The Cell Cycle and Cancer

Question 1

What are oncogenes and how do they behave?

Answer 1

Genes that when mutated or expressed at abnormally high levels contribute to converting a normal cell into a cancer cell.
They are mutated in ways that render the gene constitutively active.
They usually behave as dominant.

Question 2

What are tumour suppressor genes?

Answer 2

Genes whose protein products suppress tumour formation by inhibiting progression through the cell cycle.

Question 3

What is the Knudson’s double hit hypothesis?

Answer 3

Both copies of a tumor suppressor gene must be lost or mutated for cancer to occur. A person who carries a germline mutation in a tumor suppressor gene has only one functional copy of the gene in all cells. For this person, loss or mutation of the second copy of the gene in any of these cells can lead to cancer.

Question 4

What is the period between mitosis and interphase called and what happens here?

Answer 4

G1 phase - growth and preparation of chromosomes for replication.

Question 5

What is the period between interphase and mitosis called and what happens here?

Answer 5

G2 phase - growth occurs, synthesis of new ribosomes, membranes, ER and cellular proteins

Question 6

What are cyclins?

Answer 6

Proteins that are formed and degraded during each cell cycle and act as regulators of CDKs.

Question 7

What is the G1 CDK?

Answer 7

CDK4

Question 8

What is the S-phase CDK?

Answer 8

CDK2

Question 9

What is the M-phase CDK?

Answer 9

CDK1

Question 10

By what two distinct mechanisms can Rb regulate E2F-dependent transcription?

Answer 10

1. Rb binds to the transactivation domain of E2F family members and blocks their ability to activate transcription.
2. Rb can interact with Histone deacetylases and chromatin remodelling factors. The interaction of Rb with E2F allows these chromatin remodelling enzymes to be targeted to promoters where they can promote nucleosome assembly, and prevent transcription.

Question 11

What do the E2F family of transcription factors do?

Answer 11

They play an important role in the G1 to S phase transition of the cell cycle.
They regulate genes encoding proteins involved in DNA synthesis, CDK2 and cyclins A & E.

Question 12

What are the three mechanisms of quality control in the cell cycle?

Answer 12

DNA damage checkpoints
Monitoring okasaki fragments
Spindle checkpoints

Question 13

What are the two families of CDK inhibitors?

Answer 13

1. INK4a family of inhibitors

2. CIP family of proteins.

Question 14

In which cancer is the p16INK4a gene commonly inactivated?

Answer 14

Pancreatic cancer

Question 15

What does overexpression of INK5 family members result in?

Answer 15

Inhibition of progression through G1

Question 16

What is the role of p21?

Answer 16

It facilitates Cyclin D-CDK4/6 complex formation.

Question 17

What happens if DNA damage occurs during G1 and before S phase?

Answer 17

p53 usually binds MDM2 and is degraded by proteolysis.
If ATM and ATR sense DNA damage they will phosphorylate p53 on Ser15 OR CHK2 kinase will phosphorylate p53 on Ser20.
p53 then activates the transcription of p21 gene which leads to G1 arrest and blocks entry into S phase.

Question 18

What gene is mutated in 90% of pancreatic cancers?

Answer 18

K-ras.

Question 19

What is Smad4?

Answer 19

A tumour suppressor gene for pancreatic cancer, mutated or deleted in at least 50% pf pancreatic cancers.

Question 20

What did Jones et al. (2008) find out about pancreatic cancer?

Answer 20

That pancreatic cancers contain an average of 63 genetic alterations, the majority of which are point mutation.

Question 21

What are the effective treatments for pancreatic cancer?

Answer 21

Resection (possible in 20% of patients)
Fluoropyrimidines - 5FU, Capecitabine (oral form),
Gemcitabine,
FOLFIRINOX ,
Paclitaxel.

Question 22

What are the statistics regarding the efficacy of common chemotherapeutics for pancreatic cancer?

Answer 22

Fluoropyrimidines (5FU) and Gemcitabine are equally effective (i.e. median survival* of ~23 months for patients treated with either drug after surgery).
The gemcitabine–capecitabine beneficial to patients with metastatic pancreatic cancer (not eligible for surgery; 19.1% response with gem versus 12.4% gemcap).
And now in resectable cases also, with almost 30% 5-yr survival survival for gemcap.

Question 23

What drugs make up the FOLFIRINOX combination of drugs?

Answer 23

leucovorin (folinic acid),
three chemotherapy drugs:
- fluorouracil (5-FU), 
- irinotecan 
- oxaliplatin.

Question 24

Treatment of which cancers is gemcitabine first line therapy for?

Answer 24

various types of solid tumors including pancreatic, NSCLC, breast, and some blood cancers, non-Hodgkin’s lymphoma.

Question 25

What is the function of gemcitabine?

Answer 25

Gemcitabine is a nucleoside (pyrimidine) analogue.
The triphosphate analogue of gemcitabine replaces the cytidine during DNA replication. Only one additional nucleoside can be attached to the ‘gemcitabine’ nucleoside, resulting cell cycle arrest and apoptosis.
Another target of gemcitabine is the enzyme ribonucleotide reductase (RNR).
The diphosphate analogue binds to RNR active site and inactivates the enzyme irreversibly.
cell cant produce the deoxyribonucleotides needed for DNA replication and repair.
Cell cycle arrest and apoptosis is induced.