The p53 pathway

Question 1

Describe the structure of p53

Answer 1

has a domain structure typical for transcription factors, with distint DNA binding and multimerisation domains

Question 2

What is the most well known job of the p53

Answer 2

tumor supression

Question 3

what are the other positive outcomes of p53 pathway

Answer 3

Development
stem cell modulation
fertility

Question 4

What are the negative outcomes of p53 pathways

Answer 4

Ischemia
Treacher Collins syndrome
Neurodegeneration
Ageing

Question 5

What are the developmental processes effected by p53 pathways

Answer 5

Apoptosis, Autophagy, Cell cycle arrest, DNA repair, Embryo implantation, inhibition of angiogenesis and ROS/survival, innate immunity, metabolsim, senescence, as well as p53 regulation

Question 6

how do NF-kB, p53 and HIF interact

Answer 6

many functions of the 3 pathways overlap, depending on context they either function cooperatively or antagonistically to help determine the response to cell stress

Question 7

What occurs to p53 in a normal cell

Answer 7

-its inactived by its negative regulator, Mdm2

Question 8

what occurs to p53 upon DNA damage or other stresses

Answer 8

-various pathways leads to the dissociation of the p53 and mdm2, activating p53

Question 9

Once activated, what does p53 do

Answer 9

induces a cell cycle arrest to allow either repair and survival or apoptosis to discard the damage cell

Question 10

what is the role of the Mdm2

Answer 10

its a E3 ubiquitin ligase, it promotes the ubiquiitination of p53 which leads to the degradation of p53. This keeps p53 levels low in undamaged cells

Question 11

how does active p53 effect mdm2 levels

Answer 11

active p53 stimulates the Mdm2 gene expression

Question 12

what is the cellular response to DNA damage to both p53 and Mdm2

Answer 12

• p53 is phosphorylated at serine 15 by the ATM or ATR kinase
• Mdm2 is also phosphorylated
• Both these phosphorylation disrupts the interactions

Question 13

What occurs to Mdm2 in cancer

Answer 13

• over-expression of Mdm2 which functionally inactivates the p53 pathways
• this prevents cell cycle arrest and the induction of apoptosis in response to oncogene activation/DNA damage

Question 14

what is p14ARF

Answer 14

a tumour supressor

Question 15

p14ARF expression is induced by what

Answer 15

oncogenes as a result of increased cellular proliferation

Question 16

what is p14ARF role in tumour suppression

Answer 16

disrupts the interactions between p53 and Mdm2

Question 17

how does ARF effect Mdm2

Answer 17

inhibits its ubiquitin ligase activity

Question 18

How does ARF activity effect p53

Answer 18

results in increased levels of transcriptionally active p53

Question 19

In almost all cancer cells find ways to inactivated p53. What are these ways?

Answer 19

• Viral infection (E6) or a loss of function mutation of ATM decreases p53
• Loss of function mutation for ARF and amplification of Mdm2 causes p53 to be inactive
• There could also be a loss of function mutation as well as defects in sub-cellular localisation of p53

Question 20

which domain in p53 is the most mutated in cancer

Answer 20

DNA-binding domain

Question 21

what is Li-Fraumeni syndrome (LFS)

Answer 21

hereditary cancer predisposition

Question 22

what is LFS most commonly caused by

Answer 22

Loss of function mutation in a gene called TP53, which is the gene responsible for p53 protein

Question 23

What percentage of families with LFS will have a mutation in the TP53 gene

Answer 23

70%

Question 24

how do the NF-kB and p53 pathways interact

Answer 24

There has to be a balance between them as they work as opposites
- they’re activity are integrated