Responding to Hypoxia

00:01 Okay, this is just an example.

00:02 This is just an example of how proteasomes are important and how diseases occur when we don't have the appropriate sequence of events.

00:11 So, how do we respond to hypoxia? Low oxygen levels.

00:15 We don't just give up and we don't try to find new oxygen.

00:18 We have cellular ways of responding. How does this happen? Well, as you might expect, it involves proteasomes.

00:26 So, under normoxic conditions, that is to say 21% as we walk around, we have regular levels of oxygen, and they interact with a protein factor called, a transcription factor called HIF-1-alpha.

00:42 Hypoxia inducible factor one, that's what HIF stands for.

00:47 And with high levels or normal levels of oxygen, we get hydroxylation of that protein, HIF-1-alpha, and that OH is what you see on the next little one, and we get a conformational change.

00:58 That conformational change under normal oxygen conditions is recognized by another protein called Von Hippel-Lindau.

01:05 This is based after the doctor who discovered the disease associated with the mutated form of this.

01:10 We'll peek back to that in a minute.

01:11 Anyway, Von Hippel-Lindau, that protein binds to this now rearranged hydroxylated protein, and targets it for ubiquitin linkage and degradation.

01:24 So, we get rid of the HIF-1-alpha transcription factor.

01:28 That's under normal hypoxic conditions, so we don't get any signaling through that.

01:32 Perfect, that's when it's working properly.

01:35 And it does that by targeting HIF-1-alpha to the proteasome and we get our little peptide fragments. Beauteous, nice job.

01:44 Now, under hypoxia, we don't have the normal oxygen levels, so we don't get the proline hydroxylation.

01:52 And the HIF-1-alpha doesn't have that conformational change, so Von Hippel-Lindau doesn't bind to it, the ubiquitin doesn't ligate to it, and we don't target to the proteasomes, so now the HIF-1-alpha in our bottom slide is present in high levels, can get across the membrane, joining with its buddy, HIF-1-beta, bind to hypoxia response elements, that's HRE, and then we get transcription of proteins that are going to be important for saving the cell under low oxygen conditions.

02:24 So, that includes changing metabolism from systems that will utilize oxygen to anaerobic metabolism.

02:34 It also means that we will make more erythropoietin appropriately so that we get more red blood cells.

02:41 That's an appropriate effect if we're feeling hypoxic.

02:44 It also means that we will induce new blood vessel formation.

02:47 So, there are a variety of effects that happen when we get HIF-1-alpha getting across into the nucleus because it didn't undergo that modification.

02:55 Okay, so that's the way it's supposed to work.

02:58 Now, let's mutate it. Let's do what Dr. Von Hippel-Lindau did when he kind of discovered this disease.