The von Hippel–Lindau Tumor Suppressor Protein

Kaelin, William G.

doi:10.1146/annurev-cancerbio-030617-050527

Cited by 15 publications

(12 citation statements)

References 165 publications

(203 reference statements)

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“…the model as a tool for exploratory data analysis. Germ-line mutations that inactivate the von Hippel-Lindau (vhl) gene cause the VHL syndrome, a rare inherited disorder characterized mainly, but not only, by renal cancers 25,26 . The VHL protein drives ubiquitination and finally degradation of the hypoxia-inducible factor alpha (HIF) which in turn regulates a number of intracellular pathways that collectively confer resistance to hypoxia to cancer cells 25,26 .…”

Section: Role Of Carbonic Anhydrasementioning

confidence: 99%

“…Germ-line mutations that inactivate the von Hippel-Lindau (vhl) gene cause the VHL syndrome, a rare inherited disorder characterized mainly, but not only, by renal cancers 25,26 . The VHL protein drives ubiquitination and finally degradation of the hypoxia-inducible factor alpha (HIF) which in turn regulates a number of intracellular pathways that collectively confer resistance to hypoxia to cancer cells 25,26 . However, experimental findings suggest that both HIF-dependent and HIF-independent mechanisms are essential for VHL-mediated tumor suppressor effects 25,26 .…”

Section: Role Of Carbonic Anhydrasementioning

confidence: 99%

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The control of acidity in tumor cells: a biophysical model

Piasentin

Milotti

Chignola

2020

Sci Rep

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Acidosis of the tumor microenvironment leads to cancer invasion, progression and resistance to therapies. We present a biophysical model that describes how tumor cells regulate intracellular and extracellular acidity while they grow in a microenvironment characterized by increasing acidity and hypoxia. the model takes into account the dynamic interplay between glucose and O 2 consumption with lactate and CO 2 production and connects these processes to H + and HCO − 3 fluxes inside and outside cells. We have validated the model with independent experimental data and used it to investigate how and to which extent tumor cells can survive in adverse micro-environments characterized by acidity and hypoxia. the simulations show a dominance of the H + exchanges in well-oxygenated regions, and of HCO − 3 exchanges in the inner hypoxic regions where tumor cells are known to acquire malignant phenotypes. the model also includes the activity of the enzyme carbonic Anhydrase 9 (CA9), a known marker of tumor aggressiveness, and the simulations demonstrate that CA9 acts as a nonlinear pH i equalizer at any O 2 level in cells that grow in acidic extracellular environments.

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Section: Role Of Carbonic Anhydrasementioning

confidence: 99%

Section: Role Of Carbonic Anhydrasementioning

confidence: 99%

The control of acidity in tumor cells: a biophysical model

Piasentin

Milotti

Chignola

2020

Sci Rep

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“…At low oxygen levels, HIF-1 activates a gene expression program to respond to hypoxia. Under normoxic conditions, Pro402 or Pro564 of the HIF-1α subunit is hydroxylated and bound by VHL, leading to ubiquitination and degradation (Huang et al 1998, Kaelin 2018, Pugh et al 1997. Shape complementarity and VHL residues positioned for optimal hydrogen bonding with the degron explain the exquisite sensitivity for a single hydroxyl group, with an affinity of 30 nM (Hon et al 2002, Min et al 2002.…”

Section: Regulated Recruitment Of Substrate To Ligasementioning

confidence: 99%

Small-Molecule Approaches to Targeted Protein Degradation

Faust

Donovan

Yue

et al. 2021

Annu. Rev. Cancer Biol.

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Many essential biological processes are regulated through proximity, from membrane receptor signaling to transcriptional activity. The ubiquitin-proteasome system controls protein degradation, with ubiquitin ligases as the rate-limiting step. Ubiquitin ligases are commonly controlled at the level of substrate recruitment and, therefore, by proximity. There are natural and synthetic small molecules that also operate through induced proximity. For example, thalidomide is effective in treating multiple myeloma and functions as a molecular glue that stabilizes novel protein-protein interactions between a ubiquitin ligase and proteins not otherwise targeted by the ligase, leading to neo-substrate degradation. Emerging data on new degrader molecules have uncovered diverse mechanisms distinct from molecular glues, which often mirror the regulatory mechanisms that control substrate-ligase proximity in nature. In this review, we summarize our current understanding of biological and synthetic regulation of protein degradation and share our view on how these diverse mechanisms have inspired novel therapeutic directions. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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“…During inflammation, rapid energy consumption by cells for activation, biosynthesis, and the generation of reactive oxygen species results in hypoxia, a reduction in oxygen levels, even in the presence of environmental normoxia. Hypoxia-inducible factor 1-α (HIF1α) is an evolutionarily conserved transcription factor whose protein expression is determined in an oxygen-dependent manner ( Graham and Presnell, 2017 ; Kaelin, 2018 ; Schofield and Ratcliffe, 2004 ; Semenza, 2014 ). Briefly, when oxygen is readily available, hydroxylation of target residues on HIF1α results in ubiquitination and proteasome degradation while, during hypoxia this modification does not occur, allowing for protein accumulation and translocation into the nucleus.…”

Section: Introductionmentioning

confidence: 99%

HIF1α is required for NK cell metabolic adaptation during virus infection

Victorino¹,

Bigley²,

Park³

et al. 2021

eLife

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Natural killer (NK) cells are essential for early protection against virus infection, and must metabolically adapt to the energy demands of activation. Here, we found upregulation of the metabolic adaptor hypoxia inducible factor-1α (HIF-1α) is a feature of mouse NK cells during murine cytomegalovirus (MCMV) infection in vivo. HIF-1 α -deficient NK cells failed to control viral load, causing increased morbidity. No defects were found in effector functions of HIF-1α KO NK cells however, their numbers were significantly reduced. Loss of HIF-1 α did not affect NK cell proliferation during in vivo infection and in vitro cytokine stimulation. Instead, we found HIF-1α -deficient NK cells showed increased expression of the pro-apoptotic protein Bim and glucose metabolism was impaired during cytokine stimulation in vitro. Similarly, during MCMV infection HIF-1α -deficient NK cells upregulated Bim and had increased caspase activity. Thus, NK cells require HIF-1α-dependent metabolic functions to repress Bim expression and sustain cell numbers for an optimal virus response.

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The von Hippel–Lindau Tumor Suppressor Protein

Cited by 15 publications

References 165 publications

The control of acidity in tumor cells: a biophysical model

The control of acidity in tumor cells: a biophysical model

Small-Molecule Approaches to Targeted Protein Degradation

HIF1α is required for NK cell metabolic adaptation during virus infection

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