Cell Cycle and Disease

Question 1

Cell Replication

Answer 1

As development proceeds, the cell cycle becomes increasingly more complex

In early embryogenesis, only DNA synthesis (S) and mitosis shages of the cell cycle occur

Cell cycle regulators ore maternally derived until the mid blastula stage, when 2 GAP stages are added

Question 2

Cell Cycle

Answer 2

Regulation by growth factors and other cytokines

Shifts in cyclin concentrations regulate movement through each cycle phase

The end result of the cycle is division of a single cell into two identical cells

Question 3

Quiescence: Gap0 (G0)

Answer 3

The cell is not actively replicating and has left the cell cycle

Some cells, once differentiated, permanantly 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)

Question 4

Labile Cells

Answer 4

cells that are always in the cell cycle

Question 5

stable cells

Answer 5

cells that are usually in G0, but that can enter the cell cycle

Question 6

Permanent Cells

Answer 6

Cells that do not enter the cell cycle

Question 7

Interphase

Answer 7

Cells grow and develop in order to be able to divide again.

Consists of:

• Gap 1 - first growth phase
• S phase - DNA replication
• Gap 2 - Second growth phase

This accounts for about 90% of the cell cycle time

Question 8

Interphase:

Gap 1

Answer 8

This is a time of rapid cell growth, with increase in organelles, cellular proteins and biosynthesis

Question 9

Interphase:

S phase

Answer 9

DNA sysnthesis occurs

Question 10

Interphase:

G2 Phase

Answer 10

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

Question 11

Interphase:

M phase

Answer 11

Nuclear Division (Karokinesis) occurs

This is a very short but complex phase

Stages include:

• Prophase
• Prometaphase
• Metaphse
• Anaphase
• Telophase

Cytokines follow with separation into 2 genetically identical cells

Question 12

Cell cycle regulation

Answer 12

Fluxes in Cyclin-Cyclin-Dependent Kinase concentrations move the cell through the cycle

Question 13

G1 checkpoint

Answer 13

Once past this, the cell is committed to cell division

Regulated by G1/S cyclins

Cell must have adequate raw materials for division to pass this point

unhealthy or malnouriched cells can get stuck here

Question 14

G2/M checkpoint

Answer 14

This checks for DNA damage before proceeding to M phase

Regulated by p53

This assures there is enough cytoplasm and membrane phospholipid to form 2 cells

Important decision point on wheter the cell will complete the cell cycle

Question 15

Checkpoints

Answer 15

Metaphase check point assures that all chromosomes are aligned on the spindle before anaphase occurs

Question 16

Aplasia Cutis Congenita (ACC)

Answer 16

Heterogeneous Group of congenital disorders in humans characterized by focal or widespread absence of the skin

Most cases affect the scalp, but can also have defects in the underlyinng bone, dura mater, or cerebral vasculature

Sometimes associated with other abomalies, such as abdominal call defects, limb abnormalities, and cleft anomalies

Question 17

ACC pathogenesis

Answer 17

Mutation in the BMS1 ribosome biogenesis factor fene occurs in ACC that is associated with a delay in 18S rRNA maturation

Influences the 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 (Skin)

Question 18

Epitheliogenesis Imperfecta

Answer 18

Epithelio - epithelium

Genesis - growth

Rare autosomal recessive disorder of skin development

Reported in cats, dogs, calves, sheep, pigs, horses, and various non-domestic species

Term has been used for cases of epidermolysis bullosa wehre the skin is fragile, but present

Term aslo used when skin is absent

Characterized by the absence of focal areas of skin

-common locations include the limbs, back, nose, oral mucosa

Question 19

Canine Mammary Tumors

Answer 19

Most frequent type of tumor found in intact female dogs

Cell cycle associated genes linked with canine mammary neoplasia

• p53
• BRCA1 / BRCA2
• RAD51
• STK11
• PIC3CA

Many of these genes are also associated with mammary neoplasia in humans

Question 20

p53

Answer 20

the most frequent mutated gene in human neoplasia

Mutations found in 50-55% of all human cancers

Mutations found in 15-34% of human breast cancers

Mutations in dogs have been associated with mammary carcinoma

Other neoplasms associated with p53 mutations in dogs

• thyroid adenoma/carcinoma
• oral papilloma
• osteosarcoma
• circumanal gland tumor
• lymphosarcoma

Question 21

Chronic Kidney Disease (CKD)

Answer 21

common in both old cats and aging humans

28-50% of geriatric cats

Clinically there is chronic renal failure

Pathologically there is chronic tubulointerstitial inflammation of fibrosis

Question 22

Transforming Growth Factor-B1

Answer 22

TGF-B1 drives a variety of processes

• activates genes that directly and indirectly induce ECM production
• Induces a mesenchymal phenotype in tubular epithelial cells
• Induces apoptosis at high concentrations
• Inhibits epithelial cell proliferation

Inhibits cell proliferation by inducing G2.M arrest in kidney proximal tubule epithelium through induction of p21

There is a correlation between the precentage of epithelial cells in G2.M arrest and the development of fibrosis

• Arrested cells activates profibrotic pathways
• Interstitial pericytes and fibroblasts proliferate and produce excessibve ECM