final - molecular biology of neoplasia 1 and 2

Question 1

name three types of genes involved in cancer

Answer 1

• oncogene
• tumor suppressor gene
• caretaker gene

Question 2

what is a protooncogene?

Answer 2

Gene that encodes a protein that stimulates or mediates cell proliferation; normal counterpart to an “oncogene;” typically activated by gain of function mutations

Question 3

what is an oncogene?

Answer 3

Activated proto-oncogene, via either mutation or aberrant expression (over-expression or ectopic expression via chromosome rearrangement) that can promote cell growth in absence of normal mitogenic signals (autonomous proliferation); roughly 100 identified

Question 4

example of a growth factor protooncogene

Answer 4

v-sis (these are rare)

Question 5

what is an autocrine stimulation loop?

Answer 5

when a cell is stimulated to produce both a GF and its receptor simultaneously (PDGF/PDGF receptor)

Question 6

what types of proteins can be encoded by oncogenes? (6)

Answer 6

• growth factors
• growth factor receptors
• signal transduction proteins
• nuclear regulation factors
• cell cycle proteins (cyclins)
• steroid type growth factor receptors

Question 7

most common way for oncogene to affect growth receptors

Answer 7

• over expression of normal receptor

- ex. EGF-R family over expressed in 80% of squamous cell carcinomas

Question 8

why are tumor suppressor genes (TSG) referred to as recessive oncogenes?

Answer 8

both alleles must be knocked out, which differentiates them from oncogenes

Question 9

name some types of tumor suppressor genes

Answer 9

• transcription factors
• cell cycle inhibitors
• signal transduction molecules
• cell surface receptors

Question 10

explain loss of heterozygosity (LOH) in TSGs

Answer 10

• almost all familial cancer involves one TSG mutation. When the complement allele is mutated there is loss of heterozygosity
• usually recombination or nondisjunction
• point mutation rare because usually repaired

Question 11

what proteins regulate Rb?

Answer 11

cyclin D/CDK

Question 12

what does Rb do?

Answer 12

• regulates G1/S phase transition
• key negative regulator of cell cycle
• shuts down E2F which is a TF for genes that promote cell cycle progression

Question 13

what effect does a mutation in Rb have?

Answer 13

• removes key negative regulator of cell cycle

- LOH in Rb seen in many types of cancers

Question 14

what does p53 do?

Answer 14

• induces apoptosis upon DNA damage
• guardian of the genome
• induces CD inhibitor p21 which shuts everything down at G1 and G2 and allows time for repair
• apoptosis through BAX if repair fails

Question 15

result of p53 mutation

Answer 15

• in 50% of cancers

- increased mutation rate

Question 16

unique quality of p53 mutations

Answer 16

can be a dominant negative allele, knocking out the other allele

Question 17

why do some cancers over express p53?

Answer 17

a common mutation is MDM2 oncogene which increases the half life of p53

Question 18

two mechanisms for evading apoptosis

Answer 18

• dysregulation of anti-apoptotic signals

- loss of pro-apoptotic signals

Question 19

what is senescence and how can it be avoided?

Answer 19

• normal process by which cells enter G0 and stop dividing

- loss of Rb or p53 can circumvent this and multiply until crisis

Question 20

what is immortalization

Answer 20

a cell finds a way to avoid senescence, for example by reactivation telomerase

Question 21

what is required for angiogenesis?

Answer 21

• increased ratio of angiogenic inducers to anti-angiogenic regulators, knowns as “angiogenic switch”
• can happen during wound healing
• induced by cancer cells

Question 22

name some common angiogenic inducers

Answer 22

• VEGF

- bFGF

Question 23

define the steps that lead to tumor metastasis and the proteins involved (8 steps)

Answer 23

1) detachment and decreased cellular adherence: loss of cadherins
2) matrix degradation: increase of metalloproteinases and decrease in TIMPs
3) cell matrix attachments: integrins
4) angiogenesis: VEGF/VEGF receptors
5) motility and migration: GFs, cytokines, matrix molecules
6) vascular extravasion: integrins, host platelets, fibrin, and clotting factors
7) avoiding immune surveillance: cloaking of tumor antigens, inactivating leukocytes
8) survive and proliferate: first capillary bed? homing mechanism?

Question 24

briefly explain monoclonality and clonal evolution

Answer 24

• mutations get passed on and subsequent divisions have additional mutations. can look at early lesion and find origin of mutations.