Winter Exam 2 Flashcards
What are the 3 types of extracellular molecules in ECM?
1) GAGs and proteoglycans 2) fibrous proteins -collagen, elastin 3) adhesive proteins - fibronectine, laminin
What are GAGs?
aka mucopolysaccharides, are repeating disaccharides. Neg surface charge that attracts water to create turgor. Bottle brush or fir tree appearance. HA acid backbone
Describe Collagen
resistent to shear, make up 25% of protein mass, composed of a triple helix strucutre (a chains). Every third residue is Gly
How is collagen synthesized?
translated from mRNA -> pro-a chins -> proline and lysine hydroxylated (VitC) -> hydroxylysine glycosylated -> triple helix secreted into ECM -> propeptides cleaved -> tropocollagens -> crossling to form collagen fibrils ->allysine (lysil oxidase) -> mature fibrils
What happens when there is not enough Vit C (Scurvy)?
no stable triple helix is formed and there are defective pro-a chains. Immediate degradation. Only newly produced collagen is effected.
Tissues w rapid collagen turnover are effected most - vessels, bruising, wounds, teeth
What is Osteogenesis Imperfecta?
abnormal collagen type 1 production, aka brittle bone disease, never have normal collagen, mostly autosomal dominant.
Type 1: low concentration of collagen of normal structure
Type 2: abnormal collagen; severe
What is Ehlers-Danlos syndrome?
defect in fibrillar collagen, joint and skin effected
Describe the structure of Elastin
non-polar amino acids: gly, ala, val. Also rich in pro and lys.
Describe elastin synthesis
secreted tropoelastin interact with fibrillin-1 -> 4 (3 allysines and 1 lysine sidechains) elastins form desmosine that can stretch and recoil
What is Marfan syndrome?
Fibrillin-1 mutation, improper elastin structure. Effects aorta, eye, lungs, dura, abnormally long people
What is a1-antitrypsin deficiency?
a1-antitrypsin keeps destructive neutrophil elastase in check so it does not cause too much inflammation. A deficiency tho, has a reduced ability of this. Lung tissue cannot regenerate and predesposed to emphysema.
Where are the adhesive glycoproteins fibronectin and laminin found?
Fibronectin: CT
Laminin: Epithelium
What are the 3 binding domains of fibronectin and laminin?
1) cells (via integrins)
2) collagen
3) proteoglycans
What is the purpose of fibronectin and laminin?
To link ECM to cells (as well as the actin/cytoskeleton within the cell)
Describe Cadherins
transmembrane Ca-dependent cell to cell adhesion. Cadherins bind to each other (P,E,N-Cadherins). Hold cells together and tissue integrity
Describe Selectins
Cell surface, carb binding proteins that join cells. Selectin on one cell binds to glycoprotein/lipid on other (P,E,L-selectins). For blood stream and WBCs
Immunoglobulin Superfamily
Ca-INDEPENDENT cell-cell adhesino. Ligands for integrins. (ICAMs, MadCAM). During development
Describe Integrins
a/b transmembrane chains, b2 on leukocytes
What is the principal receptor for cell binding to ECM components?
integrins (weak affinity)
What is inside out signaling?
When changes within a cell results in alterations of inegrin properties.
What are examples of adhesion diseases?
cancer, Leukocyte adhesion deficiency, pemphigus, Asthma, RA, infections
An adhesion molecule binds to collagen. This adhesion molecule most likely belongs to which family?
Integrins
What is primary hemostasis?
Formation of platelet plugs, initiated in response to a vascular injury
What are platelets derived from?
Megakaryocytes.
Normal concentration of platelets?
150,000-3000,000 /microL blood
What is thrombocytopenia dn thrombocytosis?
thrombocytopenia: 400,000 platelets
What is Platelt Derived Growth Factor PDGF?
produced by platelets. They activate tyrosine kinase that promotes cell proliferation and wound healing
Why does normal epithelium not interact with blood components?
1) endothelial cells and platelets both have neg. charges
2) Endothelial cells produce factors (PGI2) that inhibit hemostasis and platelet aggregation
What happens to a vessel wall when there is injury?
1) physical barrier lost
2) No PGI2 synthesized
3) platelets interact with subendothelium
What are the different platelet receptors and what do they bind to?
Gp Ia-IIa : collagen in subendothelium
Gp Ib-IX : von Willebrand factor in subendo
Gp IIb-IIIa : fibrinogen in blood
What is a platelet disorder that has an absence of the receptor Gp Ib-Ix?
Bernard - Soulier disease
What is a platelet disorder with the absence of Gp-IIb-IIIa?
Glanzman thrombasthenia
What is von Willebrand disease?
defect in vWf. Excess bleeding but no spontaneous bleeding. Most common. Equally common in males and females
What do activated platelets release?
ADP and Thromboxane A2 (TXA2) - a required potent inducer of platelet aggregation
How is TXA2 produced?
arachidonic acid metabolism: platelet membrane -> arachidonic acid -> TXA2 (through cyclooxygenase pathway)
How does aspiring work?
It is an anti-platelet agent. It inhibits the cyclooxygenase (COX) pathway by acetylating COX-1. This inhibits TXA2 production
How does platelet activation effect platelet receptors?
induces conformation of Gp IIb-IIIa (integrin) so platelets can bind to fibrinogen with high affinity. Binding of fibrinogen mediates platelet-platelet interactions
What is secondary hemostasis?
Formation of fibrin to stablilize the platelet plug
What is the intrinsic pathway for coagulation?
all components are in plasma to form fibrin
What is the extrinsic pathway for coag?
require external factors (tissue factor) to form fibrin
What is the current understanding of the balance bw intrinsic and extrinsic hemostasis pathways?
the extrinsic pathway initiates coagulation while the intrinsic pathway continues the process
What is another name for Factor 2 and 2a?
Prothrombin and thrombin
Which factors are considered coenzymes as well?
Factor 5a and 8a
Which cofactor is required for the formation of zymogen forms of serine proteases?
Vit K
Which factor initiates the extrinsic pathway?
Factor 7
Which factor is produced in both the intrinsic and extrinsic pathway?
Factors 7 and 10a
Which factor converts prothrombin to thrombin?
Factor 10a
also Ca, Factor Va, and phospholipds are needed
What does thrombin do?
Converts fibrinogen to fibrin
What causes Hemophila A and B?
Deficiencies in Factor 8 and 9 repectively. They are both lcinically identical - X-lined recessive, same reaction effected.
What is the Tissue Factor Pathway Inhibitor TFPI?
protease inhibiting F7 and F10a.
associates with surface endothelium.
1) first binds to F10a and once there is excess
2) Then binds to F7 so neither component works in hemostasis
What is Antithrombin?
protease inhibiting thrombin and F10a.
Major inactivator of Thrombin, F10a, F9a
Much faster in presence of heparan sulfate and heparin (drug)
What is antirhthrombin deficiency a risk factor for?
thrombosis
Describe the difference bw low and high molecular weight heparin.
LMWH activates antithrombin to inhibit F10a only, while HMW inhibits F10a AND thrombin
What is the Protein C/S Pathway
Thrombin binds to thrombomodulin, so now thrombin is able to cleave Protein C to Ca. Protein Ca associates with S and destroys cofactors, F5a, F8a
What are risk factors form thrombosis?
Protein Ca def, Protein S def, Factor V Leiden, Antithrombin def., Factor Vleid:ProteinCa resistence (Arg->Gln), Elevated homocysteine
Describe the fibrinolysis pathway
plasminogen is converted to plasmin by PAs (serine protease). Then plasmin degrades fibrin into D-dimers.
What are some inhibitors of fibrinolysis?
a2-antitrypsin which inhibits plasmin
PAI-2 and PAI-2 inhibit tPA and uPA
Name some conditions where venous thromboisis is a frequent problem
MI, CHF, chronic lung disease, stroke
How do platelet receptor inhibitors work?
They bind to platelet receptors, which inhibits platelet adhesion and aggregation
EX: plavix, GpIIb-IIIa inhibitors
How does heparin therapy work and what are some complicaitons?
Activates antithrombin
Bleeding, thrombocytopenia
How does Warfarin work?
inhibts VitK-dependent gamma-carboxylase in liver.
How is Vitamin K involved in coagulation pathway?
Vit K is a coenzyme for gamma-carboxylase. Helps form factors 2, 7, 9, 10 so that it can bind to calcium
What is prothrombin time PT and what is the normal range?
time required to form a clot after tisue factor is added to plasma. 11-12 sec
What is INR?
International normalized ratio. Normal = 1. If INR>7, risk of bleeding. Therapeutic range is 2-3
Name a few clot busters
t-PA, u-PA, streptokinase. They activate plasminogen
What is the final product of the porphyrin senthetic pathway?
heme
Where are the major sites of heme biosynth?
1) liver
2) erythroid cells of bone marrow (majority)
What are the mian porphyrins and their corresponding sidechains?
1) uroporpyrin - acetate and propionate
2) Coporporphyrin - methyl and propionate
3) Protoporphyrin IX - vinyl and propionate
Which distribtion of porphyrin side chains is found in humans and what is the structre?
Type III - alternating A and Ps except for the D ring (bottom left ring)
What is heme consisted of
one ferous ion in the center of a protoporphyrin IX
When cellular requirements of heme are met, what happens?
Heme is converted to hemin by ferrous oxidation. Hemin inhibits hepatic ALA synthase activity by decreasing mRNA stability of ALAS
What is derepression?
It is the upregulation of ALA synthase (and therefore heme) after drug exposure enhances heme utilization (lowering [heme])
How does Lead inhibit heme formation?
Lead replaces Zn containing enzymes such as ALA dehydratase and ferrochelestase.
Non-competitive inhibition
What is observed in lead poisoning?
Elevated ALA and anemia
What is porphyria?
inherited (usually autosomal dominant) defect in heme synthesis. Results in low heme. Leads to an increase in ALA synthase via derepression. Erythropoietic or Hepatic (chronic or acute hepatic)
Describe porphyria cutanea tarda
most common. chronic.
Def of unrporphyrinogen decarb. So accumulation of U3
Describe ALA dehratase deficiency
IDK
How much bilirubin can the liver excrete and how much does it actually excrete?
3000mg vs 300 mg
Where is conjugated bilirubin normally found?
In hepatocytes. NOT in blood.
What is Gilbet Syndrome>
gluconyltransferase deficiency. benign
What test is indicative of alcohol abuse?
If AST:ALT is 2:1 or greater
What is indicative of hepatocellular disease?
Disproportinately high AST, ALT levels compared to ALP levels
What do low and normal levels of albuin indicate?
low: chronic disease (cirrhosis/cancer)
normal: acute (viral hepatitis)
Which LDH isozyme is specific to liver?
LDH5
What is cholestasis?
obstructino of bile duct perhaps to tumor or bile stone
What test levels are associated with cholestasis?
elevated: ALP, ALT, AST, 5NT, GGT
What is jaunice?
Deposition of bilirubin due to increased bilirubin levels i nblood
What is hemolytic jaundice?
massive lysis of RBCs leads to production of more bilirubin. Liver cant conjugate it. High unconjugated bilirubin. Urine is dark yellow.
INCREASED INDIRECT BILIRUBIN
What is hepatocelluar jaunice?
damage to lieer cells so high AST and ALT. Excess urobilinogen in blood. red/orange urine. Insufficeitn secretion ofbile from liver to bile (leaks into blood) -> INCREASED conjugated/DIRECT bilirubin
What is obstructive jaunice?
Bile duct obstructed. Liver regurgitates conjugated bilirubin into blod. red/orange urine.
INCREASED DIRECT BILIRUBIN
Why are some newborns jauniced?
low activity of Glucuronyl transferase so bilirubin accumulates
Which LFT is most likely to be high in sickle cell anemia?
Unconjugated bilirubin (hemolytic jaunice
What are the 3 domains for receptros with tyrosine kinase activity?
1) ligand binding N terminus
2) alpha helical domain across bilayer
3) effector region
Explain the mechanism of steroid signaling
1) GF binds
2) tyrosine kinase of receptor activate each other
3) tyrosine residues phophorylated
4) SH2 adaptor proteins dock
How does Ras work?
GTP binding protein. binds to SH2 that binds to tyrosine receptors. Ras activates a Ser/Thr cascade called MAP kinase cascade. Longer lived. MAPK activates trancription factors
What are STATs?
Signal, Transducers, and activators of transcription. Contain SH2. STATs form dimers, go to nucleus and then bind to DNA
Describe the PI3 pathway
PI3 binds to phosphoryltaed tyrosines. PIP2 gets phosphrylated. Akt phophorylates Bad (cell survival). PTEN dephosphrotayles PIP3 to inactivate pathway.
Where are the IRS proteins found?
IRS 1 and 2: widely expressed
IRS3: adipose
IRS4: thymus, brain, kidney
What are examples of PI3 kinase pathway?
glucose transport, protein synth, glycogen synth, cell prolif, cell survivial
MISS vs NISS
membrane initiated vs nuclear initiated sterioid signaling. MISS is faster
Which cells are permanently in G0 phase?
Neurons
waht is quiescence and senescence
Quiescence: cells that can be activated reversibly
Senescence: when proliferative capacity irreversibly decreases w age
How are antimetabolites involved with anticancer drugs?
interfere w purin or pyrimideine by inhibiting synthesis. S phase specific
How are anticancer antibiotics involved in cancer treatmtent?
specific and non specific. interruption with DNA
Mitotic Spindle Poisons
M phase specific, Vinca plants. Binds to tubulin causes depolymerizaiton.
Through what does the degradation of cyclins occure?
protesomal pathway (ubiquitin is added for degredation)
Which CDKs drive cell through M and S phases, repsectively?
CDK1 and CDK2. Present in constant amount but activity fluctuatesd
What are the targets for CDK1?
mitotic specific - mitosis machinery, microtubules…
What are the targets for CDK2?
DNA specific enzymes
Name the cyclins and CDKs that associate w each other
Clyclin D with CDK 4/6 - through R point
Cyclin E/A with CDK 2 - DNA synth init
Cyclin B with CDK1 - M transition
What does the retinoblastoma protein do/
prevents advacne of cell cycle into s phase by holding tranx factors. . Underphosphorylated RB is active.
function of p53
1) regulates genes
2) arrests cycle
3) apoptosis
Apoptosis process?
1) cells shrin from lamin cleavage
2) chromatin breaks down.condenses
3) fragmentation. macrophages
4) Phosphotidyl sering translocation
Which 3 amino acids can be phosphoylated?
Ser, Thr, Tyr
What do Ser Thr kinases associate with?
Smad
What are some ligands for SerThr kinases
TGF-B, BMPs
What do SH2 and SH3 interact w?
SH2-phosphorylated tyrosines
SH3- other intracellular signaling molecules
Describe Ras
momomeric GTPase. active when GTP is bound
What is neurofibrin?
a type of GTPase, that inactivates Ras
Which post translational mod is needed for Ras functiom?
farneslation
Mutations in KRAS can cause carcinomas in which parts ofb body?
lung, pancreas, colon
What is Burkitts lymphoma?
translocation of 8 to 14. Overproduces c-myc gene. No mutation tho!
What factor is overproduced in RA?
Tumor Necrosis Factor -alpha TNF-a
Do tumor repressors act dominantly or recessively?
recessively
What is Bcl2
a pro survivor facor. activation mutation tho will cause cancer
What is Warburgs phenomenon?
Cancer shifts to glysoclysis even in aerobic conditions
How does APC and inactivating mutations fo APC work?
Inactivating mutations disregulates beta-catenin, which then moves to the nucleus and activates genes. in proliferation.
