Tumour suppressors

Question 1

which was the first tumour suppressor gene discovered

Answer 1

RB1

Question 2

what is the result of loss of RB

Answer 2

increased risk of osteosarcoma

Question 3

which virus is related to RB inactivation

Answer 3

HPV

Question 4

what is the role of RB in the cell cycle

Answer 4

cyclin D and E phosphoryate Rb in the G1 phase. this inactivates it, releasing E2F ad driving the cell cycle into S phase

Question 5

what is E2F

Answer 5

a very promiscuous transcription factor involved in up regulation of DNA synthesis, metabolism, repair, mitosis, cell cycle, apoptosis and chromatin remodelling factors

Question 6

how does Rb normally inhibit E2F

Answer 6

it stops binding to promoters and can also bring in other transcription repressor proteins

Question 7

how can Rb mutation also lead to secondary mutations such as an altered spindle

Answer 7

it leads to overexpressin of MAD2 which causes issues with spindle formation, preventing correct chromosome alignment and distribution

Question 8

what can be the result of Rb inactivation in an ageing cell

Answer 8

hyperproliferation as Rb regulates chromatin structures which activate senescence t

Question 9

what is the effect of COX2 overexertion in tumour cells as a result of Rb mutations

Answer 9

plays a role in motility and invasion leading to metastasis

Question 10

in what prcentage of cancers is P53 mutated

Answer 10

50

Question 11

which syndrome is a result of P53 mutations

Answer 11

Li-Fraumeni syndrome

Question 12

what does P53 do

Answer 12

it controls Ras expression, is thought to be involved in senescence due to its role in up regulating p21 which inhibits Rb, inhibiting release of E2F resulting in senescence. it also mediates apoptosis by recognising over expression of oncogenes or DNA damage and demonstrates action as a transcription factor under oncogenic stimuli in which case it forms a tetramer which is translocated to the nucleus to bind promoters containing the P53 response element, resulting in transcription of various genes involved in cell-cycle control, apoptosis, DNA repair, senescence and differentiation. Finally it forms interactions with apoptotic suppressor proteins to prevent inhibition of BAX protein which is responsible for forming pores in the membrane

Question 13

how is P53 regulated

Answer 13

mdm2 binds p53 inhibiting it as a transcription factor forming a auto regulatory loop. in the cytosol it can also be modified which will either stabilise or degrade it

Question 14

how do oncogenes promote p53 stabilisation

Answer 14

upregulate ARF which binds MDM2 and relocates it to the nucleus

Question 15

what are the 9 signals that effect p53

Answer 15

oxidative stress, NO, hypoxia, ribonucleotide depletion, mitotic apparatus dysfunction, oncogene activation, DNA replication stress, double stranded breaks and telomere erosion

Question 16

how does mutated p53 cause tumour progression

Answer 16

mutant binds with wt to prevent it binding promoters or changes the properties of p53 so it binds proteins it otherwise wouldn’t resulting in hyper proliferation and differential gene expression. it an cause genomic translocations and aberrant gene expression and gain of function mutants can up regulate anti-apoptotic genes and repress pro-apoptotic

Question 17

how can p53 mutants be treated with gene therapy

Answer 17

infect with adenovirus delivering wt p53

Question 18

what is PRIMA-1

Answer 18

it is a therapy for p53 mutations which reverses mutations and corrects DNA binding ability so that it will bind to the correct promoter elements within the genome. this is in clinical trials