Block 3 Lecture 6 -- Tumor Suppressors

Question 1

What is Rb?

Answer 1

protein that is a negative regulator of S-phase proteins (inhibits G1 to S transition)

Question 2

What are the 4 major domains of p53?

Answer 2

1) DNA-binding, 2) oligomerization, 3) regulatory, 4) transactivation and MDM2-binding

Question 3

How does p53 bind DNA?

Answer 3

as a tetramer

Question 4

What is p53?

Answer 4

a transcription factor that regulates transcription of growth arrest and apoptotic factors

Question 5

What are the big-picture functions of p53?

Answer 5

prevent the passing on of mutated DNA through: 1) inhibit angiogenesis, 2) DNA repair, 3) apoptosis, 4) cell cycle arrest

Question 6

How is p53 activated?

Answer 6

1) DNA damage, 2) cell stress (hypoxia, nucleotide depletion), 3) aberrant growth signals and oncogene activation

Question 7

What is the pathway where p53 is activated by DNA damage?

Answer 7

ATM kinase activated – ChK2 kinase – results in p53-P

Question 8

What is the pathway where p53 is activated by cell stress (hypoxia, nucleotide depletion)?

Answer 8

ATR kinase activated – casein kinase II – results in p53-P

Question 9

When is p53 active?

Answer 9

when the p53 - MDM2 interaction is interrupted?

Question 10

How is the p53 - MDM2 interaction interrupted?

Answer 10

1) low [MDM2], 2) p53-PO4, 3) p14arf - an oncogene product that binds MDM2

Question 11

How is p53 inactivated?

Answer 11

p53 degradation or MDM2 suppression

Question 12

How is p53 degraded?

Answer 12

ubiquitin

Question 13

How is MDM2 suppressed?

Answer 13

1) nuclear export, 2) inhibition of transcriptional activity

Question 14

What are p63 and p73?

Answer 14

proteins related to p53 but not tumor suppressors

Question 15

How can viruses cause cancer without mutating p53 or Rb?

Answer 15

viral proteins (E6 and E7 of HPV) bind to and soak up tumor suppressor proteins

Question 16

What are the specific end-results of p53 to accomplish its big-picture goals?

Answer 16

1) inhibit cell cycle by inducing p21 transcription, 2) induce apoptosis by activating Bax transcription and inhibiting Bcl-2 transcription, 3) induce DNA repair by inducing XPC transcription, 4) inhibit angiogenesis by inducing thrombospondin transcription

Question 17

Where do most p53 mutations occur?

Answer 17

DNA-binding domain

Question 18

Describe most p53 mutations?

Answer 18

usually missense, and almost always in DNA-binding domain. Mutants almost always more stable than wildtype

Question 19

Where do other p53 pathway mutations occur?

Answer 19

Chk2 and MDM2

Question 20

Which tumor suppressors follow the 2-hit hypothesis?

Answer 20

RB, BRCA1/2, p53