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Characterization of the Human Prolyl 4-Hydroxylases That Modify the Hypoxia-inducible Factor*
It is found that the longest and shortest isoenzymes have major transcripts encoding inactive polypeptides, which suggest novel regulation by alternative splicing, and it should be possible to develop specific inhibitors for each class of P4Hs and possibly even for the individual HIF-P 4Hs.
Collagens: molecular biology, diseases, and potentials for therapy.
The collagen superfamily of proteins now contains at least 19 proteins formally defined as collagens and an additional ten proteins that have collagen-like domains, and a number of experiments suggest it may be possible to inhibit collagen synthesis with oligo-nucleotides or antisense genes.
Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates
The data indicate that the transcriptional activity of HIF is quite high even when binding of the coactivator p300 is prevented, and support recent suggestions that the increased fumarate and succinate levels present in the FH and succinated dehydrogenase-deficient tumors, respectively, can inhibit the HIF-P4Hs with consequent stabilization of Hif-αs and effects on tumor pathology.
Catalytic Properties of the Asparaginyl Hydroxylase (FIH) in the Oxygen Sensing Pathway Are Distinct from Those of Its Prolyl 4-Hydroxylases*
Rec recombinant FIH has unique catalytic and inhibitory properties when compared with those of the HIF prolyl 4-hydroxylases, and it should be possible to develop specific small molecule inhibitors for the two enzyme classes involved in the hypoxia response.
Collagens and collagen-related diseases
The collagen superfamily of proteins plays a dominant role in maintaining the integrity of various tissues and also has a number of other important functions. The superfamily now includes more than
Effect of desferrioxamine and metals on the hydroxylases in the oxygen sensing pathway
The purified HIF‐P4Hs showed considerable activities even without added Fe2+, their apparent Km values for iron being markedly lower than that of FIH, and the well‐known stabilization of Hif‐α by cobalt and nickel is thus not due to a simple competitive inhibition of HIF'S, but probably leads to full transcriptional activity of H IF‐α even in concentrations that produce no stabilization.
Inactivation of the Lysyl Oxidase Gene Lox Leads to Aortic Aneurysms, Cardiovascular Dysfunction, and Perinatal Death in Mice
Lox has an essential role in the development and function of the cardiovascular system and inactivation of the Lox gene causes structural alterations in the arterial walls, leading to abnormalities in the cardiovascular functions.
Roles of the human hypoxia-inducible factor (HIF)-3α variants in the hypoxia response
Unexpectedly, siRNA knock-down of the endogenous HIF-3α variants led to downregulation of certain HIF target genes, while overexpression of individual long Hif-3 α variants upregulated certain Hif target genes in a variant and target gene-specific manner under conditions in which HIF -β was not a limiting factor.