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Questions > Ch7.12 pvhl > Flashcards

Ch7.12 pvhl Flashcards

1
Q

What is Von Hippel–Lindau (VHL) syndrome?

A

VHL syndrome is a hereditary predisposition to tumors, including kidney clear-cell carcinomas, pheochromocytomas, and hemangioblastomas of the CNS and retina.

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2
Q

What gene is mutated in Von Hippel–Lindau disease?

A

Germ-line mutations in the VHL tumor suppressor gene.

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3
Q

How frequent is VHL syndrome in the population?

A

It affects about 1 in 35,000 people.

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4
Q

What type of inheritance pattern does VHL syndrome follow?

A

It follows an autosomal dominant inheritance pattern.

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5
Q

What happens to the VHL locus in patients with VHL syndrome?

A

It undergoes a loss of heterozygosity (LOH), resulting in a VHL–/– genotype in tumor cells.

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6
Q

What percentage of sporadic kidney carcinomas involve inactivation of the VHL gene?

A

About 70%.

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7
Q

How is the VHL gene often inactivated in sporadic tumors?

A

Through promoter methylation leading to transcriptional silencing.

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8
Q

What is the primary function of the VHL protein (pVHL)?

A

To foster the destruction of the hypoxia-inducible factor-2 (HIF-2) transcription factor.

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9
Q

What is the relationship between HIF-1α and pVHL under normal oxygen conditions?

A

pVHL degrades HIF-1α, preventing its accumulation and the activation of HIF-1.

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10
Q

What happens to HIF-1α under hypoxic conditions?

A

HIF-1α is not degraded, allowing it to accumulate and activate the HIF-1 transcription factor.

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11
Q

What cellular processes are regulated by HIF-1 under hypoxia?

A

Angiogenesis, erythropoiesis, glycolysis, and glucose transport.

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12
Q

What is the role of vascular endothelial growth factor (VEGF) in hypoxic tissues?

A

VEGF attracts and stimulates the growth of endothelial cells to form new blood vessels.

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13
Q

How does platelet-derived growth factor (PDGF) contribute to the angiogenic response?

A

PDGF stimulates endothelial and mesenchymal cells, such as pericytes and fibroblasts.

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14
Q

What is the role of transforming growth factor-α (TGF-α) in hypoxic conditions?

A

TGF-α stimulates various cell types, including epithelial cells.

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15
Q

What is the role of HIF-2 in the hypoxic kidney?

A

HIF-2 activates the gene encoding erythropoietin (EPO), increasing red blood cell production.

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16
Q

What is the function of the VHL complex in cells?

A

The VHL complex tags proteins like HIF-1α with ubiquitin for degradation by the proteasome.

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17
Q

What modification allows pVHL to recognize and bind HIF-1α?

A

The hydroxylation of proline residues on HIF-1α by proline hydroxylase.

18
Q

What prevents pVHL from binding HIF-1α under hypoxic conditions?

A

Lack of hydroxylation on HIF-1α’s proline residues under low oxygen levels.

19
Q

How does the HIF-1 transcription factor affect tumor growth?

A

It upregulates genes like VEGF, PDGF, and TGF-α, promoting angiogenesis and cell proliferation.

20
Q

What additional pathway contributes to increased HIF-1α levels in cancer cells?

A

PI3K/Akt/mTORC1 pathway, which increases HIF-1α mRNA production and translation.

21
Q

How does the PI3K/Akt/mTORC1 pathway affect metabolism in cancer cells?

A

It shifts metabolism towards aerobic glycolysis, known as the Warburg effect.

22
Q

What is the consequence of point mutations in pVHL’s hydrophobic pocket?

A

They prevent proper recognition and degradation of HIF-1α, leading to tumorigenesis.

23
Q

How does EPO contribute to the phenotype of VHL syndrome patients?

A

Elevated EPO levels stimulate erythropoiesis, leading to high red blood cell counts.

24
Q

What is the role of pVHL in extracellular matrix assembly?

A

It binds fibronectin and is essential for proper assembly of the extracellular matrix.

25
Q

How does pVHL interact with microtubules?

A

pVHL is associated with cytoplasmic microtubules and regulates their stability.

26
Q

What additional tumor suppressor protein does pVHL affect?

A

p53, a key protein involved in the apoptotic program and tumor suppression.

27
Q

How does pVHL impact NF-κB signaling?

A

It regulates NF-κB signaling, which is involved in immune response and inflammation.

28
Q

What is the epithelial–mesenchymal transition (EMT), and how is it linked to pVHL?

A

EMT is a process where epithelial cells become mesenchymal; pVHL affects this transition.

29
Q

What group of enzymes is associated with cancer through metabolic pathways?

A

Succinate dehydrogenase (SDH), isocitrate dehydrogenase (IDH), and fumarate hydratase (FH).

30
Q

How do metabolic enzymes like SDH and IDH contribute to cancer development?

A

They are involved in carbohydrate metabolism, which can intersect with cancer-promoting pathways.

31
Q

What is the Warburg effect?

A

The shift of cancer cells to aerobic glycolysis for energy production, even in the presence of oxygen.

32
Q

How do prolyl hydroxylases contribute to HIF regulation?

A

They hydroxylate proline residues on HIF-1α, targeting it for degradation under normoxia.

33
Q

What is the role of α-ketoglutarate in prolyl hydroxylase activity?

A

It acts as an electron acceptor for prolyl hydroxylases, linking metabolism to HIF regulation.

34
Q

How does pVHL affect tumor cell proliferation in VHL syndrome?

A

By failing to degrade HIF-1α, pVHL loss leads to increased expression of growth-promoting genes.

35
Q

What are the consequences of constitutive HIF-1 activity in tumors?

A

It drives angiogenesis, cell proliferation, and metabolic reprogramming, supporting tumor growth.

36
Q

How is erythropoiesis linked to tumorigenesis in VHL syndrome?

A

Tumor cells produce excess EPO, leading to increased red blood cell production.

37
Q

What role does fibronectin play in cells lacking pVHL?

A

Cells cannot properly assemble fibronectin, affecting the extracellular matrix structure.

38
Q

How does pVHL affect cytoskeletal dynamics?

A

It is involved in stabilizing cytoplasmic microtubules, impacting cell structure and transport.

39
Q

What role does pVHL play in apoptosis?

A

It influences the activation of the p53 tumor suppressor, which regulates the apoptotic pathway.

40
Q

What do the functions of pVHL reveal about tumor suppressors like APC?

A

They have been co-opted to regulate diverse cellular processes beyond their initial roles.

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