Madura - Hif-1 and Altitude

Question 1

Von Hippel Landua (VHL)

Answer 1

Basically Hif-1 is constitutively made and then immediately degraded. But we can also have the VDU2 enzyme come and release the multi-Ub chain from Hif-1 so that it is not degraded.

Question 2

PDH 1,2,3

Answer 2

It puts an OH group onto Hif-1alpha so that it can be recognized by VLH. If we are in hypoxic conditions, then we ubiquinate and destroy PDH 1,2,3 so that Hif-1 is not hydroxylated so it can join Hif-1beta and cause transcription of hypoxia genes

Question 3

VHL in hypoxic conditions

Answer 3

In hypoxic conditions it gets ubiquinated and degraded so that Hif-1alpha can continue through the process even though it has an OH group on it.

Question 4

VDU in hypoxic conditions

Answer 4

Another way that we can get from normoxia to hypoxia is by using the VDU protein which essentially dismantles the ubiquitin chain and thus allows it to enter the nucleus and induce transcription

Question 5

Body under stress - Fe2+ mechanism

Answer 5

Body under stress - mitochondrial damage will cause Fe2+ to be oxidized to Fe3+ through ROS. Fe2+ is a cofacter for PDH1,2,3 - Fe3+ is not. When this happens, the pathway to degrade Hif1 does not proceed and we see that Hif1 stays on and transcription occurs

Question 6

ubiquitin pathway in inflammatory response pathway

Answer 6

1) making p65/50 out of p105.
2) labeling IkappaBalpha for destruction
3) activating NFK complex to activate IkappaBalpha

Question 7

mir210

Answer 7

It is a microRNA that is activated in hypoxic conditions and shuts down normoxia genes.

Question 8

mTOR, S6 kinase pathway

Answer 8

Essentially all translation is stopped in hypoxic conditions. Therefore the mTOR, S6 kinase pathway is responsible for selectively translating the Hif-1 mRNA.

Question 9

mTOR and proteasome inhibitors in cancer therapy

Answer 9

mTOR = rapamycin and everolimus
Proteasome = Bortezomib, Carfilzomib

Question 10

Hif-1 subunits

Answer 10

It is a heterodimer made up of alpha and beta subunit. There are 3 types of alpha. Alpha is in cytosol and beta is in nucleus. In order for hypoxic response, alpha must come into nucleus and bind beta.

Question 11

Are hypoxic conditions always a bad thing?

Answer 11

No. We see low oxygen levels as blood travels through the body. Hypoxia is also the proper stimulus required for wound healing and embryogenesis.