Exam 1 Flashcards
Name of Dr. Rubinstein’s Puppy
Legend
What embryonic derivatives does epithelium come from
All 3. Ectoderm, mesoderm, endoderm
What type of epithelium lines the small intestine
simple columnar
What are the three types of endocytosis
- Phagocytosis - ingestion of large particles into phagosomes.
- Receptor-mediated endocytosis
- Fluid phase endocytosis (pinocytosis)
What are the two types of exocytosis
- Regulated exocytosis - signal before the secretory vesicles fuse with the membrane.
- Constituitive secretion - secretory vesicles continuously fuse with the plasma membrane.
Names of the 2 surfaces of an epithelial cell
Apical (top), basal (bottom)
Types of transport through an epithelium (2 types)
Transcellular (larger molecules, through the cell)
Paracellular (between cells, smaller, and regulated by tight junctions)
What causes Cystic Fibrosis
apical Cl chanels do not open, disrupting polarity in epithelium and thickening the mucous layer covering the epithelia.
Protein is misfolded and never makes it to the cell membrane, it is retained in the ER.
What is in the basement membrane
The basal lamina (top layer, known as lamina densa), which contains laminin, fibronectin, type IV collagen, proteoglycans
The reticular lamina (lower) which contains type III collagen (reticular fibers)
lamina lucida is the top layer, which contains adhesive glycoproteins (integrins) - links to anchor proteins at hemidesmosomes and focal adhesions
What are the adhesive proteins that link the basal lamina to anchor proteins on the epithelial cell at hemidesmosomes and focal adhesions
Integrins
What do microvilli do and what are they made of
increase surface area, contain a core of actin filaments that attach to the terminal web, where they interact with horizontal actin filaments. Villin anchors actin filaments in the tip. Actin and myosin interact at the terminal web to form a contractive matrix, causing the microvilli to spread.
What are sterocillia (villi), what do they do, and where are they found
Epididymis, proximal part of ductus deference, and sesory cells of the innear ear. Actin filament core, interconnected by cytoplasmic bridges.
What are motile cilia (true cilia), and what do they do
Have a 9+2 pattern of microtubules, dynein is motor protein by splitting ATP, has synchronous movement
Monocilia
Have a 9+0 arrangement of microtubule pairs, they are immotile cilia that can function as mechanoreceptors that respond to fluid displacement, may create left-right assymetry
What are the types of glands and what do they do
Endocrine - no duct - secreted dirrectly into connective tissue and diffuses into blood
Exocrine - duct system
Unicellular (goblet cell containing mucinogen, a hydrophilic glycoprotein)
Multicellular
Simple (single duct) or compound
What are actin filaments and what do they do
Form core of microvilli, provide cell motility by polymerizing, form contractile ring for cell division
What are intermediate filaments and what do they do
Stable tissue specific, maintain cell integrity by linking to intercellular junctions (so cells do not rupture when stretched). They do not change length, and make up keratins, vimentin, neurofilaments, and lamins. They attach to desmosomes.
What are microtubules and what do they do
Treadmill by maintaining a constant length while polymerizing and depolymerizing. Polarize the organelles, form mitotic spindle and core of cilia. They move using kinesin and dynein.
Zonula Occludens (Tight Junction)
Semipermeable barrier between apical and basolateral membranes, Linked to actin filaments in the terminal web by claudin/occludin. Tight junction membranes are linked by the cadherins occludin and claudin that are bound to several classes of ZO proteins that are linked to actin.
Can seal of the apical surface of the cell from the basal and lateral borders, so that cell polarity is possible.
Zonula adherens
lower than the zonula occludens. Linked to actin filaments in the terminal web by cadherins. Cadherins are calcium dependent.
Desmosome (Macula adherens)
Anchors intermediate filademtns, linked by cadherins (desmocollins and desmogleins).
Gap Junctions
Form connexon channels that permit cell to cell communication. No link to anchor proteins, allow free flow of ions and messengers between cells.
Hemidesmosome
Links cells to matrix, uses integrins linked to intermediate filaments. Use integrins instead of cadherins for adhesive proteins.
Focal Adhesions
Links cells to matrix, using integrins linked to actin microfilaments. Molecular basis for cell migration. Integrins connect to fibronectin.
Explain the secretory pathway in a cell
Begins at RER, vesicular transport to the Golgi apparatus, vesicular transport either directly to the cell surface or into secretory vesicles, with these then moving to the cell surface upon a signaling event.
The Golgi complex distributes everything
Why does RER stain blue in H&E
abundant, negatively charged mRNA associated with it
How do proteins get to the ER
membrane and secretory proteins have signal sequences, that are recognized by Signal Recognition Particles (SRPs). They stop translationand bind to a docking protein in t he RER, where the SRP falls off and translation continues.
Any protein without a signal sequence is moved to the cytoplasm.
Proteins that stay inthe ER have retention signals, interacting with receptors in the ER that prevent them from leaving.
Functions of the ER
Protein folding (possible toxic gain of function by aggregation, Parkinsons, Alzheimers), glycosylation (addition of carbohydrate), sorting, quality control, degredation, and integrating responses to cellular stresses
How is protein folding accomplished
folding enzymes
molecular chaperones that bind to newly made proteins and stop them from aggregating. As the protein folds, chaperone binding sites are hidden.
Chaperones as clinical targets
In parkinsons, there is aggregation of proteins, so if more chaperone can be introduced and overexpressed, it can cause the mutated protein to fold correctly more often
Drugs that correct folding defects
Read-through editors: read through premature stop codon
Correctors - help to fold the protein properly
Potentiators - improve the function of the misfolded protein after it is made
ER-Associated Degredation
Misfolded protein complexed with ubiquitin is transported out of the ER, where it is degraded by the proteosome
Things that cause accumulationof unfolded proteins
hypoxia, glucose deprivation, calcium abberations, viral infection, cancers (chaperone limited), misfolding mutations
How to proteins get to the Golgi
Transport vesicles bud from the ER, moving on microtubules to the Golgi where they fuse with the cisternae.
Functions of the Golgi apparatus
Glycosylation (adding carbohydrates), Lipid biosynthesis, proteolytic processing, secretion and sorting
How does the Golgi make lysosomal enzymes, and what happens when it goes wrong
A mannose 6 phosphate is added, allowing them to go to lysosomes. In lysosomal storage diseases, enzymes are secreted because this M6P is not added.
Signaling for secretory granules to fuse with the membrane
Signal causes an influx of calcium, leading to massive degraulation and release of contents
What is vesicle/membrane fusion catalyzed by
SNARE proteins, one on the vesicle (vSNARE), one on the target membrane (tSNARE)
Botox cleaves SNARE proteins, preventing neurotransmitter release
General structure of the endocytic system
Early endosomes are mildly acidic, here they either recycle to the cell surface or deliver contents to more acidic late endosomes, late endosomes (site of mebrane degredation MVB) send material to lysosomes
High Cholesterol caused by failure of endocytosis
LDL cannot bind to a cell receptor with a mutation and is not endocytosed. Therefore, LDL is present in blood at a high level.
H&E Staining
Hematoxylin is a basic stain and stains strong acid containing material blue
Eosin is an acidic stain and stains basic substances (such as proteins) red
Endothelium vs. mesothelium
Endothelium lines blood vessels, mesothelium lines body cavities
simple Squamous Epithelia and where they are found
thin, nucleus bulging out into the lumen. Found in alveoli of the lung
found in mesothelium
Simple cuboidal epithelia and where they are found
tall and wide, found in liver, endocrine and exocrine glands, and kidney
simple columnar epithelia and where they are found
tall, in endocrine and exocrine glands, lining of intestine
stratified squamous epithelia and where they are found
basal layer is cuboidal, top layer squamous. Found in skin, digestive tract, vagina.
Stratified cuboidal epithelia and where they are found
Rare. found in larger ducts of some exocrine glands
stratified and pseudostratified columnar epithelia and where they are found
stratified - anorectal region, very large exocrine ducts
psuedo - tall cells that span whole membrane and short that do not. Lines the trachea, bronchi, and ducts of epididymis.
Transitional epithelium and where it is found
Accomodates strethcing, lines bladder, ureter
Fibronectin
binds basal lamina components to integrins on the cell membrane
What is the darkly staining line near the surface of epithelial cells
The terminal web, and array of actin filaments that connects to the actin in the microvilli
Names and order of junctions found at the apicolateral border of the cell
- zonula occludens
- zonula adherens (belt desmosomes)
- macula adherens (spot desmosomes, desmosomes)
Calcium Influx and Gap Junctions
Causes gap junctions to close immediately, so neighboring cells cannot be damaged.
Progenitor cells
Transit amplifying, arise from stem cells and divide rapidly to produce daughter cells tha differentiate to generate and maintain tissues
Totipotent vs. pluripotent vs. multipotent
toti: zygote, can make all tissues, including placenta
pluri: all embryonic tissues, not placenta
multipotent - can make multiple cell types in tissue
2 types of stem cell asymmetry
divisional asymmetry - “stemness” factor only into one daughter cell
environmental asymmetry - nice provides signals that help stem cells retain self-renewal
HSC’s
Hematopoetic stem cells, in bone marrow, are very rare and hard to identify
In the current view, Long term reconstituting cells devide into short term reconstituting cells. These STR’s become a common myeloid (everything other than immune) progenitor or a common lymphoid progenitor.
Label-retaining cells are called stem cells
Localize to the endosteal region of the bone marrow, must stay in this niche to retain potency, can migrate in blood to other niches (because of this we can take bone marrow from blood)
How are stem cells separated out
Flow cytometry techniques that separate cells based on flourescently labeled antibodies, followed by fluorescence activated cell sorting, or FACS
MSC’s
Mesenchymal stem cells - multipotent cells derived from many tissues. CAn be injected into the blood stream, and they will migrate to places where we know stem cells exist. They adhere to plastic and have a few markers that are notable.
Induced pluripotent stem cells and their problems
convert differentiated fibroblasts into ES-like cells taht are self-renewing and pluripotent. However, this may promote cancer development
Cancer and Stem Cells
only a small number of cancer cells are capable of producing a new tumor
Could be from transformation of a normal SC through mutation - rare
activation of self-renawal pathways in already cancerous cells
Shown by AML-causing oncogene injected in mice, cell’s gain self-renewal. This self-renewal correlates with gene expression.
Ki67 antigen
expressed at all phases of active cell cycle but not in G0 in resting cells
Cell Cycle restriction point
G1-S boundary. If GF’s are withdrawn before this cells do not divide. However, having passed this the cell is committed.
pRB
protoypical tumor suppressor protein in retinoblastoma. Rb encodes this protein. It represses E2F transctipion factors (inhibited when bound to pRB). Kinases phosphorylate pRB, and it releases E2F.
CDK
Cyclin dependent kinase complexes. These regulate pRB through phosphorylation, and are activated by cyclins.
Cyclin/CDK complexes
These regulate different stages of the cell cycle. Cyclin D/CDK4/6 and cyclin E.CDK2 pushes cells to the restriction point by hyperphosphorylating pRB.
CDK2 vs. CDK4/6
CDK2 is a much better kinase than CDK4/6 and hyperphosphorylates pRB after it is slighlty phosphorylated by 4/6.
pRB remains hyperphosphorylated until the end of mitoses, and is dephosphorylated by phosphatases.
CKI (INK4)
(Inhibitors of CDK4) inhibits cyclin/CDK activity in response to cell stresses
loss leads to cancer
p16INK4a gene
often lost or silenced in cancer cells
causes protective cell cycle arrest in melanomas
features of Apoptosis
Highly ordered, ATP dependent, proteases and nucleases destroy cell, puts everything in vesicles.
Distinct from necrosis, that is cell lysis
Two layers of skin
Epidermis - stratified squamous, keratinized
dermis - connective tissue containing vessels, glands, nerve endings, roots)
Below this there is the superficial fascia, loose connective tissue
Layers of the epidermins and their properties
Stratum basale
Stratum spinosum
Stratum granulosum
stratum lucidum
stratum corneum
stratum basale
cuboidal or columnar, divide frequently. All cells attached to basement membrance by hemidemsosomes.
keratin 5 and 14 proteins that dimerize to form intermediate filaments
stratum spinosum
intercellular spindle bridges attached by desmosomes, extensive intermediate filaments. Membrane-coating granules, or lamellar bodies, spinosum cells produce keratins 1 and 10
stratum granulosum
flattened nucleated keratinocytes multilayeed, keratohyalin granules that make the cells dark.
Synthesizes filaggrin, which induces keratin aggregation
Has many lamellar bodies
Stratum lucidum
Nucleus not visible, dead cells (only in thick epidermis)
stratum corneum
keratin filaments crosslinked with fillabgin. Complex of lipids from lamellar bodies cross links the cell envelope and is highly resistant to degredation. Moist surfaces don’t have a stratum corneum.
Two layers of the dermis
papillary layer (superficial, loose connective tissue)
Reticular layer (ticker and less cellular, Langer’s lines of tension are formed here)
Attachment of epidermis to dermis
dermal papillae are fingerlike projections from the epidermis into the dermis
Basal side: Anchoring fibrils extend from the basal lamina to the collagen (reticular) fibrils of the connective tissue.
Epithelial side: laminin, collagen XVII, and integrins adhese the basal lamina and there are hemidesomsomes.
Four classes of cutaneous mechanoreceptors
Merkel corpuscles, Meissner corpuscles, Pacnian corpuscles, and hair receptors
Pacnian corpuscle
Looks like an onion, central region has nerve process. Found near the junction of the dermis and the hypodermis.
Respond to pressure and vibration and are tickle receptors
Meissner’s corpuscles
smaller than pacnian, found in dermal papillae especially in fingertips.
Respond to light touch. Fingers, toes, lips
Langerhan’s cells
Antigen-presenting cells in skin, between keratinocytes, leave the skin and move to lymphoid organs
melanocytes
melanosome organelles rpduce melanin. Located between the basal and spinosum layers. melanin is secreted in the interstitial space and is taken up by keratinocytes.
Derviced from neural crest tissue. UV stimulated.
Merkel cells
mechanoreceptors in stratum basale, linked to keratinocytes by desomosomes
KLK’s
Cleave desmosomes in a pH dependent manner. Inhibited at high pH of the bodly, but at lower pH surface of skin) Corneal cells are shed
constitutive receptor activity
some receptors stay in the R(a) form instead of the R(i) form even in the absence of ligand binding
5 transmembrane signaling mechanism
- diffuse across membrane (steroid) and act on intracellular receptor
- receptor spans domain, signal binds to EC domain and activates enzymatic activity in the cytoplasmic domain (cytokine receptors)
- Signal binds to EC domain which activates a tyrosine kinase on cyto side
- ion channel opened by signal
- G-protein coupled receptor
steroid receptor mechanism
bind to a protein that releases repressors (like HSP90, heat shock) when the steroid is bound, activates dNA transcription
cytokine receptors
dimerize when activated, then activate separate mobile protein (JAK) molecules, which phosphorylates signal transducers and activates STAT molecules
(Growth hormone, erythropoietin, interferon)
Stat molecule
Signal Transducer and Activation of Transcription
receptor tyrosine kinase
dimerizes and the cytoplasmic domains become phosphorylated, and they catalyze phorphorylation of substrate proteins
(EGF, PDGF, TGFB, insulin)
Ligand Ion Channel
several subunits, ligand binds to site on one of the subunits (neurotransmitters)