14-3-3 proteins in neurodegeneration

Among the first reported functions of 14-3-3 proteins was the regulation of tyrosine hydroxylase (TH) activity suggesting a possible involvement of 14-3-3 proteins in Parkinson's disease. Since then the relevance of 14-3-3 proteins in the pathogenesis of chronic as well as acute neurodegenerative diseases, including Alzheimer's disease, polyglutamine diseases, amyotrophic lateral sclerosis and stroke has been recognized. The reported function of 14-3-3 proteins in this context are as diverse as the mechanism involved in neurodegeneration, reaching from basal cellular processes like apoptosis, over involvement in features common to many neurodegenerative diseases, like protein stabilization and aggregation, to very specific processes responsible for the selective vulnerability of cellular populations in single neurodegenerative diseases.Here, we review what is currently known of the function of 14-3-3 proteins in nervous tissue focussing on the properties of 14-3-3 proteins important in neurodegenerative disease pathogenesis.     

Dynamic Histone Acetylation of Late Embryonic Genes during Seed Germination

Histone acetylation is involved in the regulation of gene expression in plants and eukaryotes. Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from histones, which is associated with the repression of gene expression. To study the role of histone acetylation in the regulation of gene expression during seed germination, trichostatin A (TSA), a specific inhibitor of histone deacetylase, was used to treat imbibing Arabidopsis thaliana seeds. GeneChip arrays were used to show that TSA induces up-regulation of 45 genes and down-regulation of 27 genes during seed germination. Eight TSA-up-regulated genes were selected for further analysis – RAB18, RD29B, ATEM1, HSP70 and four late embryogenesis abundant protein genes (LEA). A gene expression time course shows that these eight genes are expressed at high levels in the dry seed and repressed upon seed imbibition at an exponential rate. In the presence of TSA, the onset of repression of the eight genes is not affected but the final level of repressed expression is elevated. Chromatin immunoprecipitation and HDAC assays show that there is a transient histone deacetylation event during seed germination at 1 day after imbibition, which serves as a key developmental signal that affects the repression of the eight genes. Electronic supplementary material Electronic supplementary material is available for this article at and accessible for authorised users.     

Estrogen regulation of trefoil factor 1 expression by estrogen receptor alpha and Sp proteins

Estrogen-responsive genes in human breast cancer cells often have an estrogen response element (ERE) positioned next to an Sp1 binding site. In chromatin immunoprecipitation (ChIP) assays, we investigated the binding of estrogen receptor alpha (ER), Sp1, and Sp3 to the episomal and native estrogen-responsive trefoil factor 1 (TFF1; formerly pS2) promoter in MCF-7 breast cancer cells. Mutation of the Sp site upstream of the ERE reduced estrogen responsiveness and prevented binding of Sp1 and Sp3, but not ER to the episomal promoter. In the absence of estradiol (E2), Sp1, Sp3, histone deacetylase 1 (HDAC), and HDAC2, and low levels of acetylated H3 and H4 are associated with the native promoter, with the histones being engaged in dynamic reversible acetylation. Following E2 addition, levels of ER and acetylated H3 and H4 bound to the native promoter increases. There is clearance of Sp1, but not of Sp3, from the promoter while HDAC1 and HDAC2 remain bound. These data are consistent with a model in which Sp1 or Sp3 aid in recruitment of HDACs and histone acetyltransferases (HATs) to mediate dynamic acetylation of histones associated with the TFF1 promoter, which is in a state of readiness to respond to events occurring following the addition of estrogen.     

cda1+, encoding chitin deacetylase is required for proper spore formation in Schizosaccharomyces pombe

In Schizosaccharomyces pombe, a major role of chitin is to build up a complete spore. Here, we analyzed the cda1(+) gene (SPAC19G12.03), which encodes a protein homologous to chitin deacetylases, to know whether it is required for spore formation in S. pombe. The homothallic Deltacda1 strain constructed by homologous recombination was found to form a little amount of abnormal spores that contained one, two, or three asci, similar to (but not as strong as) the phenotype observed in a deletion mutant of chs1 encoding chitin synthase 1. This phenotype is reversed by expression of S. cerevisiae chitin deacetylase CDA1 or CDA2, suggesting that cda1 encodes a chitin deacetylase. To support the role of Cda1 in sporulation, the timing of expression of cda1(+) mRNA increased during sporulation process. We also found that the Cda1 protein self-associated when its binding was tested both by two-hybrid system and immunoprecipitation. Thus, these data indicated that cda1(+) is required for proper spore formation in S. pombe.     

Modulation of angiogenesis-related protein synthesis by valproic acid

Recent studies have attested to the antiangiogenic effects of HDAC inhibitors on solid human tumors. The HDAC inhibitor butyrate has been reported to impair tumor-cell-induced angiogenesis. However, due to its poor bioavailability in vivo, the therapeutic use of butyrate is limited. On the other hand, valproic acid has inhibitory effects on carcinoma cells, is known to be well tolerated, and has an excellent bioavailability. We therefore set out to investigate whether the HDAC inhibitor valproic acid also impairs angiogenesis. Our findings indicate that valproic acid represses the relevant angiogenic factors VEGF and FGF in Caco-2 cells. Both, protein expression as well as mRNA levels of VEGF, were reduced to a similar degree. Suppression of ubiquitin-proteasome activity could be a possible reason for valproic acid effects on regulatory angiogenesis proteins. These results suggest that the HDAC inhibitor valproic acid could become a valuable new addition in the attempt to develop alternative therapeutic approaches in the treatment of colon carcinomas.