The alignment of multiple sites in the HIF cis-acting apparatus with RCC-susceptibility polymorphisms strongly supports a causal model in which minor variation in this pathway exerts significant effects on RCC development. This conference focused on "the role of hypoxia under physiological conditions as well as in cancer" and took place in Nantes, France, in October 6-7, 2016.
The main objective of this conference was to bring together a large group of scientists from different spheres of hypoxia.
Recent advances were presented and discussed around different topics: genomics, physiology, musculoskeletal, stem cells, microenvironment and cancer, and oxidative stress. | Show Abstract | Read more Investigation into the regulation of the erythropoietin gene by oxygen led to the discovery of a process of direct oxygen sensing that transduces many cellular and systemic responses to hypoxia.
This review summarizes the major highlights of the meeting. The oxygen-sensitive signal is generated through the catalytic action of a series of 2-oxoglutarate-dependent oxygenases that regulate the transcription factor hypoxia-inducible factor (HIF) by the post-translational hydroxylation of specific amino acid residues. | Show Abstract | Read more Ribosomal protein (RP) gene mutations, mostly associated with inherited or acquired bone marrow failure, are believed to drive disease by slowing the rate of protein synthesis.
These programmes range across, protein science, structural biology and enzymology, through cell biology, systems physiology, epigenetics and cancer biology, to translational programmes in ischaemia therapeutics and integrative human physiology. To identify genes regulated by hypoxia at the transcriptional level, we pulse-labeled HUVEC cells with 4-thiouridine and sequenced nascent transcripts.
Then, we searched genome-wide binding profiles from the ENCODE project for factors that correlated with changes in transcription and identified binding of several components of the Sin3A co-repressor complex, including SIN3A, SAP30 and HDAC1/2, proximal to genes repressed by hypoxia.
The amino acid substitutions lie in two highly conserved loop regions of u S12 with known roles in maintaining the accuracy of m RNA codon translation.
Primary cells revealed one substitution severely impaired OGFOD1-dependent hydroxylation of a neighboring proline residue resulting in 40S ribosomal subunits that were blocked from polysome formation.
Working initially on regulation of the haematopoietic growth factor erythropoietin (which shows strong transcriptional upregulation by hypoxia), the laboratory discovered that the underlying oxygen sensitive signal pathway is widely operative in mammalian cells, extends to invertebrates, and mediates a range of other transcriptional responses including those regulating angiogenesis and metabolism.
Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins.
Moreover, we demonstrate that the risk-associated polymorphisms increase chromatin accessibility and activity as well as HIF binding to the enhancer. | Show Abstract | Read more The 2016 Albert Lasker Basic Medical Research Award is being awarded to Gregg Semenza, William Kaelin, and Peter Ratcliffe for discovery of the pathway by which human and animal cells sense and adapt to changes in oxygen availability-an essential requirement for survival. | Show Abstract | Read more Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate.
SIN3A interference revealed that it participates in the downregulation of 75% of the hypoxia-repressed genes in endothelial cells.
Unexpectedly, it also blunted the induction of 47% of the upregulated genes, suggesting a role for this corepressor in gene induction.
Here we review the implications of the unforeseen complexity of the HIF transcriptional cascade for the physiology and pathophysiology of hypoxia, and consider the origins of post-translational hydroxylation as a signaling process. Here de novo missense mutations in the RPS23 gene, which codes for u S12, are reported in two unrelated individuals with microcephaly, hearing loss, and overlapping dysmorphic features.