Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility

Germline mutations in the von Hippel–Lindau disease (VHL) and succinate dehydrogenase subunit B (SDHB) genes can cause inherited phaeochromocytoma and/or renal cell carcinoma(RCC). Dysregulation of the hypoxia-inducible factor (HIF) transcription factors has been linked to VHL and SDHB-related RCC; both HIF dysregulation and disordered function of a prolyl hydroxylase domain isoform 3 (PHD3/EGLN3)-related pathway of neuronal apoptosis have been linked to the development of phaeochromocytoma. The 2-oxoglutarate-dependent prolyl hydroxylase enzymes PHD1 (EGLN2), PHD2 (EGLN1) and PHD3 (EGLN3) have a key role in regulating the stability of HIF-a subunits (and hence expression of the HIF-a transcription factors). A germline PHD2 mutation has been reported in association with congenital erythrocytosis and recurrent extra-adrenal phaeochromocytoma. We undertook mutation analysis of PHD1, PHD2 and PHD3 in two cohorts of patients with features of inherited phaeochromocytoma (nZ82) and inherited RCC (nZ64) and no evidence of germline mutations in known susceptibility genes. No confirmed pathogenic mutations were detected suggesting that mutations in these genes are not a frequent cause of inherited phaeochromocytoma or RCC

Overview over the neutral gas pressures in Wendelstein 7-X during divertor operation under boronized wall conditions

During the first test divertor campaign of the stellarator experiment Wendelstein 7-X (Pedersen et al 2022 Nucl. Fusion 62 042022), OP1.2b, 13 neutral gas pressure gauges collected data in different locations in the plasma vessel, enabling a detailed analysis of the neutral gas pressures, the compression ratios and the particle exhaust rates via the turbomolecular pumps in the different magnetic field configurations. In Wendelstein 7-X, the edge magnetic islands are intersected by the divertor target plates and used to create a plasma-wall interface. As the number and position of the magnetic islands varies in different magnetic field configurations, the position of the strike line on the target plates and thus the neutral gas pressure in the subdivertor differs between the configurations. Neutral gas pressures on the order of few 10−4 mbar were measured in the subdivertor region. The highest neutral gas pressure of $1.75\times 10^{-3}$ mbar was obtained in the so-called high iota configuration featuring four edge magnetic islands per cross section. The neutral particle flux through the pumping gaps into the subdivertor volume was provided by EMC3-EIRENE simulations and allowed to analyze the relation between the particle flux entering the subdivertor and the pressure distribution in the subdivertor. Finite element simulations in ANSYS provide a detailed picture of the pressure distribution in the subdivertor volume and agree with the neutral gas pressure measurements in the subdivertor in the standard configuration featuring an island chain of 5 edge magnetic islands. Surprisingly high neutral gas pressures that were not predicted by the simulation were measured in the subdivertor region away from the main strike line for discharges in the most used magnetic configuration, the standard configuration. While the pressure ratio between the two sections of the subdivertor volume, the low and high iota section is 0.06 in high iota configuration, a ratio of 2–5 was obtained in the other configurations, indicating significant particle loads and exhaust rates on the high iota section of the subdivertor in magnetic configurations with the main strike line on the low iota divertor targets

pVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2

The VHL tumor suppressor protein (pVHL) is part of an E3 ubiquitin ligase that targets HIF for destruction. pVHL-defective renal carcinoma cells exhibit increased NF-κB activity but the mechanism is unclear. NF-κB affects tumorigenesis and therapeutic resistance in some settings. We found that pVHL associates with the NF-κB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C-terminus by CK2. Elimination of these sites markedly enhanced Card9's ability to activate NF-κB in VHL+/+ cells and Card9 siRNA normalized NF-κB activity in VHL−/− cells and restored their sensitivity to cytokine-induced apoptosis. Furthermore, downregulation of Card9 in VHL−/− cancer cells reduced their tumorigenic potential. Therefore pVHL can serve as an adaptor for both an ubiquitin conjugating enzyme and for a kinase. The latter activity, which promotes Card9 phosphorylation, links pVHL to control of NF-κB activity and tumorigenesis