Cell cycle and cancer

Question 1

Phases of the Cell cyle

Answer 1

The goal of the cell cycle is to generate 2 identical cells, if not you get cancer

G1 ( gap 1) the cell has choices could senesce (G0) it could differenctiate (G0) it could die (apoptosis) or it could proliferate and continue on the cell cycle. The cell ahas many coiches in this phase and can choose to stay longer in any of those choces so the Tg (generation time) could change

S phase: where synthesis of chromatin occurs (copy the chromatin)–> histones naturally double

G2 phase: prep for M phase, centrosome (scaffolding) duplicates

M phase: mitosis

Question 2

Proteins that regulate the cell cycle

Answer 2

External factors: hormones, cytokines and growth factors (?GF)

Internal factors:
early response factors: myc, fos, jun
delayed factors: cyclins and CDKs (cyclin dependent protein kinases) they can come together and make a Cyclin/CDK protein kinase heterodimer

Question 3

Cyclin/CDK protein kinase heterodimer

Answer 3

Cyclin : regulatory subunit (cyclin D-> E-> A-> B)
amount of cyclin increases during the cell cycle

CDK: catalytic subunit
they phosphorylate target proteins, the content does NOT change during cell cycle, but instead they just get activated
CDK4-> 2> 2> 1

kinases are proteins that reversible that phosphorylate target proteins (usually at S, T and Y residues) that regulate cell cycle the phosphorylation causes a shape change and regulates a proteins activity and its ability to bind to other factors

Question 4

what happens when the Cell-Cycle is induced

Answer 4

This happens during G 1 phase
1. p27 (a CDK inhibitor) concentration goes doen and stays down for the whole cell cycle Cyclin D goes up and STAYS up (this is important bc all other cyclins go back down at some point during the cell cycle)

2 then cyclins E A and B sequentially and transiently increase

Question 5

There are four check point regulators in the cell cycle

Answer 5

Point 1: controlled by Cyclin D/CDK4 (initiation of proliferation)

Point2: controlled by cyclin E/CDK2 (this also called R-restriction point that allows the cell to go into S phase, once passed the cell has to finish the cycle)

Point 3: controlled by cyclin A/CDK2 (occurs throughout S phase)

Point 4: controlled by cyclin B/CDK 1 (gate to M phase)

Question 6

Checkpoint one early G1

Answer 6

controlled by Cyclin D/CDK4
an extra cellular growth factor activates the cells transcription of an intracellular growth factor (myc), then Cyclin D gets upregulated (p27 downregulated)

the Cyclin D/CDK4 dimerize in cytoplasm and phosphorylate retinoblastoma (Rb) which releases E2F

E2F activates gene upregulation of Cyclins E and A

p16 will inhibit the CDK4*

Question 7

Check point 2 “ the restriction checkpoint”

Answer 7

Regulated by Cyclin E/ CDK2

E2F upregulates CyclinE which goes out of nucleus and dimerizes with CDK2 the CyclinE/CDK2 heterodimer goes back into the nucleus and breaches the restriction checkpoint, R, and initiates the S phase

The R, restriction checkpoint, is highly regulated by P53

P53 induces p21 which will bind to CDK2, p53 gene is mutated in 50% of all cancers

P53 can also activate apoptosis

Question 8

Checkpoint 3

Answer 8

Transient throughout S phase
Cyclin A is upregulated by E2F and cyclin heterodimerizes with CDK2 and the dimer comes back into the nucleus to upregulate DNA replication protein complexes

Question 9

Checkpoint 4

Answer 9

Activation of the M phase from G 2 phase

This is a wierd phase because you actually need to de-phosphorylate CyclinB/CDK 1 heterodimer (specifically the CDK) to activate mitosis

This is done by a protein called cdc25 (a phosphatase)

Dephosph. cyclin B/ CDK1 enters the nucleus and phosphorylates like crazy causing the:

• breakdown of nuclear envelope
• assembly of mitiotic spindle
• metaphase arrest

Question 10

Cancer charchteristics

Answer 10

mutations in the genome-> point mutations, chromosome rearrangement, loss, gain
mutant cells clones expand-> tumor
A decrease in cell differentiation and an increase in cell proliferation

becomes pathogenic when it becomes invasive

Question 11

5 gene groups that are mutated in cancer

Answer 11

1. proto-oncogenes
2. tumor suppressor genes
3. genes that regulate apoptosis
4. genes that regulate cell senescence (telomerase)
5. Genes that repair DNA

Question 12

Proto-oncogenes

Answer 12

Proto oncogenes are genes that encode: cell membrane receptors for growth factors, cytoplasmic and transcription factors, cyclins/CDKs (so these are the external and internal growth factors)

when mutated protooncogenes become “oncogenes”
Oncogenes cause pathological activation of the encoded protein-> cell-cycle activation-> tumor

Question 13

Tumor Suppressor Genes

Answer 13

These are proteins that normally suppress the cell cycle

Major tumor suppressors:
p21: inhibits CDK4 and CDK2
p16: inhibits CDK 4 
p53: induces apoptosis and transcribes p21 (cigarrets)
Rb: binds and inhibits E2F
BRCA 1 and 2 repair broken DNA

Mutation inactivate the tumor suppressors

Question 14

Genes that regulate Apoptosis

Answer 14

apoptosis=programmed cell death
Defecticve cells die

Steps in apoptosis: Macrophages secrete TNF-> TNF receptor-> upregulation of Pro apoptotic (Bax)

Bax and anti apoptotic factors (Bcl-2) get unbalanced
Bax goes up in outer mito membrane
Cytochrome c leakes-> caspase protease
Caspase fragments the chromatin-> cell disruption

Mutated apoptosis genes cause cancer
mutated Bcl2 (inhibits apoptosis too much)

Question 15

Genes that regulate Cell senescence

Answer 15

Telomerase
should be inactive in somatic cells
when mutated it causes an immortalization of the cells

Question 16

Genes that repair DNA

Answer 16

self explanatory, if you dont repair your DNA, the cells continue to divide messed up cells-> tumors

Question 17

Remidies to cancer

Answer 17

DNA testing for mutations, most treatments are non specific, target the metastasis, target angiogenisis (choke out the tumor) target specific molecules