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140 Cards in this Set
- Front
- Back
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Signaling moleculesinclude |
soluble proteins, amino acid derivatives,steroids, gases, membrane bound proteins |
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Contact dependent |
signal mem protein express on one cell canconnect to receptor on another cell & two can communicate |
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Paracrine |
signal secreted & acts over short distance,neighboring cells in close vicinity |
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Endocrine |
signals secreted from cell & signals (likehormones) enter bloodstream & go to distal locations to interact w/ cellsfar away |
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Synaptic |
axon can be long in length so body of two cellsare far apart from each other |
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Signal recognition(2) |
on cell surface or intracellular receptors |
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Hydrophilic signals |
secreted by cell & once they are inextracellular space will bind receptors exposed on cell surface, do not haveability to cross plasma mem |
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Hydrophobic signals |
able to diffuse across plasma mem & bindreceptors inside cell (hormones) |
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Hormones (structure& function) |
small hydrophobic molecules, released &cross plasma mem, receptor for hormones are proteins presented in cytoplasm ofcell, many receptors are TF so hormones bind TF & translocate fromcytoplasm to nucleus & activate transcription |
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Cell surfacereceptors |
each has unique AA sequence exposed onextracellular domain, lock & key with signaling molecule & AA residueon receptor, some receptors can bind many signals but have specificity for oneor a class of signals/ligands, form non-covalent highly specific interactionsw/ signaling molecules |
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Response to extracellularsignal can be fast |
signal will activate receptor & receptor canactivate a protein kinase that can phosphorylate protein already in cytoplasm,get quick response. When protein is phosphorylated would change its activity& would give immediate response to that phosphorylation = fast |
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Response toextracellular signal can be slow |
signal transmitted from receptor to cytoplasm tonucleus where turn on expression of new gene to synthesize new protein, thistakes time for protein to synthesize in response to signal |
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Cell has wide rangeof response |
bc express combination of diff receptors,signaling pathways intersect & modify each other’s responses, specificcombinations of signals define cell behavior (depends on factors w/in cell) |
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Cell with receptorfor both kinase and phosphatase |
outcome is determined by amount of protein thatis phosphorylated, which is dependent on whether kinase (high level),phosphatase (low level), or both receptors are activated (intermediate level) |
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Same signal on diffcell types |
effects determined by specific receptor &specific downstream targets present in cell |
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Factors (5) actingdownstream of receptor |
extracellular signal transduced (conf change ofreceptor), signal is relayed (activation of effector proteins), signal often amplified,signal often distributed, each step can be modulated by other factors (fromother signaling pathways) |
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5 ways to silence (oradaptation) to signaling |
receptor sequestration, down regulation,inactivation, inactivation of signaling protein, production of inhibitoryprotein |
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Receptorsequestration |
in response to ligand binding, receptor can beendocytosed & removed from cell surface which involves ubiquitination ofreceptor & ubiquitination acts as signal for endocytosis & can go backto plasma mem. Have adaptation or lessening of signal/response |
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Receptor downregulation |
Receptor endocytosed then go to lysosome &be degraded so completely remove that receptor results in silencing |
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Receptor inactivation |
receptor activates downstream kinases, receptoritself may be substrate of kinase it turns on, feedback inhibition & kinaseturns receptor off |
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Inactivation ofsignaling protein |
intracellular signaling molecules (adenylylcyclase) inhibits activity of downstream protein involved in signal relaypathway |
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Production ofinhibitory protein |
activate effector protein kinase that canphosphorylate inhibitory protein & phosphorylation of inhibitory proteinallows it to bind receptor & block receptor function |
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Three classes of cellsurface receptors & signal transduction |
ion channel coupled receptors & ions Gprotein coupled receptors & G protein / downstream effectors Enzymecoupled receptors & kinases/phosphorylation |
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Ion channel coupledreceptors |
ion channels activated in response to ligandallows ions to flow into cell, transduction through entry or exit of ions fromcell |
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GPCR |
receptor coupled to trimeric G protein, Gprotein bound GTP activated by receptor will bind downstream effector proteinsto relay signal |
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Enzyme coupledreceptors |
in response to ligand binding receptor kinasedomain will activate proteins in cytoplasm (kinases) |
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Kinase activation |
when ligand binds receptor activate kinases thatpromote cell proliferation / growth (many mutated in cancer) |
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Receptor TyrosineKinases |
have domain outside cell that binds ligand &domain on cytoplasmic side w/ Tyr kinases. Receptors are monomeric inactivestate. In response to ligand binding, cause conf change allows protein todimerize & kinase domain on receptors autophosphorylate kinase domains onreceptors to further activate kinase. Once receptor phosphorylated recruitsproteins including soluble kinases that can go into cytoplasm to relay signal(kinase cascade) |
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3 steps of receptortyr kinases |
1. Signaling complexes form at activatedreceptors 2. Activation of kinase cascades 3. Phosphorylation of effectors ofcell growth |
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GPCR structure |
900+ kinds, important for sensing, 7 transmemprotein that form barrel-like protein in mem & ligand binding site inmiddle. Each GPGR has diff AA sequence that specifies ligand it will bind, allreceptors transduce signal to trimeric G protein |
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GPCR pathways aretargets for many FDA drugs |
many drugs target GPCR or G proteins thatfunction downstream to treat disease |
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Trimeric G proteins |
alpha subunit if small G protein, beta γ are interacting proteins. In inactive state trimeric G protein is onplasma mem (alpha & gamma have lipids that anchors to plasma mem) |
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Effector proteins |
membrane bound channels/enz that relay signalwhen stimulated by active G proteins |
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GTPase molecularswitch |
G protein is GTPase. In absence of ligand Gprotein inactive GDP bound state, when GPCR binds ligand its GEF (exchangefactor) interacts w/ G protein stimulates GDP to GTP exchange. Regulator of Gprotein signal (RGS) are GAP (activating protein) stimulates GTP hydrolysis toinactivate G protein |
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Signal induceactivation of GPCR 6 steps |
1. GPCR binds ligand/hormones 2. GPCR confchange enables bind to G protein (GDP to GTP) 3. GTP-G protein conf changealpha separates from gb 4. Alpha binds effector protein 5. Activate effectorprotein relays signal 6. GTP hydrolysis by RGS silence signal |
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Fluorescent ResonanceEnergy Transfer (FRET) Assay |
alpha separates from gamma-beta. Alpha fused CFP(excites 440nm), gamma fused YFP (excites 527nm). When in inactive state,excitation light 440nm excites CFP absorbed by YFP cause yellow to fluoresce(energy transfer, physically bound). Active receptor get separation, excite440nm & CFP emits blue, no longer absorbed bc separated |
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FRET graph |
can measure how fast separation is occurring, ifextended time can remove signal & see protein come back together |
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3 Most commoneffector proteins |
adenylyl cyclase (ATP to generate cAMP), Kchannels (ion channel), phospholipase C (generates two second messenger) |
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Adenylyl cyclase Gsvs Gi |
Gs- stimulated adenylyl cyclase, Gi- inhibitedadenylyl cyclase |
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GPCR regulate ion Kchannels in heart |
GPCR binds acetylcholine activates G protein& gamma/beta binds effector to stimulate opening of K channel (leads to hyperpolymerizationslows heart muscle contraction) |
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GPCR action onadenylyl cyclase |
GPCR that bind ligand AC activate cAMP synthesisor binds ligand to inhibit cAMP synthesis |
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Second messengers |
transmit & amplify signals from receptors |
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Synthesis °radation of cAMP second messenger |
Adenylyl cyclase generates cAMP from ATP,activated enz cAMP phosphodiesterase cleaves cAMP to 5’AMP (turns signal off).Degradation quick after synthesis. Phosphodiesterase recruited to plasma mem towhere cAMP is synthesized for rapid degradation |
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cAMP activation |
activates primary target Protein Kinase A (PKA),differs for diff cells/tissues/organs |
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PKA |
inactive is tetrameric (two copes catalyticsubunit bound to two copies of repressor protein w/ cAMP binding site). WhencAMP produced binds repressor protein & induces conf change to releaseactive PKA, PKA has many substrates (can go in nucleus to activate TF) |
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Synthesis °radation of glycogen in liver |
regulated by PKA activation. Glycogen synthetasetakes UDP-glucose & polymerizes to make glycogen. Glycogen phosphorylaseconvert glycogen back to glucose 1 phosphate – both enz regulated by PKA/cAMPsignal |
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Regulation ofglycogen metabolism PKA activation |
GPCR binds epinephrine/glucagon activatesadenylyl cyclase binds repressor on PKA, PKA activated |
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Regulation ofglycogen metabolism in liver/muscle |
in response to PKA activation, phosphorylatesGPK (glycogen phosphorylate kinase) activates kinase activates GP (cleavesglucose for glycogen breakdown). PKA inhibits phosphatase (inhibitory proteinsthat would remove phosphate from GP, this stimulates glycogen breakdown). PKAphosphorylates GS (inhibits don’t want to make glycogen) |
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Inositol phospholipidsignaling |
G protein activates PLC that cleaves PIP(inositol phospholipid) into IP3 soluble & DAG remains on plasma mem (bothsecond messengers). DAG activates protein kinase C, IP3 binds Ca channel in ERto release Ca into cytosol |
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Calmodulin |
when Ca released from ER binds calmodulincausing conf change allows calmodulin to bind other effector proteins (kinases,phosphatases, cAMP phosphodiesterase) |
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Desensitization orinactivation of GPCR Kinases (GRKs) |
GPCR activates kinases (GRK) once activated cango back and phosphorylate GPCR, once phosphorylated GPCR recruits arrestin toblock interactions between GPCR receptor & trimeric G protein |
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Cholera toxin |
toxin binds epi cells, endocytosed, fuse w/golgi (has KDEL sequence), KDEL receptor binds, goes to ER. In ER dimeric toxindissociates, A1 subunit translocated out of ER activates ER degradation pathwayso proteins translocated out of ER to escape degradation & translocationinto cytosol. Gs (subunit of Gprotein stimulatory) activates adenylyl cyclase& cAMP synthesis, stimulates ion channel & deflux Ca/water of epicauses diarrhea |
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Acetylcholinemediated receptors of smooth muscle |
GPCR binds acetylcholine & activates PLCproducing DAG/IP3 to release Ca/calmodulin. Calmodulin activates NO synthetaseto produce nitric oxide, NO diffuse out of endothelial cell into smooth musclethat will activate pathway for relaxation |
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Asthma therapiestarget GPCR |
muscle cell of airways have GPCR (B adrenergicreceptor) binds albuterol ligand (agonist) stimulates G protein stimulatesadenylyl cyclase/cAMP production. cAMP activates PKA get phosphorylation ofsubstrates like MLCK & open K ion channel – both contribute to musclerelaxation |
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B adrenergicreceptors |
GPCR activated & cAMP synthesis to activatePKA leads to activation of Ca channel in muscle tissue to cause influx ofcalcium leads to muscle contraction |
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Beta blockers |
are B-adrenergic receptor (GPCR) antagonist,blocks action of receptors for adrenaline to slow heart rate & lower bloodpressure |
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Three classes ofcytoskeletal filaments |
actin, intermediate filaments, microtubule |
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How are the threeclasses identified |
1. Diameter 2. Type of protein subunit 3.Arrangement of subunits 4. Dynamic properties |
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Actin |
structural component, found on periphery,polymerized same way as microtubules, composed of diff protein components |
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Microtubulecomposition |
tubulin, made of alpha/beta subunits, providerigidity & structural support for cell, tract for kinases/dynamins fortransport |
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3 Special functionsof microtubules |
1. Microtubules provide polarity for absorptiveproperties in diff tissues 2. Axonal transport in neuronal cells for delayingactivation from one end to another 3. Regulates mitotic spindle to organize& coordinate accurate separation of sis chromo during mitosis |
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MTOC, spindle poles |
polarity of orientation of microtubulesthemselves, microtubules emanate from MTOC (minus end) will grow towards posend |
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Microtubule dynamics |
MTOC & spindle poles help direct cellpolarity & dynamics important for cell function, chromo movement & MTassembly |
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Kinesin motors |
pos end directed vesicle & chromo transport |
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Dynein motors |
neg end directed vesicle transport spindleassembly |
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Alpha subunit |
binds GTP |
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Beta subunit |
binds GTP & hydrolyzes GTP |
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Protofilament |
made of 13 diff alpha/beta subunits together,pos end and neg end, rigid, distinct polarity, very dynamic |
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Dynamic instabilityof microtubules |
shrinks & grows |
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Molecular basis formicrotubule assembly |
1. Longitudinal assembly of tubulin dimers formshort protofilament 2. Lateral interactions between 13 protofilaments formstubule 3. Addition of GTP bound dimers to pos end |
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Assembly is affectedby |
1. Alpha/beta conc 2. Presence of nuclei (MTOC,microtubule fragments) 3. MT associated proteins (MAPs) |
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Dynamic instabilitygrowth/shrink |
GTP bound a/b bind +end, after incorporation GTPbound b slowly hydrolyzed to GDP, only microtubules w/ GTP caps are stable,elongation favored at high conc of GTP-tubulin, if rate of GTP hydrolysis isfaster than rate of GTP tubulin addition, microtubule depolymerizes |
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GTP hydrolysis oftubulin subunit |
weakens interaction between subunits allowingfor depolymerization, allows GDP to fall off tubule at minus end. As long as capis present energy is stored but when energy is released bc of hydrolysis causesrapid disassembly |
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MAP (microtubuleassociated proteins) |
destabilizing proteins aid in catastrophe/dephosphorylation event |
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MT based axonaldegeneration in Alzheimers Disease |
Tau proteins bind microtubule for stabilization,Tau will get phosphorylated & hyperphosphorylation of Tau makes bindingunstable, makes aggregates & microtubule prone to destabilization byKatanin (MAP destabilizer). During AD microtubules depolymerize & causeaggregates of phosphorylate Tau (MAP stabilizer) |
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MTOC/centrosomes |
defines polarity, nucleates microtubules to helptubulin subunit make 13 protofilaments, microtubules grow from minus end atMTOC to plus end |
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MTOC/centrosomesstructure |
contain a pair of centrioles, microtubulesnucleated by pericentriolar matrix (PC), duplicated in S phase & formsorganizing centers for mitotic spindles in mitosis |
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Centriole |
made of gamma tubulin (makes ring around tubulesubunit), centriole duplicate during mitosis, tubulin subunits don’t want tocome together but gamma tubulin complex once initiated assemble microtubule bynucleating tubulin to bind gamma & assemble |
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Gamma Tubulin RingComplex (yTURC) |
nucleates microtubule assembly, containsy-tubulin & accessory proteins, localizes to MTOC, stimulatespolymerization of a/b dimers |
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Bidirectionalmovement along microtubules |
cargo can transport in opp direction ATPdependent by kinesis (+) & dynein (-) |
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Charcot marie toothdisease |
disease caused by one gene in kinesis motorprotein, cant travel cause defect in long axonal function, neurological disease |
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Mitosis andcentrosomes |
duplicated in S phase so in mitosis there aretwo centrosomes (one for each daughter) |
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Microtubule functionsduring mitosis |
centrosomes duplicated in S phase & generate2 spindle pores at beginning of prophase. Microtubules grow & capturekinetochores (joining point of sis chromatids, equal segregation), sis align atmetaphase plate, once all microtubule-kinetechore attachments w/ proper tensionundergo anaphase (w/ check points for equal segregation), mitotic exit w/telophase |
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Centromere specifiesregions for kinetochore microtubule attachments |
centromere on chromo recruit kinetochoreproteins & make scaffold for microtubules to bind. Microtubule +kinetochore attachment is search & capture during pro-metaphase, oncecapture get metaphase alignment, alignment + tension = division/anaphase |
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Inner centromere |
where chromo passenger complex resides |
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Inner kinetochore |
anchor another set of protein that bind &interact w/ inner centromere |
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Outer kinetochore |
helps recruit scaffold & bind microtubuleattachment |
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Microtubule growthduring search & capture |
during mitosis growth of microtubule continues,during metphase will stay stagnant w/ dynamic instability of growth/depletionof tubulin, once microtubules bind kinetochore motor proteins will walk chromoto end of microtubule (towards minus end) |
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Kinetochoreassociated factors affect microtubule dynamics & facilitate capture |
ring complex binds plus end of microtubule tostabilize kinetochore physically to microtubule, as soon as criteria met getrapid depolymerization & get disassembly so ring slides down |
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CENP-E |
binds microtubule to kinetochore |
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Microtubule tension |
microtubules during search and capture canattach & detach to kinetochore but once tension made by opp chromo gettension & disassembly begins to separate sister chromatids |
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Spindle assemblycheckpoint (SAC) |
SAC inhibitory signal turned on when chromo notyet aligned/no criteria to inhibit activity of anaphase promoting complex. Oncespindles have tension w/ kinetochores & at metaphase plate SAC turned off,microtubules sense tension activates anaphase promoting complex- degradation ofcyclin B1 & secruin promotes anaphase |
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Anaphase promotingcomplex/ cyclosome (APCC) |
E3 ubiquitin ligase, with cavity to bind mitoticcheck point complex to Ub & turns off SAC. Helps Ub cyclin B1 & securinsend them to proteasome. Degraded securing allows separase to cleave |
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SAC/APCC duringprophase |
unattached kinetochores (no proper alignment)phosphorylate & promote mitotic check point complex that assembled onkinetochores then diffuse to inhibit APCC & binds APCC until propertension/orientation |
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SAC/APCC duringmetaphase |
proper tension/orientation causes disassembly ofmitotic check point complex, no longer on kinetochores, allows activation ofAPCC so securin & cyclin B1 are degraded enter anaphase |
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Cyclin B1 |
regulatory protein, cyclin dependent kinase 1during mitosis & allows for mitotic exit |
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Securin |
inhibits separase, APCC mediated Ub of securingallows separase to cleave cohesion allowing sis chromatids to separate |
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Drugs (taxanes &vinca alkaloids) |
inhibit chromo separation used as chemotherapeutics,block MT dynamics preventing proper chromo segregation & mitoticprogression (halts at diff stages of cell cycle) |
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Skin functions (6) |
protection, barrier (H20), sensation, immunity,thermoregulation, metabolism |
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Dermis function |
connective tissues, vasculature, innervation,signals/molecules to provide support & homeostasis |
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Innervationsimportance |
for sensory organs (touch, temp, pressure, pain) |
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Architecture ofepidermis (bottom up) |
dermis, basal, spinosum, granulosum, corneum |
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Epidermis cell type |
stratified (multiple layer of cells) squamous(ultimate product is squame) |
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Squamous cells (whatthey look like & function) |
flat cells that has long all organelle includingnucleus, it is dead. Stacking provides physical barrier |
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Basal layer function |
relatively undifferentiated supplying tissuewith cells that need to maintain barrier, mitotically active, progenitors, willstop cycling and differentiate and move to next layer |
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Granulosum function |
cells still alive but highly differentiated,will lose everything and undergo terminal differentiation into squame |
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Keratin |
intermediate filaments |
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3 criteria forintermediate filaments |
1. Conserved tripartite domain structure 2.Conserved features w/in alpha-helical rod domain (highly conserved at N & Cterminus of central rod domain) 3. Self-assembly into 10nm wide filaments(requires more than one type of IF) |
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Heptad repeats |
enable IF to form coil-coiled dimers |
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Lamin |
type of IF that contains nuclear localizationsignal |
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IF sequence typeclassification based upon (2) |
gene structure & nucleotide homology (roddomain) |
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IF heterogeneity |
at protein level (size & charge), some shortor long, AA sequence of rod has heterogeneity |
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IF regulation |
gene regulation related to cell differentiation(what is occurring in cell), phosphorylation, post translation modifications |
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Keratin gene family |
in vivo regulations is such that type 1co-regualted w/ specific type 2 forming pairs |
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Keratin in basalcells |
K5-K14 |
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Keratin indifferentiating cells |
K1-K10 |
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Differentiationdependent regulation of keratin genes in skin |
to move from basal to differentiated cells willbe transcriptionally signaled to upregulate other keratin pairs, get additionalgene expression |
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Keratin abundance |
highly abundant in basal layer at level ofundifferentiated keratinocytes |
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How IF forms(keratin) |
2 IF proteins aligned parallel & heptadrepeats intertwine along hydrophobic seam (heptad 1st & 4thresidue are hydrophobic). Keratin form heterodimers type 1 + type 2. Dimersinteract to form anti-parallel tetramers. 8 tetramers expand length of IF,there is heterogeneity in final filament |
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Implications of antiparallelorientation of IF |
dimer structurally polar (monomers areparallel), tetramer structurally apolar (dimers are anti-parallel). 10nm IF areapolar fibers |
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Assembly ofcytoplasmic IFs in cultured epithelial cells (keratin cycle) |
small subunits form at cell periphery,elongate/mature into filament fibers, integrate w/ existing fibers at perinuclearspace, whole system migrates to nucleus. Some filaments disassemble &subunits recycled for another cycle. Regulated assembly/disassembly byphosphorylation |
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Keratin IF attachment |
at sites of adhesion, early stage ofdifferentiation is spinuous spikes which are desmosome |
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Desmosome (function) |
glues membrane of one cell & membrane ofanother, keratin filaments loop through desmosomes in intracellular side.Desmosome essential for keratin IF attachment & tissue integrity (cell tocell) |
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Role of Plakins |
mediate attachment of keratin IF to one anotherfor adhesion. If remove desmoplakin cells no longer attach at surface &causes blistering & tissue comes apart |
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Role of Plectin |
integrates IF and microtubules, will get blisterbc plectin important for keratin filamnets to hemidesmosomes (cell toextracellular matrix or nucleus) |
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Phosphorylation ofkeratins during mitosis experiment |
temporal & spacial dependence modifications.Ab recognizes phosphoepitope, interface see low epitope, mitosis (keratin reorganized/ disassembled) epitope lights up until cytokinesis. Protein epitope is stablebut PTM is very short during mitosis |
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Assembly ofcytoplasmic IF in keratinocytes in culture experiment |
K14 null mice, reconstitute w/ GFP-K14. Normal-filament forms at periphery & moves toward center cell. Mutant K14-filaments born at periphery, migrate then stop, don’t make it to nucleus bccell mobile. Mutant stripped of cysteine (no disulfide bonds) cant formperinuclear cage of keratin filaments |
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Keratin X factor |
coil-coiled dimer of rod in K14 bc of disulfidebond |
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Experimentalmutagenesis of K14 coding sequence |
what do IF do. Mutate K14 deletions from C &N terminus to observe epi cell formation in culture. Once remove elements fromcentral rod start having aberrant cell behavior |
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Experiment addingback WT K14 |
if put back 50% WT (50% mutant) restore butnormal behavior, put 90% WT normal but aberrant, 1% mutant enough to disruptstructure of normal filament |
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Keratinocytefragility in K14 mutant expressing epidermis (method & findings) |
use K14 promote to drive expression of K14mutant, see blistering disease at sites of friction. Basal cells are rupturing& skin peeling off, have fragility. IF is important for structural support |
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EBS subtypes |
simplex (within basal cells), junctional (defectin attachment of basal cell to basal lamina), dystrophic (split in level ofepidermis) |
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Mutation in human K14gene of EBS |
found Arg of rod domain mutation, disruptsfilament architecture enough to cause disease |
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What makes it difficultto treat EBS |
over 500 mutations along K5K14 filaments, whenmutations affect highly conserved at beginning or end causes severe mutations |
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Phenotype genotypecorrelations in EB Simplex |
more frequency of mutations causes increase inEBS severity |
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What kind ofphenotype is EBS |
loss of function, not enough K5K14 in basallayer |
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EBS mutationsfragilize keratin network experiment |
take fluorescent bead & put in network offilaments, WT or mutant K5K14 & monitor displacement over time. WTassembly- low amount of displacement (beads trapped) little time dependence.Mutant assembly- moving over time, time dependent, material weaker/soft |
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K14 mutation function |
disrupts assembly, subunits born in periphery& grow bigger but don’t elongate & vanish when should be integratinginto existing network, specific point in cytoplasm when they disassemble. Pointof cleavage is within basal cells about midway between nucleus & attachmentto ECM |
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Keratin & tissuerepair |
during repair specific keratins are expressed& down regulate normal keratin while replacing epithelium |
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IF function (6) |
mechanical support, cyto-architecture, cellfragility disorders, cell stress, signaling, disease modifiers |
