Thyroid function parameters during a selenium repletion/depletion study in phenylketonuric subjects.

Phenylketonuric (PKU) subjects have a limited supply of selenium (Se) in their phenylalanine-restricted diet. A Se repletion (1 microgram Se/kg/day)/depletion study was conducted in PKU children to determine the effect of Se on thyroid function parameters. The initial plasma Se concentration (mean +/- SD: 0.26 +/- 0.12 mumol/L, p < 0.00003, n = 10) and glutathione peroxidase (GSH-Px) activity (140 +/- 58 U/L, p < 0.00003, n = 10) were significantly lower compared to age-matched controls. After 14 weeks of supplementation, the plasma Se concentration (mean +/- SD: 0.74 +/- 0.20 mumol/L) normalized (normal range: 0.57-1.15 mumol/L, mean +/- SD: 0.76 +/- 0.13 mumol/L, n = 32) and remained stable thereafter during repletion. Plasma GSH-Px activity reached normal values after 18 weeks of supplementation (312 +/- 57 U/L; normal range: 238-492 U/L, mean +/- SD: 345 +/- 54 U/L, n = 32) and increased significantly for up to eight weeks thereafter (332 +/- 52 U/L). Individual and mean thyroid parameters were initially normal in all cases. The mean concentrations of plasma thyroxine (T4: p < 0.025), free T4 (FT4: p < 0.01) and reverse triiodothyronine (rT3: p < 0.005) decreased to 75% of their initial value within three weeks of Se supplementation and remained stable thereafter, within a normal physiological range during selenium supplementation. They increased back to their initial values three weeks (T4: p < 0.05, FT4: p < 0.05) and six weeks (rT3: p < 0.025) respectively, after the end of the supplementation. In conclusion, Se supplementation modifies thyroid function parameters in Se-deficient PKU subjects most likely by an increase in activity of type I 5'-deiodinase (5'-DIase I).Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

HIV-1 tat transcriptional activity is regulated by acetylation.

The human immunodeficiency virus (HIV) trans- activator protein, Tat, stimulates transcription from the viral long-terminal repeats (LTR) through an RNA hairpin element, trans-activation responsive region (TAR). We and others have shown that trans-activator protein (Tat)-associated histone acetyltransferases (TAHs), p300 and p300/CBP-associating factor (PCAF), assist functionally in the activation of chromosomally integrated HIV-1 LTR. Here, we show that p300 and PCAF also directly acetylate Tat. We defined two sites of acetylation located in different functional domains of Tat. p300 acetylated Lys50 in the TAR RNA binding domain, while PCAF acetylated Lys28 in the activation domain of Tat. In support of a functional role for acetylation in vivo, histone deacetylase inhibitor (trichostatin A) synergized with Tat in transcriptional activation of the HIV-1 LTR. Synergism was TAR-dependent and required the intact presence of both Lys28 and Lys50. Mechanistically, acetylation at Lys28 by PCAF enhanced Tat binding to the Tat-associated kinase, CDK9/P-TEFb, while acetylation by p300 at Lys50 of Tat promoted the dissociation of Tat from TAR RNA that occurs during early transcription elongation. These data suggest that acetylation of Tat regulates two discrete and functionally critical steps in transcription, binding to an RNAP II CTD-kinase and release of Tat from TAR RNA