Resulting Condition: von-Hippel-Lindau Disease

by Richard Mitchell, MD, PhD

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    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.

    About the Lecture

    The lecture Resulting Condition: von-Hippel-Lindau Disease by Richard Mitchell, MD, PhD is from the course Cellular Housekeeping Functions.

    Included Quiz Questions

    1. Cerebral hemangioblastoma
    2. Bilateral meningioma
    3. Café au lait spots
    4. Adrenocortical adenoma
    5. Cardiac rhabdomyosarcoma

    Author of lecture Resulting Condition: von-Hippel-Lindau Disease

     Richard Mitchell, MD, PhD

    Richard Mitchell, MD, PhD

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