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exam 3 material

Cell cycle an orderly sequence of events in which a cell duplicates it's contents and divides in 2; two phase process: interphase and M phase
Interphase period between cell divisions characterized by growth and chromosome replication (S phase)
M phase mitosis (easily observed by light microscopy) and cytokinesis
G1 growth and metabolism, duplication of organelles
G0 cell cycle arrest, regulated re-entry into the cell cycle
S phase DNA replication, observed by incorporation of radioactive nucleotides
G2 growth, preparation for mitosis, checkpoint for errors in replication; discovered because radionucleotide incorporation stops for a period before mitosis
Time for S+G2+M is <<<total time of cell cycle = another gap phase G1
Apoptosis programmed cell death; mitochondrial proteins leak out, caspases degrade nucleus, cytoskeleton collapses, genome degraded; happens in multicellular organisms
Why regulated cell cycle allows multicellular eukaryotes to create body plan
Cell cycle regulation prevents growth and division at the wrong time, too rapid, too slow, failure to stop
Cyclin dependent protein kinases (Cdks) enzymes that initiate entry into S or M phase of cell cycle, phosphorylate proteins necessary to bring about various events in cell cycle
Phosphorylation can control protein's enzyme activity, lifetime of protein, protein to protein binding, subcellular location
Cdks inactive on their own must bind cyclin; expression of cyclins tightly regulated, concentrations of cyclins rise and fall during cell cycle and the activity of Cdks rises and falls
Rb retinoblastoma protein, inhibits transcription factor (E2f) inhibitor, substrate for Cdk
Cyclin control controlled transcription and controlled protein degradation; ubiquitin proteasome degradation pathway
Ubiquitin 76 amino acid protein that is joined to specific lysine residues in proteins (post transcriptional), poly-ubiquinated proteins are targeted to proteasome where they are chewed up into short fragments
Cancer genetic disease (not inherited), malignancy requires multiple genetic alterations (almost always in somatic cells)
Common properties of cancer cells most easily studied by culturing dissociated cancer cells in vitro; lack contact inhibition, anchorage independent, can be grown in suspension, growth factor independent, immortal, aneuplody (chrom aberrations)
HeLa cells diagnosed with cervical cancer in 1951, cancer cells isolated from her cervical biopsy, cells have been grown in thousands of labs since 1951 and are still widely used today
How chrom aberrations occur failure of DNA synthesis checkpoints, quality control checks in G2, failure to undergo apoptosis
Chrom aberrations (aneuploidy) translocations, deletion of parts or entire chromosomes, duplication of parts or entire chromosomes
Causes of cancer major contributor is environment first proposed by Percival Pott who worked with chimney sweeps
Benzopyrene metabolic derivative that covalently modifies guanine, found in coal tar, auto exhaust, cigarette smoke, charbroiled meat
Some viruses can lead to cancer Human papillomaviruses (HPV), carry genes whose products block growth-inhibiting functions of some cellular proteins or promote inappropriate re-entry into cell cycle; HPV gene products alter function of tumor suppressor genes (like Rb)
Genetics of cancer very common (1 in 3 in Western countries), but rare
Tumor suppressor genes normal genes encoding proteins that prevent proliferation; mutations that inactivate them cause LOF on proliferation and promote cancer
Oncogenes mutated versions of normal, proto-oncogenes encoding proteins that promote proliferation; mutations that cause them to be expressed at the wrong time create inappropriate signals to proliferate and promote cancer
Cancer Treatment usually target cells which are growing fast; leads to toxicity in tissues that divide frequently (blood cells, lining of gut, hair follicles), damage causes apoptosis
Proto-oncogene codes for a normal enzyme involved in some phase of initiating cell cycle; can be regulated; RAS, SRC
Oncogene a proto-oncogene that has become mutated and therefore no longer responds to regulation (ALWAYS ON -> cancer)
Tumor suppressor normal protein that functions to regulate cell division or remove aberrant cells (p53, Rb)
Oncogenes what they do promote genetic instability, allow cells to grow and divide despite signals saying not to, prevent apoptosis of bad cells, promote invasion of other tissues
Dominance proto-oncogene and its oncogene ca co-exist in the same cell but oncogene acts dominantly; single copy of oncogene sufficient to cause alterations in behavior of cell
Proteins from oncogenes disrupt normal cell signal transduction pathways usually ones that promote cell growth and proliferation
Signal transduction pathways means by which a cell converts an extracellular signal (hormones, gfs) into intracellular signals that effect metabolism, gene expression, movement, survival, growth and proliferation
Second messenger diffusible product of an effector protein that initiates a cascade of protein activation
Enzyme-linked receptors biind extracellular molecules which activates a receptor or receptor associated protein kinase, very low conc, polypeptide and protein growth and differentiation factors
Enzyme linked cell surface receptors transmembrane proteins, cytoplasmic domain (has its own enzyme activity or is associated with a protein that has enzymatic activity)
Receptor Tyrosine kinase growth factor receptors; each cytoplasmic domain of RTK monomers has enzymatic activity as tyrosine kinase
RTK dimerization can be constitutive or triggered by ligand binding, brings the cytoplasmic domains in close enough proximity to cross phosphorylate each other
Cross phosphorylation increases kinase activity of the receptor and creates high affinity binding sites for proteins with phospho-tyrosine binding domains
Ras activates MAPK (sequential serine/threonine kinases), final MAPK (ERK) transmits signal to nucleus, phosphorylating gene regulatory and other proteins (G1 cyclins)
Viral proteins that cause cancer vRas (tells cell that it is getting growth factors); vSrc (tells cell that it is adherent), viral proteins disconnect cell from its ability to sense its surroundings
Loss of tumor suppressor gene both copies of gene must be lost (recessive)
Rb gene transcription factor inhibitor that prevents G1 to S phase transition in the cell cycle
Retinoblastoma rare childhood cancer, known to be caused by loss of Rb gene due to a deletion in one copy of chrom 13; two hit hypothesis
p53 restores genetic stability by 2 means: cell cycle control and promotion of apoptosis, mutated in about 50% of all human cancers
Factors that generally affect progression exposure to chemical carcinogens, exposure to UV light or ionizing radiation, diet and alcohol consumption, age
Cancer hard to cure gene products involved in development of cancer have wide variety of activities (cell cycle regulation, cell to cell adherence, DNA repair, signaling, apoptosis), different combos of mutated genes, genetic difference between people
Development of resistance to chemotherapy attack rapidly dividing cells, reduce number of cancer cells, mutation, chemotherapy, takeover and proliferation of mutant population results in drug resistant tumor
Resistance to chemo: mutations decreased uptake and retention of drug by cancer cell, block in required lethal synthesis to antimetabolite, altered interactions of drug with specific enzymes, increased rate of catabolism of antimetabolites to inactive form
Virus not free-living organisms that are nucleic acid wearing a protein coat
Bacteria vs viruses viruses are small, genomes are small (3 to 100 genes), contain single type of nucleic acid (RNA or DNA), don't have their own lipids, glycolipids, sugars, polysaccharides and metabolites
What viruses look like consist of a protein shell called the capsid which contains the viral nucleic acid, capsids are arranged, based on 2 fundamental plans: the helix and icosahedron
Inside the virus viral genomes can be either double stranded or single stranded DNA or RNA, only one strand contains all the genetic info
Positive strand RNA can serve directly as an mRNA molecule for translation of viral proteins,
How viruses infect depends on type of virus; enveloped viruses acquired a lipid bilayer from host cell during budding; non-enveloped viruses don't have lipid bilayer because they exit host cells by lysis
Encocytosis (enveloped virus) virus bound to receptor is targeted to a clathrin coated pit, the pit closes off to become a vesicle (endosome), lower pH inside endosome causes conformational change that fuse the endosomal membrane with lipids coating the virus
Gaining entry into cell both enveloped and non-enveloped viruses must bind a host cell surface protein to gain entry
Viruses can disrupt cell cycle viruses need a host cell's DNA polymerase to replicate their genetic material; most cells that become infected are in G0, DNA poly present at sufficient levels only during S phase
Viruses force cell into S phase by inactivating Rb and p53 (tumor suppressor genes)
Cytolytic effect huge expansion of viral particles can cause host cell to rupture (herpes) or symptoms caused by body's immune response to lysis (rhinovirus)
Viruses as hitchhikers rely on host cell gene expression and replication machinery to get where they want to go; need lots of viral proteins, modify host cell transcription and translation machinery so they preferentially make viral proteins
AIDS described and HIV isolated 1981, 1984; as of 2011 only one single man has been cured by means of removing all his bone marrow cells, and replacing them twice; 90% of the people live in developing countries
Course of HIV infection acute (fever, enlarged lymph nodes, rash, muscle aches, headaches, T cells decrease), Chronic phase (Viral RNA increase), AIDS (decrease immune system, <200 CD4 T cells per ml blood)
Inside T cell (with drugs) Reverse transcriptase (AZT, 3TC, ddI), CD4 + cell nucleus (viral integrase) to make RNA, gag-pol to protease (atazanavir and indinavir)
Reverse transcriptase in lab Virus particles bring reverse transcriptase which synthesizes a DNA copy of its RNA (5 to 3'), digests viral RNA (RNase H), synthesizes another DNA strand to generate dsDNA which can integrate into host DNA
Retroviruses have noncovalently bound tRNA, acquired from host, which acts as primer for DNA synthesis; in lab RT used to synthesize cDNA (no introns) from mRNA isolated from cells
HIV structure retrovirus; contains RNA, use RT to transcribe ssDNA into dsDNA, integration of dsDNA obligatory step in life cycle, can integrate nearly anywhere in cell genome, retro-transposon which have acquired ability to move between cells
Enzymatic activities of reverse transcriptase RNA directed DNA polymerase (synthesize DNA copy of viral RNA), RNase activity (digest RNA strand), DNA directed DNA polymerase (synthesize another DNA strand to generate dsDNA to integrate into host cell
Ever changing HIV genome HIV reverse transcriptase is error-prone (incorporates wrong base with freq of 1/2000 - 1/4000 polymerized), HIV reverse transcriptase lacks a 3' to 5' exonuclease activity for error correction
Mutation rate of exogeneously replicating retroviruses at least 1000 times higher than that of a typical cellular gene
Retroviral proteins LTR (helps viral DNA insert into host DNA), GAG (encodes capsid protein), pol (encodes RT), Env (encodes envelope protein), Onc (encodes cancer causing protein)
Viral receptors of host cell surface charges of viral glycoproteins first interact with negatively charged extracellular matrix, virus attaches to CD4 (cell surface antigen), conformational change in envelope glycoprotein exposes region of gp120 which can now bind to co-receptor
Co-receptor normally bind cytokines (chemokines), about 12 coreceptors possible, depending on HIV strain), CCR5 (for HIV1, strains replicating in macrophages), CXCR4 (HIV strains replicating in T cells)
Protease viral gene products produced by host transcription machinery, 3 polyproteins (gag, pol, env), necessary to cleave the polyproteins (aspartic protease) that utilizes 2 Asp residues in active site
Gag, pol, env gag (encodes nucleocapsid and core proteins), pol (encodes RT, protease, integrase, ribonuclease), env (encodes glycoproteins gp120 and gp41
Freq of mutant allele of CCR5 co receptor HIV infected individuals (2 copies of standard 85%, 1 standard + mutant (15%), uninfected individuals (2 standard copies 83%, 1 standard + mutant (14%))
gp120 binds 2 proteins on cell surface, CD4 (integral Ab protein on macrophages and helper T), and CCR5 (receptor for chemokines, proteins responsible for lurking immune cells to injured or diseased tissue), homozygote for mutant allele is protective
Resistance allele: freq of mutant CCR5 receptor mutation arose after humans left Africa 50,000 years ago, individuals with mutation had survival advantage, virus which causes black plague also binds CCR5, individuals homozygous for CCR5 mutation survived, heterozygotes chronic phase lengthened
AZT: T analog used to inhibit RT, lacks 3'OH group, taken up by cells, phosphorylated and incorporated into DNA synthesized from HIV template by RT, RT has high affinity for phosphorylated AZT but cellular DNA polymerases have low affinity for AZT
Targets for inhibitors of HIV1 replication RT (nucleoside and non-nucleoside analogs), protease, and fusion mechanism, 20% of patients can't tolerate antiviral cocktails, long-term metabolic effect of protease inhibitors,
Other targets for HIV replication inhibitors block membrane fusion, uncoating, nuclear import, integration by viral integrase enzyme
Body fluids (water 60 body weight), intracellular fluids (64%), extracellular (33%, interstitial fluid (25%), blood (blood plasma 8%, other 3%, half of RBC; lymph)
Circulation functions transport and homeostasis (gas exchange, nutrients), liver (make plasma proteins, conjugate bilirubin, detoxify, bile salts), kidney (N disposal, pH buffer, ionic buffer), communication, blood clot, infection fighting
Circulation closed system; systemic (heart and limbs), pulmonary (lungs)
Lymphatic system one-way drainage system fro fluid outside vascular bed
Lymph nodes filter debris and infection
Composition of blood 55% plasma, 45% cell and cell fragments; 0.1% glucose, water 91.5% of plasma, salts, sugars and fats (1.5% of plasma), proteins 7% of plasma, platelets and WBC 1% of cells, RBC 99% of cells
Hematocrit cell volume/total blood volume (normal range 45-54%)
Serum plasma - fibrinogen and other clotting factors
Types of blood cells pleuripotent stem (common precursor), erythrocytes (carry O2 and CO2), platelets (blood clotting), macrophages (phagocytes), mast cells (allergic reactions), lymphocytes (infection fighting), B cells (plasma cells), T cells
Exchange among body fluid compartments water moves freely (osmosis), proteins in blood and cells do not exchange much, ions exchange between blood and interstitial fluid but not with cells; ion pump (ATPase moves ions)
Composition of body fluids Na major cation in extracellular fluid; K major cation in intracellular fluid, Na/K ATPases use ATP to maintain gradients, protein accounts for most differences in osmotic pressure
Exchange of nutrients/waste between blood and tissues Arterial side blood vessel diameter shrinks, bp 45 mm Hg, Osmosis 30 mm Hg net is 15 mm Hg), (bp exceeds osmotic pressure, unloading on blood interstitial fluid)
Exchange of nutrients (venous) vessel diameter increases; osmosis 30 mm Hg, Blood pressure 15 mm Hg, net decrease 15 mm Hg) (osmotic pressure exceeds bp reabsorption on interstitial fluid blood)
Protein loss from blood is bad traumatic shock (increase capillary permeability, less water returns from interstitial fluid to blood, less blood vol, decrease bp, decrease oxygen)
Protein loss from blood (2) Kidney failure (protein loss into urine is slow), blood vol and pressure have time to adjust but water doesn't return from interstitial to blood leads to edema
Protein loss from blood (3) starvation (albumin in blood metabolized as energy, lower protein conc in blood leads to edema)
Major proteins in plasma albumin, alphaglobulin, betaglobulin, gammaglobulin; albumin is the major protein, osmotic effect in blood (oncotic pressure), transport (fatty acids, bilirubin, drugs, hormones), small, ellipsoid shape (low viscosity even at high conc)
RBC diameter versus capillary diameter greater, good lots of surface exposure for gas exchange; bad for a sickle cell anemia patient
Hemostasis arrest of bleeding; cut blood vessel, blood vessel constriction (serotonin), platelet plug formation (platelet aggregation), blood clot formation (fibrin matrix); eicosanoids involved in constriction and platelet plug formation
Clotting inactive protease in blood (prothrombin) is converted to active thrombin, thrombin coverts soluble fibrinogen to insoluble fibrin which aggregates to form the clot.
Activation of thrombin complex and involves platelets and zymogen activation cascades
Platelets thrombocytes (broken off pieces of megakaryocytes in bone marrow), love collagen (exposed on damaged vessel surfaces, adhering platelets get sticky and aggregate
Plavix clopindogrel; autocatalytic effect, blocks ADP binding (inhibits aggregation); sticky platelets --> /ADP + serotonin
Platelet aggregation/activation involves omega 6 (or omega 3 analogs) eicosanoids, exposes phospholipids on membrane surface
Coagulation clot formation = fibrin aggregates; cascade of zymogen activations
Formation of blood clot involves coagulation factors (soluble proteins in blood made in liver), inactive protein precursors (zymogens) --> active proteases (IIa,etc), cascade of zymogen protease activations (rapid response to small stimulus)
Vitamin K fat soluble; required for synthesis of many clotting factors; makes gamma-carboxyglutamate from glutamate residues on clotting factors (glutamate with an extra COO-), clinically important coagulants are Vit K analogs (interfere with clotting factor synt)
Ca ions vital to blood clotting; form bridges between activated platelets and clotting factors in blood
Clotting factor synthesis gamma-carboxyglutamate modification occurs in liver
Ca bridges between gamma-carboxyglutamate residues on clotting factors and phosphate groups of membrane phospholipids of platelet membranes
Hemophilia genetic disorder in blood clotting; type A (X linked recessive, mom carries, sons suffer)
Anticoagulants interfere with Vitamin K function (most look similar to Vit K), warfarin (rat poison), dicoumarol (moldy hay)
Regulation of blood clotting factors are short lived diluted by blood and removed by liver; protein C protease activated by thrombin deactivates clotting cascade by degrading clotting factors, natural anticoagulants (antithrombin III), lysis of fibrin clot (dissolves during healing)
Diffusion best for short distances, lots of surface area, close contact (air/blood in lungs, blood/interstitial fluid/cells)
Major function of proteins binding of ligands, use non-protein cofactors to bind small ligands,
Cooperativity in binding ligands possible in polymeric proteins due to interaction between subunits
Regulatory molecules bind to protein and alter its ability to bind its specific ligands
Hemoglobin transports oxygen from lungs to all tissues
Myoglobin and cytoglobin transport oxygen from cell membrane to cell's mitochondria
Ligand anything that binds specifically with a protein; macromolecules and smaller molecules
Cofactors non-protein molecule, usually bound tightly (heme ring of hemoglobin), metal ions, flavins, nicotinamide and electrons
Non-protein factors 2,3 bisphosphoglycerate (BPG) or diphosphoglycerate (DPG); heme: porphyrin ring an organic molecule binds metals at the center (iron)
pO2 atmospheric pressure of oxygen (conc) units of torr
p50 conc of oxygen at which 50% of a globin is bound with oxygen
Hemoglobin conformations T conformation that binds oxygen weakly (good for releasing oxygen), R conformation that binds oxygen strongly (good for loading oxygen)
HbA erythrocytes; lungs to tissues, p50 = 27 torr
HbF fetal erythrocytes; lungs to tissues, p50 = 7 torr
myoglobin muscle; cell membrane to mitochondria, p50 = 0.9 torr
cytoglobin brain and peripheral tissues, membrane to mitochondria, p50 = 5.4 torr
Why oxygen carrier oxygen low solubility in water; oxygen solubility @ pO2 of 158 torr is 2 ml O2/100 ml or deciliter, with 15Hb/100 ml O2 content in blood is 20 ml/ 100 ml, human needs 260 ml O2/min at rest, max use 4300 ml/min by athletes
Two log rule protonation of bicarb --> carbonic acidl; deprotonation of carbonic acid --> bicarb as function of hydrogen ions = pH
Oxygen delivery Hb 26.6 torr pO2 in lungs is 120 torr; Mb 0.9 torr pO2 cells at 2-8 torr
Hb cooperativity binding depends on affinity for O2, concentration of O2 (mass action which leads to more binding)
Effectors Mb p50 is almost at 0 torr, Hb is at 10 torr, BPG is at 18 torr, BPG and CO2 is at 28 torr with p50 at about 28 torr
pH effect decrease in pH causes Hb to unload oxygen
Mechanism of cooperativity p50 of 26.6 torr is for an ensemble mixture containing many Hb molecules and in various binding states
Bohr effect Hb's oxygen binding affinity is inversely related both to acidity and to the conc of carbon dioxide; an increase in blood CO2 conc leads to decrease in blood pH which leads to Hb releasing oxygen load
Effect of Temperature affects affinity of Hb for oxygen; as oxyhemoglobin is exposed to higher temperatures, affinity decreases and Hb unloads oxygen
Oxygen (ligands that bind Hb) binds at heme, decreases p50
2,3 bis-PG binds between beta subunits, increases p50
Hydrogen ions binds at many residues on all 4 subunits, increases p50
CO2 binds near N terminus on all 4 subunits, increases p50
CO binds at heme (binds 200x more tightly), displaces oxygen
Temperature increases p50
Fetal Hb binds oxygen more tightly
Positive effector increase p50 and increase oxygen unloading
Negative effector decrease p50 and decrease oxygen unloading
Thalassemia either alpha or beta genes defective; insufficient amount of that globulin
Sickle cell anemia single mutation in beta5 globulin where glutamate changes to valine; Hb solubility decreased
alpha thalassemia result from one or more alpha Hb genes missing
beta thalassemia result from mutations that lower synthesis of corresponding protein; homozygotes usually experience severe anemia; heterozygotes are symptomless
oxygen concentration Hb is 50% saturated with oxygen at pO2 = 27 torr
F cells gamma gene is expressed in the fetus, normally replaced after birth by adult beta hemoglobin; RBCs that contain some amount of gamma hemoglobin; proportion of F cells above average for anemia, suggesting F cells survive longer
Measuring polymerization laser beam used to remove varying amount of bound CO2 to approximate any conc of Oxygen including 0
RBC making a round trip alveoli (0.7 to 0.3 sec oxygenated), arteries (3 sec oxygenated), capillaries of tissues (0.7 to 0.3 sec deoxygenated), veins (10 to 20 sec deoxygenated)
Sickling as function temperature the higher the temperature, the more sickling occurs
Hydroxyurea most widely used; least toxic, main effect is to increase expression of HbF gene
Cyanate carbanylates proteins, decrease p50 so less sickling, not accepted publicly
Nitrous oxide binding by Hb decreases p50 by 5 torr so less sicklinh, not yet approved
Hb gene therapy ongoing effort to identify new compounds to activate transcription factor for HbF gene
F cells (2) patients with >15% HbF have no serious symptoms; hybrid (sickle trait) blood contains 60% Hb-beta and 40% HbS, stress leads to greater expression of HbF, cells with high HbS destroyed faster
Hb-alpha/HbS homozygotes tetramers polymerize and sickle most readily
Hb-alpha/HbS + Hb-alpha/HbS heterozygotes tetramers polymerize but not as fast or as much
Benefits of Sickle Cell Trait parasite inside RBC decreases pH due to increased glycolysis; decrease in pH increases sickling which increases membrane permeability, increased membrane permeability decreases K+ levels, decrease in K is lethal to plasmodia
Sickle Cell Anemia homozygous for sickle globin is deleterious to humans (sickle cell anemia), only heterozygotes benefit and only with regions in malaria
Cells relaying information to each other within cells signals can diffuse or be actively transported; make a chemical messenger that is soluble in plasma membrane or package the messenger for exocytosis releasing it outside the cell
cells receiving signals hydrophobic messenger will diffuse into the target cell; hydrophillic messengers require protein receptor on external surface of cell to detect the messenger
Things that affect sickling temperature and pH
Bcl2 gene translocation normal Bcl2 blocks programmed cell death, translocated version prevents normal cell death which increases likelihood of tumor formation
HpaII/MSPI cut sites for p16 promoter p16 leads to phosphorylation of Rb which leads to cell cyle; MspI cleaves methyl and unmethyl CCGG, HpaII cleaves only unmethyl CCGG
Created by: ilk0710
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