Prefoldin 6 mediates longevity response from heat shock factor 1 to FOXO in C-elegans

Heat shock factor 1 (HSF-1) and forkhead box O (FOXO) are key transcription factors that protect cells from various stresses. In Caenorhabditis elegans, HSF-1 and FOXO together promote a long life span when insulin/IGF-1 signaling (IIS) is reduced. However, it remains poorly understood how HSF-1 and FOXO cooperate to confer IIS-mediated longevity. Here, we show that prefoldin 6 (PFD-6), a component of the molecular chaperone prefoldin-like complex, relays longevity response from HSF-1 to FOXO under reduced IIS. We found that PFD-6 was specifically required for reduced IIS-mediated longevity by acting in the intestine and hypodermis. We showed that HSF-1 increased the levels of PFD-6 proteins, which in turn directly bound FOXO and enhanced its transcriptional activity. Our work suggests that the prefoldin-like chaperone complex mediates longevity response from HSF-1 to FOXO to increase the life span in animals with reduced IIS.11Ysciescopu

AKR1C1 as a Biomarker for Differentiating the Biological Effects of Combustible from Non-Combustible Tobacco Products

Smoking has been established as a major risk factor for developing oral squamous cell carcinoma (OSCC), but less attention has been paid to the effects of smokeless tobacco products. Our objective is to identify potential biomarkers to distinguish the biological effects of combustible tobacco products from those of non-combustible ones using oral cell lines. Normal human gingival epithelial cells (HGEC), non-metastatic (101A) and metastatic (101B) OSCC cell lines were exposed to different tobacco product preparations (TPPs) including cigarette smoke total particulate matter (TPM), whole-smoke conditioned media (WS-CM), smokeless tobacco extract in complete artificial saliva (STE), or nicotine (NIC) alone. We performed microarray-based gene expression profiling and found 3456 probe sets from 101A, 1432 probe sets from 101B, and 2717 probe sets from HGEC to be differentially expressed. Gene Set Enrichment Analysis (GSEA) revealed xenobiotic metabolism and steroid biosynthesis were the top two pathways that were upregulated by combustible but not by non-combustible TPPs. Notably, aldo-keto reductase genes, AKR1C1 and AKR1C2, were the core genes in the top enriched pathways and were statistically upregulated more than eight-fold by combustible TPPs. Quantitative real time polymerase chain reaction (qRT-PCR) results statistically support AKR1C1 as a potential biomarker for differentiating the biological effects of combustible from non-combustible tobacco products

Model-based nucleosome occupancy profiles for sonicated H3K4me1 ChIP-Seq data.

<p>Panels show nucleosome positioning within bp from the top-ranked <i>in vivo</i> transcription factor binding sites that PICS detected for (A) SPI1 and (B) CEBPB from sonicated H3K4me1 ChIP-Seq data for 0 hour (blue) and 1 hour (red) after tamoxifen stimulation <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032095#pone.0032095-Heinz1" target="_blank">[20]</a>. The heatmaps show nucleosome prediction profiles for each region as pairs of blue/red horizontal lines, with darker colors indicating higher scoring, i.e. better positioned, nucleosomes. The lower part of each heatmap shows genomic regions that lack detectable nucleosome positioning. Curves below each heatmap show average occupancy profiles across all TF regions.</p

Modality and nucleosome occupancy for Foxa2 and Pdx1 binding sites in mouse adult islet tissue.

<p>Panels show the modality and nucleosome profiles for <i>in vivo</i> binding sites of the transcription factors Foxa2 (left) and Pdx1 (right) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032095#pone.0032095-Hoffman1" target="_blank">[19]</a>. (A) The number of binding sites in bimodal(bi), monomodal(mono) and NoNuc(No) groups. A NoNuc transcription factor binding site had no H3K4me1-marked nucleosome within 1 kb of its peak summit, a monomodal site had at least one H3K4me1 nucleosome within 50 bp of its summit, and all other sites were bimodal. (B) Average model-based nucleosome positioning profiles for the three classes of binding sites.</p

Expression levels for genes associated with different types of nucleosome predictions.

<p>RNA-seq data for mouse adult islets are from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032095#pone.0032095-Kim1" target="_blank">[29]</a>. Nucleosomes were predicted from H3K4me1 data for (A,B) mouse adult islets and (C,D) mouse adult liver <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032095#pone.0032095-Hoffman1" target="_blank">[19]</a>. Dashed horizontal lines show medians. In islets, genes categorized as bimodal and NoNuc respectively have significantly higher and lower expression levels than those in the monomodal group. Nucleosome prediction groups are outlined in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032095#pone-0032095-g003" target="_blank">Fig. 3</a>'s caption and in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032095#s4" target="_blank">Methods</a>.</p

RNAi targeting Caenorhabditis elegans α-arrestins has small or no effects on lifespan [version 2; referees: 2 approved, 1 approved with reservations]

Background: α-arrestins are a family of proteins that are implicated in multiple biological processes, including metabolism and receptor desensitization. Methods: Here, we sought to examine the roles of α-arrestins in the longevity of Caenorhabditis elegans through an RNA interference screen. Results: We found that knocking down each of 24 out of total 29 C. elegans α-arrestins had small or no effects on lifespan. Thus, individual C. elegans α-arrestins may have minor effects on longevity. Conclusions: This study will provide useful information for future research on the functional role of α-arrestins in aging and longevity