Cell Cycle and Disease Flashcards
1
Q
What is Cell Replication?
A
- Complex and critical to normal cell development and homeostasis
- As development proceeds, the cell cycle becomes increasingly complex
- In early embryogenesis only DNA synthesis (S) and mitosis stages of the cell cycle occur
- Cell cycle regulators are maternally-derived until the mid-blastula stage
- At the mid-blastula transition, the 2 GAP stages are added
- End result is the division of a single cell into 2 identical cells
2
Q
What are key elements of the cell cycle?
A
- Regulation by growth factors and other cytokines
- Shifts in cyclin concentrations regulate movement through each cycle phase
3
Q
What is Quiescence?
A
- Gap 0
- Cell is not actively replicating and has left the cell cycle
- Some cells, once differentiated, permanently enter G0
- Cardiac myocytes, neurons
- Some cells spend large periods in G0, but can re-enter the cell cycle
- hepatocytes
- Some cells never enter G0 and are constantly replicating
- mucosal epithelium
4
Q
What are the different types of cell activity?
A
-
Labile cells
- cells that are always in the cell cycle
-
Stable cells
- Cells that are usually G0, but that can enter the cell cycle
-
Permanent cells
- Cells that do not enter the cell cycle
5
Q
What is Interphase?
A
- Cells grow and develop in order to be able to divide again
- Interphase consists of:
- Gap 1 (First growth phase)
- S phase (DNA replication)
- Gap 2 (Second growth phase)
- Accounts for about 90% of the cell cycle time
6
Q
What is Gap 1 of Interphase?
A
- Time of rapid cell growth
- Increase in organelles, cellular proteins, biosynthesis
7
Q
What happens in S phase of Interphase?
A
- DNA synthesis occurs
8
Q
What happens in G2 phase of Interphase?
A
- Rapid growth and protein synthesis occur in preparation for cell division
- Cell has 2x DNA
- Must pass the G2 checkpoint, which checks for DNA damage, before entering M phase
9
Q
What is the M phase of interphase?
A
- Nuclear division (karyokinesis) occurs
- Short but complex phase
- Cytokinesis follow
10
Q
What are the stages of M phase?
A
- Prophase
- Prometaphase
- Metaphase
- Anaphase
- Telophase
11
Q
What regulates the cell cycle?
A
- Fluxes in Cyclin-Cyclin-Dependent Kinases concentrations
12
Q
What is the GI checkpoint?
A
- Once past this checkpoint the cell is committed to cell division
- Regulated by G1/S cyclins
- Cells must have adequate raw materials for division to pass this point
- Unhealthy or malnourished cells can get stuck here
13
Q
What is the G2/M checkpoint
A
- Checks for DNA damage before proceeding to M phase
- Regulated by p53
- Assures there is enough cytoplasm and membrane phospholipid to form 2 cells
- Important decision point on whether the cell will complete the cell cycle
14
Q
What is the Metaphase checkpoint?
A
- Assures all chromosomes are aligned on the spindle before anaphase occurs
15
Q
Summarize the Cell replication checkpoints
A
- G1 Checkpoint:
- nutrients
- Growth factors
- DNA damage
- G2 Checkpoint:
- Cell size
- DNA replication
- Metaphase Checkpoint:
- chromosome spindle attachment
16
Q
What is the cell cycle’s role in pathology?
A
- Cell division and apoptosis are balanced and integrated physiological processes that regulate homeostasis and health
-
Dysregulation contributes to pathogenesis of:
- Developmental abnormalities
- Neoplasia
- Inflammation
- Vascular disease
- Neurodegeneration
17
Q
What is Aplasia cutis congenita (ACC)?
A
- Heterogenous group of congenital disorders in humans
- Characterized by focal or widespread absence of the skin
- Most cases affect the scalp
- Some cases affect underlying bone, dura mater, or cerebral vasculature
- Sometimes other abnormalities:
- abdominal wall defects
- limb abnormalities
- cleft anomalies
18
Q
Describe the pathogenesis of ACC
A
- Mutation in BMS1 ribosome biogenesis factor gene occurs in ACC that is associated with a delay in 18S rRNA maturation
- Influences cell cycle via a p21-mediated G1/S phase cell cycle transition delay
- Reduced proliferation of skin fibroblasts
- Elevated p21 also inhibits late-stage differentiation of keratinocytes
19
Q
What is Epitheliogenesis imperfecta?
A
- Rare autosomal recessive skin development disorder
- Characterized by the absence of focal areas of skin
- Locations: Limbs, back, nose, oral mucosa
- Other anomalies may occur concurrntly
- Hydronephrosis
- Brachynathia
- Atresia ani
- Ocular anomalies
- Term is also used for cases of epidermolysis bullosa (Fragile skin) and when skin is absent
20
Q
What are canine mammary tumors?
A
- Most frequent type of tumor found in intact female dogs
- Cell cycle-associated genes linked with canine mammary neoplasia include:
- P53
- BRCA1 and BRCA2
- RAD51
- STK11
- PIC3CA
- Many of these genes are also associated with mammary neoplasia in humans
21
Q
What breeds are more susceptible to canine mammary cancer?
A
- Poodles
- Cocker Spaniels
- Chihuahuas
- Boxers
- Dachshunds
- Doberman Pinchers
- Yorkshire Terriers
- Brittany Spaniels
- English Setters
- among others.
22
Q
What is the prevalence of p53 mutations?
A
- Most frequently mutated gene in human neoplasia
- Found in 50-55% of all human cancers
- Present in 15-34% of human breast cancer
23
Q
What canine neoplasias are associated with p53?
A
- Mammary carcinoma
- thyroid adenoma/carcinoma
- oral papilloma
- osteosarcoma
- circumanal gland tumor
- lymphosarcoma
24
Q
How does mutated p53 result in a neoplasia?
A
- p53’s role is regulation of cell proliferation, cell cycle arrest, genome stability, apoptosis, and DNA repair
- Normal p53 facilitates repair or triggers apoptosis of damaged DNA
- Abnormal p53 can result in a failure to arrest the cycle at G1/S or to activate apoptosis when genetically abnormal cells are in the cell cycle
25
Q
What is Chronic kidney disease (CKD)?
A
- Common in both old cats and aging humans
- 28-50% of geriatric cats
- Clinically - chronic renal failure
- Pathologically - Chronic tubulointerstitial inflammation and fibrosis
- By virtue of inducing epithelial cell dedifferentiation, cell cycle arrest, and apoptosis, TGF-B1 likely has prominent role in the pathogenesis of feline CKD
26
Q
What is the function of Transforming Growth Factor-β1? (TGF-β1)
A
- Activates genes that directly and indirectly induce ECM production (Fibrosis)
- Induce a mesenchymal phenotype in tubular epithelial cells
- Induces apoptosis at high concentrations
- Inhibits epithelial cell proliferation
27
Q
How does TGF-β1 inhibit cell proliferation?
A
Induces G2/M arrest in kidney proximal tubule epithelium through induction of p21
28
Q
What is the correlation between G2/M arrest and fibrosis?
A
- Arrested cell activate profibrotic pathways
- Interstitial pericytes and fibroblasts proliferate and produce excessive ECM
