK-CREB (transcription factor) - NGF and receptor bound in vesicle to keep it active - Ion channel: convert ligands to electrical signals - Essential for neurons - Millisecond time scale - Transmembrane protein channel - Voltage activated channels: use difference in charge to move ions - Physical inactivation blocks movement - Sodium comes in, potassium goes out - Phosphorylation can change conformation and turn off channel - Diffusible gases and steroids initiate signaling in cell - Normally have intracellular receptor - Nitrous oxide - Acetylcholine activates nitrous oxide synthase - Arginine makes nitrous oxide - Binds guanylyl cyclase and contracts muscle - Hydrophobic molecules - Hormones, retinoids, vitamins - Receptor inside cell - Diffuses to membrane and makes cytosol receptor complex - Induces conformational change - Translocate to nucleus to trigger gene transcription - Signal transduction: transmission of signal in form of chemical modification - Signal received by cell receptors - Converted into intracellular forms - "cell surviving" - Steps: signal to receptor to signaling proteins to target proteins - Acetylcholine: different output based on cell type - Heart: decrease contraction rate - Skeletal muscle: increase contraction rate - Salivary: secretion - Cell response determine by receptors, transducers, and effectors - Transducers: half-life, localization - Effectors: gene expression, death, morphology - Similar cell responses can be induced by distinct signals - Convergent signals - Distinct cell responses can be induced by similar signals - Signal specificity - Need second messengers to identify, recruit, amplify, and transmit signals - Cell responses: signal changes cell in some way **[Cell Death]** - P75 regulates cell survival/suppressing cell death - Oligodendrocytes on express p75 - NGF induces cell death only with p75 - Questions if NGF is the p75 signal - Neutrophins cleaved by furin - Leads to 13 kD mature NGF protein - Mutated NGF is not cleaved - Long form binds p75 with high affinity but does not bind TrkA - Does not induce differentiation - TrkA binds short form with NO cell death - P75 binds short form with 30% cell death - P75 + sortilin induces cell migration - P75 + Nogo + Lingo induces neuronal regeneration - Cell motility: - P75 + MAG is cleaved - With Nogo and Lingo - Cleaved by RhoA - P75 cut by 2 proteases to activate RhoA - PI3K: PI-3-kinase activates Akt to start the cell death pathway - Linked to longevity - Pro-apoptotic Bcl-2 family proteins: induce cell death - Anti-apoptotic Bcl-2 family proteins: stop cell death - Bcl-2 and Bcl-X - Steps in Apoptosis: - Proapoptotic signals/proteins talk to mitochondria - Mitochondria releases cytochrome c - Apaf-1 associates with cytochrome c and pro-caspase - Active caspase 9: will eat up proteins - DNA/ nuclear fragmentation - Cell fragmentation - Golgi fragmentation - Caspases are regulated by IAPs - Inhibitors of apoptosis - DNA damage caught by ATM - Activates Chk2 to increase p53 - Induces apoptosis - Tumor necrosis factor (TNF) - Activates caspase-8 to induce death - Signal termination - Receptor sequestration to recycle - Receptor down-regulation - Receptor inactivation - Signal inactivation - Inhibitory protein - Endocytosis used to recycle membrane for synaptic vesicles with neurotransmitters - Used to regulate receptor interactions **[Cell Cycle ]** - Scaling: daughter cell same size as parental cell - Intrinsic phasing: limit size as it grows - Somatic cells: go through mitosis - Germ cells: go through meiosis - M phase: mitosis and cytokinesis - Quiescent cell: normal cell undergoing cell cycle normally - Interphase: majority of the cell cycle - Nerve/muscle/RBC: highly specialized cell types that will not divide - Asymmetric division: differentiation of stem cells - Maturation promoting factor (MPF) trigger entry into M phase - Kinase and cyclin - Concentration of cyclin is changes, the concentration of kinase will not - Cyclin-dependent kinases (Cdks) - Different types of cyclin (G~1~ or S, G~2~ or M) - Once the concentration of cyclin is high enough, it binds to Cdk and causes conformational change - Can now phosphorylate protein substrates - Cdk phosphorylation or dephosphorylation - Mitotic cyclin-Cdk activated late in G~2~ - Mitosis triggered - Kinases and phosphatase import to Cdk - No change in protein identity, but changes in cyclin - Turn off kinase by dephosphorylation OR inhibitory proteins OR degrading cyclin - Ubiquitin ligases: attach ubiquitin to target protein - Cyclical kinase activation - Once cell cycle starts, cell nucleus flooded with cyclin - If knockout cyclin B/A or Cdk1, embryo dies immediately - Cycle can be arrested by: - Sensors, transmitters, effectors - Chk1 inhibits Cdc25 to signal cell death - P21 inhibits G~1~ Cdk - P27 is a Cdk inhibitor into s phase - Knockout leads to excess cell proliferation and organ growth - Mitosis - Prophase - Prometaphase - Metaphase - Anaphase - Telophase - Cytokinesis - Prophase: chromosome compaction via condensing - Cohesion encircles both chromatids - Polo-like kinase and aurora B kinase phosphorylate cohesion to remove it - Centromeres hold together - Kinetochores: outer surface that attach to microtubules - Form mitotic spindle - Centrosome cycle must split - Centrosome cycle must split - Separase cleaves centrioles - Nuclear lamina separates - Prometaphase: - Chromosomes pull into center of cell - Congression: move to center - Metaphase: - Chromosomes in center - Astral microtubules: from centrosomes to regions outside spindle body - Chromosomal microtubules: move chromosomes to poles - Polar microtubules: integrity of spindle - Anaphase: - APC (anaphase promoting complex) and SCF (add ubiquitin to proteins during interphase) - Degradation of proteins regulates mitosis - Dynein and kinesin used thoroughly - KMN and Ndc80 bind farther back from the chromosome to pull the microtubules back from the edge of the filaments - Telophase: - Nuclear envelope reforms - Spindle disassemble - Goes back to interphase - Cytokinesis: - Cells split - Thin band of actin and myosin forces cells apart - Contractile ring theory - Plants: - Run into issues with cell walls - Meiosis: two cell division without intervening DNA replication - Spermatogonia make primary spermatocytes - Makes spermatids - Spermatozoon - Oogonia make primary oocytes - Secondary oocyte turns into egg ONLY when fertilized **[Cancer]** - Somatic cell mutations lead to cancerous tumors - Primary tumor cells break away and migrate to create secondary tumors by metastasis - Cancer deaths in recent years have declined due to early diagnosis and more specialized treatment - May also kill normal cells though as well - Cancer cells are not inhibited by contact inhibition or growth factor signals - Unimpacted by the treatment with serum growth factors - May become cancerous by - Increase in signaling pathways - Increase in cell division - Decrease of apoptosis - Increase in telomerase/less chromosomal shortening - Carcinogenic chemicals: lead to cancer by chemical factors - Any major shift in cell control parameters creates less control at subsequent steps - Oncogenes: promote loss of growth control - Act dominantly - Mutation that changes the pathway to be hyperactive will induce cancer - Gene output is an oncoprotein that is not regulated - RB gene (retinal blastoma) - Negative regulators of cell proliferation - Must lose both copies to decrease stability - Familial version is must faster to infect since you only lose one copy - Sporadic is much slower - Transcription factors of E2F family are targeted by pRB - Genes are silenced and deregulated by cell cycle genes - Two-hit hypothesis: must knock out both genes to be cancerous - P53 suppresses formation of tumors and maintains genetic stability - P53 alters cell cycle regulations after DNA damage - Activates expression of gene that inhibits the transition into S phase - Triggers pro-apoptotic pathway - Inactivation within senescent cells that cause cells to resume their progress toward malignancy - Sis, erbB cause excessive surface receptors to increase sensitivity to low concentrations of growth factors - Src leads to increased amounts of Ras, which activate Raf and MAP - Myc cause cells to proliferate uncontrollably - Error in DNA binding predisposes mutations in DNA transcription - Metabolism can introduce harmful byproducts if not properly regulated - No cell death (such as overexpression of BCL-2) suppresses apoptosis - Leads to cancer cell survival - Errors in apoptosis, proliferation, immortalization, and senescence will lead to cancer - Senescene: metabolically active, nondividing cell - MicroRNA: noncoding RNA that inhibit expression of mRNA that encodes anti-apoptotic protein BCL-2 - Cancer genome shows that a series of genes are normally mutated in most cancer types - Common treatments target microtubules to destabilize the cell, leading to cell death - Disrupt spindle fibers to lead to cell division