Cell Cycle Cancer

Question 1

Phases of the Cell-Cycle

Answer 1

G1 (gap): Cell has choices

S: synthesis of chromatin

G2: Preparation for M-phase

M: Mitosis

Question 2

G1 (gap 1)

Answer 2

• Senescence (Go)
• Differntiation (Go)
• Apoptosis
• Proliferation –> Cell-Cycle

Question 3

S phase

Answer 3

synthesis of chromatin

2N DNA –> 4N DNA

histone proteins replicated

Question 4

G2

Answer 4

prepartion for M-phase

centrosomes duplicates

Question 5

Duration of each phase

Answer 5

S, G2, & M ~ constant (12-24 hrs)

G1 is variable, hence, Total generation time (Tg) is variable

Question 6

Cyclin + CDK

Answer 6

Cyclin-dependent protein kinase heerodimer

Cyclin = regulatory subunit

• content increases during cell cycle

cyclin-D -> cyclin E -> cyclin-A -> cyclin B

G1 ————-> S phase ——–> Mitosis

CDK = catalytic subunit

• CDKs phosphorylate target proteins

content doesn’t change during cycle

CDK-4 –> CDK-2 –> CDK-1

G1 —–> S1 —–> M

Question 7

Kinase

Answer 7

Kinase proteins are enzymes that reversibly attach negatively-charged phosphate groups

PO4- groups are attached to serine [S], threonine [T] & tyrosine [Y] residues

Phosphorylation causes a conformation change that regulates a protein’s activity

Question 8

Cell Cycle Induction

Answer 8

1. Cells moves into G1
2. p27, a CDK inhibitor decreaes and stays low
3. cyclin-D increases and stays high
4. cyclins E,A,B sequentially & transiently increase

Question 9

Cell-Cycle Regulation

Answer 9

4 Checkpoints

1. Cyclin-D/CDK-4 at Go
2. Cyclin-E/CDK-2 before S phase

This is the Restricton Point, once past R, the cell must copy all of its DNA, otherwise it dies

3. Cyclin-A/CDK-2

sustains S phase

4. Cyclin-B/CDK-1 regulates step into M

Question 10

Checkpoint #1: Early G1

Answer 10

regulated by cyclin-D/CDK-4

1. Growth factor activates myc binding to DNA and cyclinD transcription
2. CyclinD binds CDK-4i in cytoplasm
3. CyclinD/CDK4 phosphorylates retinoblastoma (RBO
4. P-Rb releases E2F (a transcription factor)
5. E2F activates genes for cyciin E & cyclin A

Question 11

Checkpoint #2: G1/S “Restriction Checkpoint”

Answer 11

Regulated by cyclinE/CDK2

1 CyclinE binds CDK2

2. CyclinE/CDK2 phosphorylation of target proteins breaches R the Restriction checkpoint, at G1/S to initiate S-Phase

Question 12

p53

Answer 12

tummor suppresor protein

inhibits the cell-cycle at G1/S by inducing p21, which binds/inhibits CDK2

p53 is mutated in ~ 1/2 of cancers

p53 activates apoptosis

Question 13

Checkpoint #3: S phase

Answer 13

Regulated by cyclin-A/CDK2

1. Cyclin A binds CDK2
2. Cyclin A/CDK-2 phosphorylates proteins in DNA replication complexes

Question 14

Checkpoint #4: G2/M-phase

Answer 14

De-phosphorylation of cyclin-B/CDK-1 activates mitosis

1. cdc25, a phosphatase, de-phosphorylates the CDK1 subunit of the cyclin B/CDK1 heterodimer
2. cyclin B/CDK1 -> nucleus -> multiple phosphorylations
   i. nuclear envelope breakdown
   ii. assembly of mitotic spindle
   iii. metaphase arrest

Question 15

Summary

Answer 15

Question 16

Proto-Oncogenes

Answer 16

Normal protein that when mutated causes cancer

Mutations in proto-oncogenes cause pathological activation of the encoded protein

examples: cell membrane receptors for growth factors, transcription factors, cyclins/CDKs

Question 17

Tumor Suppressor Genes

Answer 17

Proteins that normally suppress the cell-cycle

p21 - inhibits CDKs

p53 - induces apoptosis and p21

Rb - binds and inhibits E2F-1

BRCA - repair broken DNA

Mutations inactivate tumor suppressors

Question 18

Genes that regulate Apoptosis

Answer 18

mutated apoptosis genes cause caner

TNF -> TNF receptor –> balances pro-apoptotic & anti-apoptotic factors

pro-apoptotic factors –> mitochondria leak cyctochrome C to cytoplasm –> activates caspase –> chromatin fragmentation –> cell disruption

B Cell Lymphoma has a mutatd bcl-2 gene that over-actively inhibits apoptosis –> tumor

Question 19

Genes that regualte Cell Senescence

Answer 19

Cells have a finite lifespan, beacuse at each generation some telomre DNA is lost from the end of each chromosome

When they shorten to a certain point the cell enters “replicative senescence”

When telomerase is mutatied in somatic cells (usually inactive in somatic cells), it becomes constitutively active, casuing cancer due to immortalized cells.

Question 20

Genes that Repair DNA

Answer 20

BRCA-1 / BRCA-2

Normally, the cell-cycle stops if DNA is damaged

If DNA repair genes are mutated, mutation pile up - clones of abnormal cells

Question 21

Treatments of Cancers

Answer 21

1. Target metastasis
2. Target angiogenesis (prvent new BV growth)
3. Traget specifc molecules