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Mechanisms of Disease I > Exam 1 > Flashcards

Exam 1 Flashcards

1
Q

What is the importance of non-coding DNA?

A 
Promoter/enhancer regions-TFs
Organize chromatin
Noncoding regulatory RNAs
Mobile genetic elements-things found all around genome
Telomeres/centromeres
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2
Q

What are the two most common DNA variations?

A

SNPs

CNVs

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3
Q

How are single nucleotide polymorphisms used?

A

Can be useful markers if inherited with a genetic disease via physical proximity
Used for multigenetic complex diseases(DM II, HTN)
Are regulatory and neutral at times
Not helpful fro prevention

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4
Q

How are copy number variations used?

A

Large stretches of DNA
Can underlie large portion of phenotypic diversity
Influence on susceptibility not well known

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5
Q

What role do histones play, including the modifying factors?

A

Histones can be regulated via methylation, acetylation, and phosphorylation, by writers
When associated with DNA a single core is nucleosome

Consist of H1 on linker and the core of H2a,b, H3, H4 with positive charge to attract negative DNA

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6
Q

How does histone methylation, acetylation, and phosphorylation affect DNA?

A

M-increase/decrease transcription based on AA(Lys, Arg)
A-increase transcription via HAT, decrease via HDAC(Lys)
P-increase/decrease transcription based on position of serine

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7
Q

What does DNA methylation do?

A

Decreases transcription(silencing genes) via methyltransferases, demethylating enzymes and methylated-DNA-binding proteins

As opposed to histones which can increase/decrease transcription

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8
Q

What are chromatin organizing factors?

A

Believed to bring TFs, gene promoters/enhancers into closer proximity(spatial relationships)

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9
Q

Why is miRNa important?

A

Silences mRNA postranscriptionally, all eukaryotes

Pri to pre in nucleus, pre to miRNA via DICER, binds RISC and either directly binds and cleaves RNA or is imperfect and stops translation physically

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10
Q

How are siRNAs used?

A

Made specifically for certain RNAs and can fit in Dicer and RISC to silence that protein translation(pathogenic)

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11
Q

What does lncRNA do and what is an example?

A

Promote histone modification inc/dec, facilitate/ inhibit TF binding, and assembly of protein complex for increased gene activity

XIST and X chromosome inactivation, XIST forms a cloak on X chromsome but itself is not silenced

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12
Q

Name the major parts of the cell and their functions

A

Nucleus-holds DNA and helps regulate transcription
Mito-powerhouse of the cell(ATP), apoptosis
RER- Protein production(membrane and secreted)
SER, Golgi-protein modification, sorting, catabolism
Lysosomes-catabolism
Proteosomes-peptide breakdown
Peroxisomes- break down FA

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13
Q

What does phosphatidylinositol do?

A

Is a linkage for membrane proteins on inner membrane

PLC can turn it into IP3 and DAG(stays on surface)

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14
Q

What is phosphatidylserine an indicator of?

A

Normally on IM but if flipped(flipase) can signal cell death(apoptosis)

Helps BLOOD CLOT

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15
Q

What do glycolipids and sphingomyelin do?

A

On EM of cell

Cell to cell/matrix interactions

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16
Q

No including the specific phospholipids, what can be found on the cell membrane?

A

TM proteins-alpha helices(positive holds to PL negative charge)
Lipid rafts-accumulation of lipids/proteins
GPIs, Prenyl groups or FAs- to anchor proteins(farnesyl, palmitic acid)
Peripheral proteins attached to TM proteins
Glycocalyx-barrier molecule

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17
Q

What is important about the lipids, proteins and their interactions on cell membranes?

A

They help in communication, interaction with ECM, polarity of cell, and anchoring to BM

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18
Q

What can cross the cell membrane passively and how?

A

Small, non polar molecules-O2, CO2
Hydrophobic molecules- steroids
Polar <75Da-H2O, EtOH, urea

water in large quantities via AQP

NO ions, glucose

Typically driven by electrical/chemical gradient

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19
Q

What are carriers and channel proteins used for?

A

Allow nutrient and waste transfer of cell if smaller than 1000Da
Ions, sugar, nucleotides

Channels create hydrophobic pores while carriers change conformation to allow transport

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20
Q

How does active transport work and what is an example?

A

ATP is used to move solutes against concentration gradient

MDR protein, pumps polar compounds(chemo) out of cells to render cancer resistant to Tx
Multidrug resistant

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21
Q

Describe caveolae mediated endocytosis

A

Non-coated membrane assocaited with GPI, cAMP binding proteins, SRC kinases and folate receptor

Potocytosis-cell sipping

Typically used to internalize receptors and integrins

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22
Q

Describe pinocytosis and receptor mediated endocytosis and what is an example

A

Cell drinking

Plasma membrane engulfs EC cargo in clathrin coated pit, then clathrin vesicle and returns that membrane to keep wall size normal, endo/exocytosis must be tightly regulated.
To degrade receptor, the clathrin coat is destroyed and the endosome binds to a lysosome, to recycle it goes back the membrane before the lysosome fusion

LDL and transferrin, the acidic environment of the lysosome causes release of cholesterol and iron(reabsorbed in cytoplasm), the receptors are resistant and can be recycled,

defect in LDL receptor transport causes familial hypercholesterolemia

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23
Q

Why, in general, is cytoskeleton important to the cell and what are the major classes or proteins?

A

Movement, structure, polarity, organization

Actin microfilaments
Intermediate filaments
Microtubules

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24
Q

Describe the function and importance of actin filaments.

A

Two types- G(globular) and F (filamentous) polymerized G-actin make up F-actin
Add at + end, subtract at - end(movement via addition and subtraction)

In muscles myosin binds actin and moves across, non-muscle cells bind actin binding proteins and help movement of cell in space

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25
Q

Describe intermediate filaments. (Especially the specifics for cell types)

A

Ropelike, are polymers usually and do not change size like actin, impart strength, and bear stress

Lamin A, B, C-nuclear lamina-can cause MD/progeria(premature aging)
Vimentin-mesenchymal cells(fibroblasts,endothelium)
Desmin- muscles cells, myosin, actin interaction
Neurofilaments-axons, strength and rigidity
Glial fibrillary acidic protein- glial cells around neurons
Cytokeratins-cell markers due to wide variety(acidic-I, basic/neutral-II)
Skin and hair strcuture

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26
Q

Describe microtubules and how they are used

A

Made of alpha and beta-tubulin, size changing hollow tubes
Polar -,+ ends, with - being in MTOC/centrosome, + end grows or shrinks
Kinesins move anterograde, dyenins move retrograde, via ATP motor proteins, important in mitosis, separating chromatids
Also provides motility to cilia(bronchial epithelium) and flagella(sperm)

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27
Q

Why are occluding(tight) junctions important in cell-to-cell interaction and what constitutes them?

A

Restricts paracellular movement or solutes
Contain occludin, claudin, zonulin, and catenin
Divides apical/basolateral cell(polarity)
Dynamic and can dissociate during proliferation and movement

28
Q

What is the importance of anchoring junctions(desmosomes)?

A

Attach cells to other cells or ECM

Between cells-spot desmosome or macula adherens
-cadherins or desmoglein, desmocollin(link to intermediate filaments and can dissipate stress over many cells)

Cell to ECM-hemidesmosome

  • integrins-link cytoskeleton to ECM
  • FAC generate IC signals due to shear stress

Broad bands are called belt desmosomes
-E-cadherins associated with actin influencing shape and motility

29
Q

Why do cells need communicating(gap) junctions?

A

Allow passage of chemicals between cells nand create syncytium (i.e., cardiac myocytes), permeability reduced by decrease in pH or increase Ca2+

Made of connexons which are made of hexamers of connexin

Permit ions, sugars, nucleotides, AA, vitamins

30
Q

What role does the endoplasmic reticulum play in the cell?

A

Synthesis of transmembrane proteins and lipids for PM, or molecules to be exported

Can have ribosomes(RER) or not(SER)
To be transcribed on RER mRNA must have signal sequence otherwise it is done by free ribosomes

RER proteins will be modified at the E(sugar groups, disulfide bonds)

If the protein does not fold correctly it will be destroyed or build up in the ER leading to UPR and stress leading to apoptosis

CFTR is the most common degraded mutant protein, cystic fibrosis, deletion of F508

31
Q

How is the golgi apparatus important for cells?

A

It modifies proteins and lipids like the ER and received from the ER from cis to trans(away from ER), certain sugar moieties are removed from the ER modification, M6P can be used to direct to lysosomes

Cis-golgi can send proteins back to ER, trans to the membrane or vesicles

golgi is larger in secretory cells(goblet, plasma cells)

32
Q

What does the SER do and in what cell is it most prominent?

A

It acts as a transition zone from RER to cis-golgi

SER can by hyperplastic in steroid producing cells(adrenal) and breakdown of lipid soluble molecules(liver)

phenobarbital catabolism by CP450 in the liver causes hyperplasia of SER

In cells the SER sequesters Ca2+ for apoptosis and in muscles to contract and relax

33
Q

What is important about lysosomes?

A

Contain acid and enzymes to breakdown various molecules
Enzymes are directed to lysosomes by M6P
Connected to pinocytosis and endocytosis, forming early endosome with acid(not much breakdown), late endosome with significant breakdown and finally lysosome, all while gaining acidity

Play a role in autophagy and phagocytosis

34
Q

Describe autophagy

A

Proteins and organelles no longer needed by the cell are engulfed in a double membrane of ER forming autophagosome, fuses with lysosome

used to preserve cell viability in nutrient depletion

35
Q

Describe phagocytosis

A

Cells engulf proteins and debris from outside the cell in a phagosome which fuses with a lysosome for degradation

36
Q

Why are proteasomes important in cells?

A

They degrade cytosolic proteins, mainly denatured or misfolded(similar to ER), proteins destined for degradation are marked with multiple ubiquitin groups, unfolded and sent into the cylindrical protease, broken into peptides

37
Q

What general roles does the mitochondria play in the cell?

A

Energy production
Cell death
Intermediate metabolism

38
Q

Describe mitochondrial energy generation

A

Metabolites are oxidized causing protons to be pumped from matrix to intermembrane space. The gradient allows H+ to go back down its gradient to the matrix and produce ATP forming CO2 as well, this also forms ROS which are important to the cell but too many can be problematic

thermogenin can use the gradient to produce heat for non-shivering thermogenesis

39
Q

Describe intermediate metabolism by mitochondria

A

Glucose and glutamine are taken up more and Ox Phos is attenuated. This allows TCA cycle intermediates to by shuttled off to make lipids and building blocks due to increased carbon moieties.

in benign and malignant cells this is known as Warburg effect

40
Q

Describe mitochondrial mediated cell death

A

Necrosis occurs if the mitochondria is injured and ATP is no longer generated

Apoptosis is mediated by the mitochondria via intrinsic or extrinsic signals, releasing Cyt C ultimately activated caspases

defects in apoptosis can lead to malignancy

41
Q

What are the general cell signal modalities?

A

Damage to neighbor cells-danger signals
Contact with neighborcells- GJ(Ca2+ or cAMP)
Contact with ECM-integrins
Secreted molecules- GF, cytokines, hormones

42
Q

What are the 4 modalities of extracellular communication based on distance?

A

Paracrine-in the vicinty
Autocrine-same cell
Synaptic- NTs via neurons
Endocrine-mediator in bloodstream can travel through body

43
Q

Describe the two major cell receptor types and how they work

A

Intracellular-TFs, lipid soluble ligands

  • Vit D, steroids-nuclear hormone receptors-
  • NO causes guanylyl cyclase to create cGMP*

Cell surface receptors-transmembrane proteins bind ligand
-cause channel to open, activate G protein, activate RTK, change conformation activating latent TF

44
Q

Describe RTKs

A

Receptors for GFs(insulin, EGF, PDGF)

Intrinsic kinase activity phosphorylates dimer

45
Q

Describe non-receptor RTKs

A

These are like RTKs but do not phosphorylate the dimer of receptor, a cytosolic protein is phosphorylated

*important in rous sarcoma virus, SRC family, SH2 binds phosphorylated groups on other proteins, SH3 mediates protein protein interactions

46
Q

Describe GPCRs

A

Serpentine 7 TM receptor
ligand binds activating GTP binding protein which GDP bound, exchanges GDP for GTP, adenyyl cyclase is activated generating cAMP, or PLC generatig DAG and IP3, then Ca2+

47
Q

Describe Notch pathways

A

Cleavage of the receptor allows cytoplasmic piece to form transcription complex

48
Q

Describe Wnt signaling

A

Wnt binds, activates Frizzled, regulating IC B-catenin, which is constituently degraded, however Wnt-Frizzled recruits Disheveled which inhibits the degradation of B-catenin which translocates to nucleus forming TF complex

49
Q

What must a TF possess to be effective?

A

Protein:protein interaction domain

Recruits histone modification proteins, RNA polymerase, chromatin remodeling complexes

50
Q

What would occur if a GOF mutation happened in GFs?

A

They are proto-oncogenes so you would get unchecked cell proliferation and tumor formation

51
Q

What are some characteristics of EGF and TGF-alpha?

A

EGF family
Produced by macrophages and epithelial cells
Mitogenic for hepatocytes, fibroblasts and epithelial cells
Receptors-EGFR1 or ERB-B1 or EGFRm mutations occur in breast, brain, lung, head, and neck CA

ERB-B2 or HER2is overexpressed in breast CAs

52
Q

What are characteristics of HGF or scatter factor?

A

Mitogenic for hepatocytes and epithelial cells
Morphogen in embryo development, cell migration and hepatocyte survival
Produced by fibroblasts and mesenchymal cells as pro-HGF activated at active site by serine proteases

MET is receptor, intrinsic RTK, over-expressed in tumors-renal and thyroid carcinomas, inhibitor as therapy possibility

53
Q

Describe characteristics of PDGF

A

AA,AB,BB are constituently active
CC,DD must be activated
Stored in platelet granules, released on activation, also produced by macrophages, endothelium, smooth muscle cells

Receptors are PDGF alpha/beta, both RTKs
Induce fibroblast, smooth muscle and endothelial cell proliferation
Chemotactic for these cells as well

54
Q

Describe characteristics of VEGF

A

A,B,C,D and F(placental)
VEGF-A is VEGF, major angiogenic factor
B and F are in embryo vessel development
C and D are used in lymphatic as well as angiogenic development
Also used for maintenance in brain, kidney and retina
Induces vasodilation and permeability, due to hypoxia mostly

HIF-1 mediates hypoxia driven VEGF along with PDGF and TGF-alpha

Receptors are RTKs, VEGFR 1,2,3
2 is higly expressed on endothelium, used for angiogenesis
Abs for receptors treat renal and colon CAs since the require angiogenesis, as well as “wet” age-related macular degeneration(AMD)
And DM macular edema
VEGFR-1…=….s-FLT-1 (soluble versions) indicated in preeclampsia by sopping up free VEGF required for normal endothelium maintenance

55
Q

Describe characteristics of FGF

A

FGF family, acidic(aFGF, FGF-1) and basic(bFGF, FGF-2)
FGF-7 known as KGF
FGF associates with heparan sulfate e in ECM, which is a reservoir for inactive factors for wound healing
FGFR1-4 are RTKs, used in wound healing, hematopoiesis, and development
FGF-2/bFGF can aid in angiogenesis

56
Q

Describe characteristics of TGF-beta

A

Not TGF-alpha, three forms TGF-B1,2,3
Family includes BMPs, activins, inhibins, mullerian inhibiting substance
TGF-B1 has widespread distribution and is known as TGF-B
Secreted as precursor needing activation
Type I and II receptors (serine/threonine kinase), phosphorylate Smads, join Smad 4 in heterodimers to allow nuclear translocation
“Pleitropic with a vengeance” because of the different effects it causes
Produces collagen, fribronectin, and proteoglycans
Inhibits collagen degradation by inhibiting MMP and increasing TIMPs
Forms scars and drives fibrosis

Anti-inflammatory serving to limit and terminate inflammatory response
Inhibts lymphocyte proliferation and leukocyte activity

57
Q

What are key functions of the ECM?

A

Mechanical support-anchoring and movement, cell polarity
Control of cell proliferation-binding GFs and signaling, latent GFs
Scaffolding for tissue renewal-require BM, deficit in liver cirrhosis
Establish tissue microenvironments-acts as boundary between CT and cells, functional in kidneys

possible therapy involving regrowing tissue/organs

58
Q

Briefly describe the two forms of ECM

A

Interstitial matrix-space between cells in CT, supportive vascular and smooth muscle structures
Made by mesenchymal cells(fibroblasts) forming amorphous gel
(Fibronectin, elastin, proteoglycans, hyaluronate)

Basement membrane-ogranized matrix arround cells(epithelial, enothelial, smooth muscle, forms mesh,
Type IV collagen and laminin

59
Q

What are the three groups of ECM proteins?

A

Fibrous structural-collagen, elastins for strength and recoil
Water hydrated gels-proteoglycans, hyaluronan
Adhesive glycoproteins-connect ECM elements to one another and to cells

60
Q

Describe collagens

A

Types I, II, III, IV, form fibrils in blood vessels, tendon, bone, cartilage and skin scars
Cross-linked triple helices via lysl oxidase depend on vit C
Deficiency in Vit C leads to bleeding easy
Collagen defects leads to Ehlers-Danlos and osteogenesis impercta

Basement membranes contain non fibrillar type IV collagen, regulare fibril diamtere via FACITs(type IX), or anchor to BM via type VII

61
Q

Why is elastin important?

A

Recovers shape after deformation
I.e. cardiac valves, and large blood vessels, as well as uterus, skin and ligaments

Core of elastin and covering of fibrillin

defect in fibrillin leads to skeletal abnormalities and weakened aortic walls(Marfan syndrome)

62
Q

How do proteoglycans and hyaluronan work together?

A 
Form highly compressible gel used in joint cartilage, and lubrication for bone surfaces
Form glycosaminoglycans(keratan sulfate and chondroitin sulfate) linked to long hyaluronic polymer(hyaluronan) like bristles
The highly negative charge pulls in cations and thus water to make the gel like matrix
*used to bind chemokines and GF to increase concentration in ECM*
63
Q

Describe fibronectin

A

Made by fibroblasts, monocytes and endothelium
Binds to ECM components and integrins
Provides scaffolding in wound healing for ECM deposition, angiogenesis and reepithelialization

64
Q

Describe laminin

A

Most abudant glycoprotein in BM, cross shaped
Connects type IV collagen and heparan sulfate
Modulates cell proliferation, motility and differentiation

65
Q

Describe integrins

A

Part of cell adhesion molecules
Alpha/beta subunits
Attach to ECM components such as laminin and fibronectin, linking IC to outside world
Mediate firm adhesion in leukocytes and transmigration to inflammation
Critical role in platelet aggregation
Attach via RGD(Arg-Gly-Asp) motif
Can trigger signaling cascade for cell proliferation, motility, shape and differentiation

Mechanisms of Disease I (1 decks)

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