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Cell cycle phases
- Checkpoints control transition between phases of cell cycle
- Regulated by: cyclins, CDKs, and tumor suppressors
- Mitosis (shortest phase): prophase-metaphase-anaphase-telophase
- G1 and G0 are of variable duration
- *G = Gap or Growth
- *S = Synthesis
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Regulation of cell cycle
- CDKs: Cyclin-dependent kinases
- -Constitutive and inactive
- Cyclins: Regulatory proteins that control cell cycle events
- -phase specific
- -activate CDKs
Cyclin-CDK complexes: Must be both activated and inactivated for cell cycle to progress
- Tumor suppressors:
- -p53 and hypophophorylated Rb normally inhibit G1-to-S progression
- -mutations in these genes result in unrestrained cell division
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Cell types
permanent, stable, labile
- Permanent: Remain in G0, regenerate from stem cells
- -Neurons
- -Skeletal and cardiac muscle
- -RBCs
- Stable (quiescent): Enter G1 from G0 when stimulated
- -Hepatocytes
- -Lymphocytes
- Labile: Never go to G0, divide rapidly with short G1
- -Bone marrow
- -Gut epithelium
- -Skin
- -Hair follicles
- -Germ cells
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Rough endoplasmic reticulum
- Site of synthesis of secretory (exported) proteins and of N-linked oligosaccharide addition to many proteins
- Nissle bodies (RER in neurons): synthesize enzymes (e.g., ChAT [choline acetyltransferase] makes ACh) and peptide neurotransmitters
- Free ribosomes: unattached to any membrane; site of synthesis of cytosolic and organellar proteins
- **Mucus-secreting goblet cells of the small intestine
- **Antibody-secreting plama cells are rich in RER
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Smooth endoplasmic reticulum
- Site of ssteroid synthesis and detoxification of drugs and poisons
- **Liver hepatocytes and steroid hormone-producing cells of the adrenal cortex are rich in SER
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Cell trafficking
Golgi
- Golgi is the distribution center for proteins and lipids from the ER to the vesicles and plasma membrane
- Modifies N-oligosaccharides on asparagine
- Adds O-oligosaccharides on serine and threonine
- Adds mannose-6-phosphate to proteins for trafficking to lysosomes
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Cell trafficking
Endosomes
Endosomes are sorting centers for material from outside the cell or from the Golgi, sending it to lysosomes for destruction or back to the membrane/Golgi for further use
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Cell trafficking
I-cell disease
- Inclusion cell disease (I-cell disease):
- -inherited lysosomal storage disorder
- -failure of addition of mannose-6-phosphate to lysosome proteins → enzymes are secreted outside the cell instead of being targeted to the lysosome
- Findings:
- -coarse facial features
- -clouded corneas
- -restricted joint movements
- -high plasma levels of lysosomal enzymes
- -often fatal in childhood
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Vesicular trafficking proteins
- COPI:
- -Golgi → Golgi (retrograde)
- -Golgi → ER
- COPII:
- -Golgi → Golgi (anterograde)
- -ER → Golgi
- Clathrin:
- -trans-Golgi → lysosomes
- -plasma membrane → endosomes (receptor-mediated endocytosis)
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Peroxisome
Membrane-enclosed organelle involved in catabolism of very long fatty acids and amino acids
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Proteasome
Barrel-shaped protein complex that degrades damaged or unnecessary proteins tagged for destruction with ubiquitin
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Microtubule
- Cylindrical structure composed of a helical array of polymerized dimers of α- and β-tubulinEach dimer has 2 GTP bound
- Incorporated into flagella, cilia, mitotic spindles
- Grows slowly, collapses quickly
- Also involved in slow axoplasmic transport in neurons
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Microtubules
Molecular motor proteins
- Molecular motor proteins: transport cellular cargo toward opposite ends of microtubule tracks
- -Dynein = retrograde to microtubule (+ → -)
- Kinesin = anterograde to microtubule (- → +)
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Drugs that act on microtubules:
- Mebendazole/thiabendazole: antihelminthic
- Griseofulvin: antifungal
- Vincristine/vinblastine: anti-cancer
- Paclitaxel: anti-breast cancer
- Colchicine: anti-gout
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Chédiak-Higashi syndrome
- Mutation in the lysosomal trafficking regulator gene (LYST):
- LYST product is required for microtubule-dependent sorting of endosomal proteins into late multivesicular endosomes
- Presentation: recurrent pyogenic infections, partial albinism, and peripheral neuropathy
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Cilia structure
- 9 + 2 arangement of microtubules
- Axonemal dynein: ATPase that links peripheral 9 doublets and causes bending of cilium by differential sliding of doublets
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Kartagener's syndrome
Primary ciliary dyskinesia
- Immotile cilia due to a dynein arm defect
- Results in male infertility and decreased female fertility
- Bronchiectasis
- Recurrent sinusitis
- Associated with situs inversus
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Cytoskeletal elements
- Actin and myosin: microvilli, muscle contraction, cytokinesis, adherens junctions
- Microtubule: Movement. Cilia, flagella, mitotic spinddle, axonal trafficking, centriolees
- Intermediate filaments: Structure. Vimentin, desmin, cytokeratin, lamins, glial fibrillary acid proteins (GFAP), neurofilaments
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Plasma membrane composition
- Asymmetric lipid bilayer
- Contains cholesterol, phospholipids, sphingolipids, glycolipids, and proteins
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IHC stains for intermediate fillaments
Stain: cell type
- Vimentin: connective tissue
- Desmin: muscle
- Cytokeratin: Epithelial cells
- GFAP: NeuroGlia
- Neurofilaments: Neurons
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Sodium-potassium pump
- Na+-K+ ATPase is located in the plasma membrane with ATP site on cytosolic side
- Each ATP: 3Na+ go out; 2K+ come in
- During the cycle, the pump is phosphorylated
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Sodium-potassium pump inhibitors
- Ouabain: inhibits by binding to K+ site
- Cardiac glycosides (digoxin, digitoxin): directly inhibit the Na+-K+ ATPase, which leads to indirect inhibition of Na+/Ca2+ exchange → ↑ [Ca2+]i, → ↑ cardiac contractility
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Collagen
- Most abundant protein in the human body
- Extensively modified by posttranslational modification
- Organizes and strengthens ECM
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Collagen
Types
- Type I: most common (90%) - Bone, Skin, Tendon, dentin fascia, cornea, late wound repair
- ----Defective in osteogenesis imperfecta
- Type II: Cartilage (including hyaline), vitreous body, nucleus pulposus
- **Type II: cartwolage
- Type III: Reticulin - skin, blood vessels, uterus, fetal tissue, granulation tissue
- ----Defective in Ehlers-Danlos **Type III: ThreE D)
- Type IV: Basement membrane or basal laminal
- **Type IV: under the floor (basement membrane)
- ----Defective in Alport syndrome
- **Be (So Totally) Cool, Read Books
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Collagen synthesis and structure
inside fibroblasts
- 1. Synthesis (RER): Translation of collagen α chains (preprocollagen) − usually Gly-X-Y (X and Y are proline or lysine)
- 2. Hydroxylation (ER): Hydroxylation of specific proline and lysine residues (requires Vitamin C; deficiency → scurvy)
- 3. Glycosylation (ER): Glycosylation of pro-α-chain hydroxylysine residues and formation of procollagen via hydrogen and disulfide bonds (triple helix of 3 collagen α chains). Problems forming the triple helix → osteogenesis imperfecta)
- 4. Exocytosis: exocytosis of procollagen into extracellular space
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Collagen synthesis and structure
Outside fibroblasts
- 5. Proteolytic processing: Cleavage of disulfide-rich terminal regions of procollagen, transforming it into insoluble tropocollagen
- 6. Crosslinking: Reinforcement of many staggered tropocollagen molecules by covalent lysin-hydroxylysine cross-linkage (by Cu2+-containing lysyl oxidase) to make collagen fibrils
- -Problems with cross-linking → Ehlers-Danlos
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- Collagen synthesis and structure
- inside and outside fibroblasts
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Osteogenesis imperfecta
- Genetic bone disorder (brittle bone disease) caused by a variety of gene defects
- Most common form is autosomal dominant with abnormal type I collagen
- Presentation:
- -Multiple fractures with minimal trauma; may occur during the birth process
- -Blue sclera due to the translucency of the connective tissue over the choroidal veins
 - -Hearing loss (abnormal middle ear bones)
- -Dental imperfections due to lack of dentin
- Incidence: 1:10,000
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Ehlers-Danlos syndrome
- Faulty collagen synthesis causing hyperextensible skin, tendency to bleed (easy bruising), and hypermobile joints
- 6 types
- Inheritance and severity vary; can be autosomal dominant or recessive
- May be associated with joint dislocation, berry aneurysms, organ rupture
- Type I or Type IV collagen most frequently affected in severe classic Ehlers-Danlos syndrome
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Alport syndrome
- Abnormal type IV collagen; due to a variety of gene defects
- Most common is X-linked recessive
- Presentation: progressive hereditary nephritis and deafness
- May be associated with ocular disturbances
- *Type IV collagen is important structural component of the basement membrane of the kidney, ears, and eyes
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Elastin
- Stretchy protein within skin, lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava (connect vertebrae → relaxed and stretched conformations)
- Rich in proline and glycine, nonhydroxylated forms
- Tropoelastin with fibrillin scaffolding
- Cross-linkind takes place extracellularly and gives elastin its elastic properties
- Broken down by elastase, which is normally inhibited by α1-antitrypsin
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Defective elastin/elastin-related diseases
- Marfan's syndrome: caused by a defect in fibrillin
- Emphysema: can be caused by α1-antitrypsin deficiency, resulting in excess elastase activity
- wrinkles of aging are due to reduced collagen and elastin production
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