Lecture 16 - Checkpoint control

Question 1

What is MIC?

Answer 1

MIC - localsied in nuclues. Mmener of BHLH family. Its a TF. Forms dimers and assoicites with gene proimoters.

Question 2

What are the 3 dimer formations of MIC?

Answer 2

1. MYC-MAX - BAD
2. MAD-MAX
3. MYC-MIZ

Question 3

What does MIC inhibition result in?

Answer 3

MYC inhibition results in tumour regression.

Question 4

What are the 2 typoes of MIC inhibitors?

Answer 4

1. Direct - blocks dimerisation of MIC-MAX, cannot bind to DNA
2. Indirect - interfere with MYC expression at transcriptional level

Question 5

What do Micro3 and Tamoxifen do?

Answer 5

Micro3 - small molecule inhibitor of the MYC-MAX. leads to tumour shrinkage and decreased proliferation.
Estrogen/ Tamoxifen - drives MYC translocation into the nucleus activating MYC

Question 6

How does TGFbeta counteract MYC?

Answer 6

TGFbeta prevents PRB phosphorylation so cell cycle is stopped. Counteracts MYC by inhibiting its expression and allows CKIs to be expressed
Cdk4/6 are inhibited to Stop cell cycle
Activates p21CIP1 and p15INK4B

Question 7

What are the ways TGFbeta can be inactivated?

Answer 7

1. Mutations in SMAD2,3 and 4
2. TGFbeta1 activity is reduced
3. When you get a tumour TFGbeta switches and promotes the tumour

Question 8

What happens to cells when TGF is inhibited?

Answer 8

TGFbeta regulates epithelial-to-mesenchymal transitions EMT.
So when it is inhibited there is less metastasis and invasiveness
Cancer cells are stimulated by TGFbeta in order to increase their cell proliferation because of the expression of Cytokines and GFs

Question 9

What does the hyperactivation of p13K/Akt pathway do?

Answer 9

Hyperactivation of p13K/Akt pathway inactivates the cytostatic activity of TGFbeta

Question 10

What are the 4 targets if TGFbeta signalling?

Answer 10

1. Antisense oligonucleotides
2. Receptor kinase inhibitors
3. Antibodies sequestering ligands
4. Neutralising antibodies that intercept receptor-ligand interaction

Question 11

What is p53?

Answer 11

p53 is a TF that regulates cell growth and is a tumour suppressor gene, and apoptosis

Question 12

How does p53 gain mutation?

Answer 12

Gains mutations from in its DNA binding domain

Question 13

What happens when there is DNA damage in the cell cycle?

Answer 13

When thers damage there’s a rapid increase in p53
Due to post-translational stabilisation

Controlled by MDM2 - Ubiquinates and degrades p53 in the absence of stresses that activate p53

When there is stress p53 is phosphorylated, blocking the MDM2 binding. Mediated by ATM, ATR and CHK2

ATM can phosphorylate MDM2 so it is inactive

GFs induce MDM2

Question 14

What doe p53 mediate and upregulate?

Answer 14

p53 mediates all the 3 checkpoints of the cell cycle and upregulates p21CIP1

Question 15

What does MYC-MAX do?

Answer 15

MYC-MAX - Promotes proliferation and inhibits differentiated. Leads to elevated levels of Cyclin D.

Question 16

What does MAD-MAX do?

Answer 16

MAD-MAX - Inhibts proliferation but promotes differentiation.

Question 17

What does MYC-KIZ do?

Answer 17

MYC-MIZ - Represses CKI transcription and liberates Cyclin E from inhibition. Promtes degradation of p27KIP1 and progression through r point