Integrated Cell Cycle & Death

Question 1

What are the 6 hallmarks of cancer?

Answer 1

ARISER

1. Angiogenesis
2. Resisting cell death
3. Invasion and metastasis
4. Sustained proliferation
5. Evade tumor suppressor
6. replicative immortality

Question 2

What do proto oncogenes code for?

What happens if this is increased/mutated?

Answer 2

code for proteins that promote cell proliferation or inhibit apoptosis.
Altered expression or mutation causes it to become an oncogene, with GAIN in function, which is a characteristic of cancer cells.

Question 3

What do tumor suppressor genes code for?

What happens if this is mutated?

Answer 3

Proteins that inhibit cell cycle progression, or promote apoptosis.
If these are mutated, it causes uncontrolled cell proliferation. Loss of function here.

Question 4

What function/loss of function is needed for cancer?

Answer 4

You need increased proliferation, loss of tumor suppressor function, and loss of apoptosis (accelerator stuck, brakes out, and can’t shut off car) and the ability to recruit new blood vessels (angiogenesis) if it is to metastasize.

Question 5

In sporadic colon cancer, what is the first mutation, and then what happens after?

Answer 5

First is loss of APC expression, which happens in 90% of all sporadic colon cancer cases
Then, mutation that permanently turns on K-Ras, essentially a proto oncogene.
Then, you lose tumor suppressor p53.
These, along with other mutations, causes a carcinoma and malignancy.

Question 6

what are the 3 ways proto oncogenes become oncogenes and gain function?

Answer 6

1. Mutation
2. Chromosomal translocation
3. Amplification

Question 7

How can growth factors and receptors be proto-oncogenes besides always being active? How does T-cell leukemia show this?

Answer 7

Some cancer cells promote their own growth by producing growth factors and receptors, and using an autocrine pathway. Since growth factors trigger entry into G1 phase of the cell cycle, this increases function.

T-cell leukemia produces interleukin-2 and interleukin-2 receptor, increasing its own growth

Question 8

How does breast cancer relate to mutations in growth factors and receptors being constitutively active? How does trastuzumab work?

Answer 8

Her2 receptor doesn’t need ligand to be on, upregulating growth.
Trastuzumab is an antibody to the mutated Her2 protein (Neu), which keeps it from working. Treatment for breast cancer.

Question 9

What is the Erb2 oncoprotein?
What type of cancer is this commonly seen in?
Treatment?

Answer 9

ERb2 oncoprotein is a constitutively active EGFR due to a deletion of its extracellular portion. Commonly seen in lung cancer.
Gefitinib (EGFR tyrosine kinase inhibitor) developed to treat this.

Question 10

Ras G protein mutations most commonly seen in what type of cancer?
What happens?

Answer 10

Pancreatic cancer

Mutation leads to decreased GTPase activity, so Ras G protein is left on, increasing MAP Kinase pathway.

Question 11

B-Raf mutation seen in melanomas. What is B-raf?

Treatment does what? What is the treatment? What issue arises?

Answer 11

It’s a MAP kinase kinase kinase.

Mutant kinase inhibitor developed (Vemurafinib) that only blocks the mutants… seemed great until resistance was build.

Question 12

Chronic myelogenous leukemia is due to what type of mutation?
What happens? Treatment?

Answer 12

Translocation mutation. Translocation of chromosome pieces making the Philadelphia chromosome.
Abl kinase gets messed up.
Gleevac a good treatment for it, and other cancers

Question 13

What is myc? What does it activate?

Answer 13

TF that activates cyclin D and E2F.

Question 14

Note: STAT-3 inhibitor could be used to treat cancer because it binds and blocks stat 3

Answer 14

.

Question 15

AMPLIFICATION of what gene is commonly seen in breast cancers?

Answer 15

cyclin D gene.

Question 16

TGF-β pathway mutations would be oncogene or tumor suppressor?
What would you get decreased production of? What did these proteins do?

Answer 16

Tumor suppressor.
It’s a negative regulator of cell growth. Mutations in either receptors or SMADs.
DECREASED PRODUCTION OF p15 and PAI-1!!
p15 is an inhibitor of cyclin D-CDK4 complexes, and PAI-1 is involved in inhibiting breakdown of ECM proteins.

Question 17

What is special about Rb?
What happened to cause the problem?
What happens when mutated?

Answer 17

First tumor suppressor to be described.
Patients were originally heterozygous, but had loss of it. Then, both alleles lacked it.

W/O Rb, E2F is always on and doesn’t require cyclin D-CDK4,6 complexes to activate.

Question 18

p21 CIP family and INK4 family are examples of what kind of inhibitors? oncogenes or tumor supp?
What do each do? Be specific on the INK4

Answer 18

CDK inhibitors. tumor suppressors.
p21 CIP family bind cyclin-CDK complexes and stop kinase activity. Considered *universal inhibitors because they work on so many.

INK4- inhibitors of cyclin D-CDK4,6 only (G1 checkpoint). Includes p15 and p16.
p16 blocks cyclin D-CDK4, and mutation in it is seen in hereditary melanoma. Loss of it is similar to upregulating cyclin D. Rb gets phosphorylated at a faster rate, and cell gets pushed through restriction point.

Question 19

Note; Anti-apoptosis oncogenes are NOT one of the before restriction point ones!!!

Answer 19

.

Question 20

Both p21 and INK4 families are examples of?

Answer 20

CHECKPOINT CONTROL PROTEINS.

Question 21

Most commonly mutated tumor suppressor in all cancer?

How does it work? What does it do?

Answer 21

p53. Also a key checkpoint regulator at G1 and G2. TF that gets degraded rapidly, so usually at low levels in cell. Under DNA damage or stress, p53 is stabilized and can activate transcription. **Induces expression of p21 CDK inhibitor.
So, it blocks cell cycle progression, giving cell time to heal.

It also activates pro apoptotic proteins, and activates DNA repair enzymes.

Question 22

If you lose p53, what all happens? 3

Answer 22

inability to stop cell cycle
Can’t induce DNA repair
Loss of apoptosis.

Question 23

BRCA1 also plays a role in…?
Functions as?
What does it enhance?
What checkpoints?

Answer 23

DNA damage induced cell cycle checkpoints
Functions as scaffold protein
Increases p53 stabilization and function
Functions at S phase and G2/M checkpoints

Question 24

How can cancer cells be immortal?

Answer 24

They induce telomerase translation, which shouldn’t be active in adults. This keeps the DNA long so that it never goes under apoptosis due to losing genetic information. Doesn’t seem to cause DNA instability.

Question 25

what triggers DNA replication?

Answer 25

cyclin A-CDK2 phosph. of proteins in prereplication complex.

Question 26

rtk, ras, raf (cell signaling) oncogene or tumor supressor?

Answer 26

oncogene

Question 27

trans. factors, cell cycle proteins, and anti apoptotic proteins are oncogenes or tumor supp?

Answer 27

oncogenes.

Question 28

p21 activated by?

Answer 28

p53