Cell Response to OS.

Question 1

What modifications allow Nrf2 activation?

Answer 1

Oxidation of Keap1 Cys residues (151, 288, 273)

Phosphorylation of Serine 40 on Nrf2.

Question 2

Is dimerisation always activatory with Nrf2?

Answer 2

No - in particular, c-Fos dimerisation suggested as a negative regulator.
Maf protein heterodimerisation has a variable response.

Question 3

How has Nrf2 been linked to cancer?

Answer 3

Nuclear expression seen in lung adenocarcinoma patients.
Nuclear expression = worse recurrence-free survival in SCC patients.
Low/ absent keap1 expression found.

Question 4

What is the canonical form of NF-kB?

Answer 4

p50/p65 (NF-kB1/RelA)

Question 5

Why are glucocorticoids believed to be immunosuppressive?

Answer 5

Enhance IkB-a expression - then binds and INACTIVATES NF-kB in cytoplasm –> reduced immune and inflammatory response.

Question 6

How are lymphoid cancers linked to NF-kB?

Answer 6

v-rel oncogene causes lymphomas in chickens.
More transforming than c-rel - less susceptible to IkB inhibition - more stable - different DNA binding properties due to mutations.

Question 7

How can viruses affect NF-kB?

Answer 7

TAX activates IKK.

Can also divert IKK into complexes which stimulate phosphorylation-dependent processing of NF-kB2/p100.

Question 8

How does pregnancy affect NF-kB?

Answer 8

RANKL (a cytokine) produced by mammary epithelial cells during pregnancy.
Autocrine loop through RANK receptor expressed on ME.
RANKL signals to NF-kB via IKKa –> elevated IKK activity seen in breast carcinoma cell lines and primary tumours.

Question 9

What evidence links colon cancer to NF-kB?

Answer 9

UC and Crohn’s have persistent NF-kB activation.
COX2 (NF-kB target gene) overexpressed in colon adenomas.
Aspirin can inhibit IKK and consumption over 10-15 Y associated with reduced colon cancer risk.