Resulting Condition: von-Hippel-Lindau Disease

00:01 So, this is normoxia. We have the Von Hippel-Lindau protein.

00:05 It's actually -- it phosphorylated, binding to the conformational rearrangement with the hydroxylated HIF-1-alpha, inducing ubiquitin to bind, and we get it degraded.

00:15 Awesome. What happens if our Von Hippel-Lindau can't bind? So, this is showing hypoxia. That's the appropriate response.

00:26 It can't bind, we don't degrade HIF-1-alpha, we get all those wonderful benefits of having the HIF-1-alpha go to the nucleus.

00:32 Now, we have a mutated protein.

00:35 This one cannot bind to the hydroxylated HIF-1-alpha.

00:40 So, even though we have normal levels of oxygen and normal HIF-1-alpha kind of responses, it's undergone this proline hydroxylation.

00:47 The phosphorylated Von Hippel-Lindau cannot bind.

00:51 And so, now, we're not degrading the HIF-1-alpha.

00:54 And now, we have a lot of the transcriptional activity.

00:57 That's what happens in the disease, Von Hippel-Lindau syndrome.

01:01 So, it's loss of the function of the VHL, the Von Hippel-Lindau tumor suppressor gene, cuz that's what it is.

01:08 It's part of the ligase complex involved in making HIF-1-alpha degrade.

01:13 Also involved with HIF-2-alpha, another story for a different day.

01:17 You get increased HIF accumulation, just as we said, and increased cellular proliferation and diminished apoptosis.

01:25 So, the cells are proliferating.

01:27 And depending on which cells have a lot of HIF-1-alpha or feel hypoxia normally, they're not getting the appropriate signal.

01:34 So, we get a lot of cysts and benign tumors due to unregulated proliferation.

01:40 In many cases as those cells proliferate, they accumulate additional mutations leading to renal cell cancer, tumors of the adrenal medulla, and pancreatic neuroendocrine tumor.

01:52 So, we get a variety of tumors where Von Hippel-Lindau is an important tumor suppressor factor.

01:58 And we could also get hemangioblastomas of multiple organs, including the brain, spinal cord, and eye, and that's what's shown in the panel B.

02:06 Okay, so that's an example of proteosome degradation of little things, and a disease associated with a defect in degrading little things like a transcription factor.