Foundations 2 Week 3-2
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Describe the different stages of the cell cycle
- G0: The normal or quiescent phase for cells that are not replicating.
- S phase: DNA is replicated (7.5-10 hours)
- G2 phase: The cell prepares for division, checks for DNA damage and unreplicated DNA.
Compare the cell cycle for cycling cells and non-cycling cells.
- Cycling cells that do not rest (ie, intestinal mucosa) go directly from mitosis to G1.
- Normal: M → G0 → G1 (→restriction phase) → S (DNA replication) → G2 → M
- Cycling: M → G1 (→restriction phase) → S (DNA replication) → G2 → M
What are the two checkpoints in the G1 phase and their role?
- G1 DNA damage checkpoint: Checks for high levels of tumor-suppressing p53 to see if DNA damage has occurred.
- Restriction checkpoint: Checks the cell’s physical size and the state of the cell’s physiological processes.
What are the components and function of stereocilia?
- Stereocilia are composed of unusually long microvilli supported by bundles of actin-filaments anchored to the membrane by ezrin proteins.
- They are very sensitive to mechanical vibration and serve as sensory mechanoreceptors
What proteins control the restriction checkpoint between the G1 – S phases?
- Cyclins D & E activate cyclin-dependent kinases (CDKs) 2, 4, & 6, which phosphorylate pRb (a family of retinoblastoma proteins than prevent E2F transcription), which cause transcription of E2F, which takes the cell past the restriction point.
- Growth factors → proto-oncogenes activated → Cyclins D, E activated → CDKs 2, 4, 6 activated → pRb phosphorylated → E2F transcribed → Restriction point passed, leading to S phase. Note, p53 inhibits CDK activation, delaying the G0 phase.
Where are stereocilia located?
- Stereocilia are limited to the male reproductive system and the inner ear.
- Specifically, they are found in the epididymis, the proximal part of the ductus deferens, and the sensory (hair) cells of the inner ear.
What comprises the core of a microvillus and the terminal web to which they are connected?
- Microvilli contain a core of 20-30 actin filaments with villin (an actin-bundling protein) at the tip and the terminal web (a horizontal network of actin filaments) at the bottom.
- In other words, the core and terminal web (bottom area) are composed of actin filaments.
How does the number and shape of microvilli influence a cell’s absorptive capacity?
- Microvilli provide increased surface area allowing increased absorption. The more surface area available, the larger the absorptive capacity.
- Therefore, longer, densely packed microvilli provide greater absorptive capacity.
What is the morphologic appearance on the apical surface of epithelial cells?
- Motile cilia have a “crew-cut” appearance and appear as short, fine, hairlike structures. A thin dark-staining continuous band of basal bodies appears at the base of the cilia.
What is the function of the 9+2 core structure of motile cilia and how does it interact with the cytoskeleton of the cell?
- The 9 + 2 pattern allows motile cilia to beat (move). Cilia in successive rows start their beat so that each row is slightly more advanced in its cycle than the following row, thus creating a wave that sweeps across the epithelium.
- (9 + 2 means 9 microtubule triplets + 2 center microtubules, for a total of 29)
What is the mechanism by which cilia move and what alteration leads to primary ciliary dyskinesia?
- Cilia produce a rapid effective stroke, propelling mucus forward, then slowly reset their position with a recovery stroke.
- The effective stroke is produced by ATP-powered ciliary dynein, which is located on the A microtubule and attached to the B microtubule.
- ATP causes ciliary dynein to slide along the B microtubule, providing torque. The recovery stroke is caused by the elastic properties of the cilia.
What is Marfan syndrome?
A disorder of connective tissues resulting in skeletal defects and tall, lanky individuals with crowded teeth, curvature of the spine, etc.
What is Cutis Laxa (CL)?
CL, AKA elastolysis, is a rare inherited or acquired disorder where the skin becomes very loose and hangs in folds.
What are the insoluble components of ECM?
- Collagen: resists tensile forces.
- Elastic fibers: made from elastin molecules, joined by covalent bonds) provide recoil after stretch.
- Fibronectin: A glycoprotein dimer secreted by fibroblasts which is important for cell adhesion, growth, migration, differentiation, and wound healing.
- Laminin: A large flexible protein arranged in the shape of an asymmetric cross. Laminin is used as a provisional matrix during wound healing and is found on the leading edge of the dermal-epidermal junction.
Describe the properties of collagen.
- Collagen is strong and resists tensile forces well.
- It is the most common protein in animals.
- Collagen is made by fibroblasts and some epithelial cells.
- Collagen is composed of 3 α chains arranged in a triple helix.
What are the major types of collagen?
- Fibrillar: Types 1, 2, 3, 5, 11. Type 1 is the most common, and is found in skin, scar tissue, arteries, tendons, and pretty much everywhere. Type 2 is hyaline cartilage.
- Sheet forming: Types 4, 8. These form basement membranes and the cornea.
- Connective: Type 6
Describe the properties of fibronectin.
- Fibronectin is a glycoprotein dimer secreted by fibroblasts which is important for cell adhesion, growth, migration, differentiation, and wound healing.
- Along with fibrin, fibronectin forms blood clots.
- Problems with fibronectin have been associated with cancer and fibrosis.
Describe the clinical implication of the extracellular matrix (ECM) in tissue repair.
- Collagen provides structural support (like scaffolding), and may interact with cell receptors to control shape, differentiation, migration, and protein synthesis.
- It is often used in wound dressings to deactivate MMP-1 with EDTA.
What is MMP-1?
- -Matrix Metalloproteinase-1 is collagenase.
- -Some MMPs are granulocyte MMPs, MMP-1 is a macrophage MMP (as is MMP-12).
- -MMPs are inhibited by Tissue Inhibitors of Metalloproteinases (TIMPS).
What is Ehlers–Danlos syndrome (EDS)?
- Ehlers–Danlos syndrome is an inherited heterogeneous group of generalized connective tissue disorders caused by a defect in the synthesis of collagen, specifically mutations in the COL5A and COL3A genes.
- Major clinical manifestations include increased skin fragility, skin hyperextensibility, and joint hypermobility.
What protein is deposited as a provisional matrix during wound healing?
What protein is expressed by keratinocytes at the leading edge of the dermal-epidermal junction?
What are the soluble components of ECM?
polysaccharide chains: Proteoglycans, Hyaluronan, Adhesive glycoproteins
What are GAGs?
- Glycosaminoglycans: A soluble element of ECMs consisting of polysaccharide chains composed of repeating disaccharide units.
- They are called GAGs because one of the two sugars in the repeating disaccharide is always an amino sugar (N-acetylglucosamine or N-acetylgalactosamine), which in most cases is sulfated.
What is Hyaluronan?
- -A very large GAG involved in Joint fluid, wound healing, and development.
- -It is is thought to have a role in resisting compressive forces in tissues and joints.
- -It is also important as a space filler during embryonic development, where it can be used to force a change in the shape of a structure, as a small quantity expands with water to occupy a large volume
Why is p53 considered to be the “guardian of the genome"?
P53 coordinates cellular responses to DNA damage by promoting arrest (so the cell has time to fix DNA), mediates activation of G1/S and G2/M checkpoints, and initiates apoptosis if DNA cannot be repaired.
What are the four phases of mitosis, and how does the mitotic spindle change in each phase?
- Prophase: Chromatids condense and become visible. The nuclear envelope begins to disintegrate. Microtubules of the developing spindle attach to the kinetochores/chromosomes
- Metaphase: The mitotic spindle becomes organized at opposite poles of the cell.
- Anaphase: Sister chromatids begin separating and are pulled to opposite poles of the cell.
- Telophase: The nuclear envelope is reconstructed at each pole, the chromatids decondense, and the cell splits into two daughter cells.
Describe the order of the cell cycle and relative length of phases.
- S phase: 8-12 hours (50 nucleotides/sec)
- M phase: 1 hour
- G1 + G2 : about 11-13 hours
- Interphase: G1 + S + G2 (everything but M phase)
- Bone marrow progenitors: 12-24 hours. Hepatocytes: 150 days. Cardiomyocytes: Never (G0)
What are ERK family enzymes?
ERK family enzymes are MAP kinases (Mitogen-activated protein kinases), which are serine/threonine-specific protein kinases.
What are the different checkpoints, and what do they check?
- G1 checkpoint: Is the environment favorable? Are there mitogens available, etc.
- G2 checkpoint: Is all DNA replicated? Is environment favorable?
- Metaphase checkpoint (aka Spindle-Attachment Checkpoint): Are all chromosomes attached to the spindle?
What is SCF?
SCF is a ubiquitin ligase complex that marks cell cycle proteins for degradation. It helps degrade p27 CKI that restricts G1/S and S phase progression.
What is APC?
APC (anaphase promoting complex) is a ubiquitin ligase complex that marks cell cycle proteins for degradation. It destroys M-cyclin and terminates M phase. (activated by Cdc20)
Cytosol from S phase cells can trigger DNA replication in the G1 nucleus, but not the G2 nucleus. How does it work?
- During G1, a pre-replicative complex (Cdc6+MCM) is formed, allowing entrance into S phase.
- During S phase, S-Cdk helps destroy Cdc6 (using SCF and ubiquitin) and phosphorylates MCM, preventing further DNA replication.
- During M phase, M-Cdk phosphorylates Cdc6 and any remaining MCM to prevent DNA replication.
- There is no more pre-RC in G2 or M, so G1 will need to produce more before progressing.
How do M and S cyclin become active?
M-cyclin combines with CDK to produce M-Cdk, and S-cyclin combines with Cdk to produce S-Cdk. Then Cdk-activating kinase (CAK) makes them fully active.
What are cyclins?
Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase (Cdk) enzymes.
In what order are cyclins activated?
- D = G1 cyclin, E = G1/S cyclin, A = S cyclin, B = M cyclin
- (pretty sure about the correlation).
What is MAD2?
- MAD2 (mitotic arrest deficient 2) is an essential spindle checkpoint protein.
- Mad2 binds unattached kinetochores and blocks Cdc20-APC induced destruction of securin (securin causes chromosome separation in anaphase) and Cdc20-APC activation of separase.
What are p21, p27, and p53?
p21, p27, and p53 are checkpoint proteins that limit G1/S-Cdk and S-Cdk action if there is DNA damage.
What does Cdc20-APC do?
- Destroys: S and M-phase (S/M) cyclins, securin
- Activates: Separase
How do the late G1 and late G2 checkpoints differ?
- Late G1: prevents S phase entry by stimulating p53 (that activates transcription of the CKI called p21 that inhibits both G1/S-Cdk and S-Cdk)
- Late G1 → p53 → p21 → no G1/S-Cdk, no S-Cdk
- Late G2: prevents M phase entry by stimulating kinases that inactivate the Cdc25 phosphatase needed for M-Cdk activation
- Late G2 → kinases inactivate Cdc25 → No MCdk activation
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