TWIK family members expression in cancer.

<p>The above threshold data for TWIK family members; KCNK1, KCNK6 and KCNK7 is shown. Data is divided into each cancer type and subtypes within that cancer. The p-value, fold change and gene rank percentile (%) for data which scored above threshold values (p-value<0.05, fold change >2 and gene rank percentile <10%) are shown. Comparative meta-analysis was performed using all available analyses for a given cancer subtype which provides median gene rank and median p-value. Overexpression ↑ and underexpression ↓ are indicated.</p

Expression of KCNK genes across different cancers.

<p>Expression of KCNK genes (KCNK1–18) in 20 cancers compared to normal tissue controls. Shown is the gene and protein names for each channel. A) overexpression of KCNK genes. B) underexpression of KCNK genes. Cancer types are organised by their tissue of origin, the degree of colour correlates to the gene rank percentile of the highest ranking analyses. Search criteria were for mRNA datasets and cancer vs. normal analysis only, with threshold values of p-value<0.05, fold change >2 and gene rank percentile <10%.</p

TREK family members expression in cancer.

<p>The above threshold data for TREK family members; KCNK2 and KCNK10 is shown. Data is divided into each cancer type and subtypes within that cancer. The p-value, fold change and gene rank percentile (%) for data which scored above threshold values (p-value<0.05, fold change >2 and gene rank percentile <10%) are shown. Comparative meta-analysis was performed using all available analyses for a given cancer subtype which provides median gene rank and median p-value. Overexpression ↑ and underexpression ↓ are indicated.</p

Summary of potassium channel expression in cancer.

<p>Potassium channels identified in specific cancer types together with the predominant behavioural characteristics. Channels are divided into family groups, voltage-gated (K_V), calcium-gated (K_Ca), inward rectifying (K_ir) and two-pore domain (K_2P).</p

Expression of the Growth Factor Progranulin in Endothelial Cells Influences Growth and Development of Blood Vessels: A Novel Mouse Model

<div><p>Progranulin is a secreted glycoprotein that regulates cell proliferation, migration and survival. It has roles in development, tumorigenesis, wound healing, neurodegeneration and inflammation. Endothelia in tumors, wounds and placenta express elevated levels of progranulin. In culture, progranulin activates endothelial proliferation and migration. This suggested that progranulin might regulate angiogenesis. It was, however, unclear how elevated endothelial progranulin levels influence vascular growth <i>in vivo</i>. To address this issue, we generated mice with progranulin expression targeted specifically to developing endothelial cells using a <i>Tie2</i>–promoter/enhancer construct. Three <i>Tie2-Grn</i> mouse lines were generated with varying <i>Tie2-Grn</i> copy number, and were called GrnLo, GrnMid, and GrnHi. All three lines showed increased mortality that correlates with <i>Tie2-Grn</i> copy number, with greatest mortality and lowest germline transmission in the GrnHi line. Death of the transgenic animals occurred around birth, and continued for three days after birth. Those that survived beyond day 3 survived into adulthood. Transgenic neonates that died showed vascular abnormalities of varying severity. Some exhibited bleeding into body cavities such as the pericardial space. Smaller localized hemorrhages were seen in many organs. Blood vessels were often dilated and thin-walled. To establish the development of these abnormalities, we examined mice at early (E10.5–14.5) and later (E15.5–17.5) developmental phases. Early events during vasculogenesis appear unaffected by <i>Tie2-Grn</i> as apparently normal primary vasculature had been established at E10.5. The earliest onset of vascular abnormality was at E15.5, with focal cerebral hemorrhage and enlarged vessels in various organs. Aberrant <i>Tie2-Grn</i> positive vessels showed thinning of the basement membrane and reduced investiture with mural cells. We conclude that progranulin promotes exaggerated vessel growth <i>in vivo</i>, with subsequent effects in the formation of the mural cell layer and weakening of vessel integrity. These results demonstrate that overexpression of progranulin in endothelial cells influences normal angiogenesis <i>in vivo</i>.</p></div

The Evolution of the Secreted Regulatory Protein Progranulin

<div><p>Progranulin is a secreted growth factor that is active in tumorigenesis, wound repair, and inflammation. Haploinsufficiency of the human progranulin gene, <i>GRN</i>, causes frontotemporal dementia. Progranulins are composed of chains of cysteine-rich granulin modules. Modules may be released from progranulin by proteolysis as 6kDa granulin polypeptides. Both intact progranulin and some of the granulin polypeptides are biologically active. The granulin module occurs in certain plant proteases and progranulins are present in early diverging metazoan clades such as the sponges, indicating their ancient evolutionary origin. There is only one <i>Grn</i> gene in mammalian genomes. More gene-rich <i>Grn</i> families occur in teleost fish with between 3 and 6 members per species including short-form <i>Grn</i>s that have no tetrapod counterparts. Our goals are to elucidate progranulin and granulin module evolution by investigating (i): the origins of metazoan progranulins (ii): the evolutionary relationships between the single <i>Grn</i> of tetrapods and the multiple <i>Grn</i> genes of fish (iii): the evolution of granulin module architectures of vertebrate progranulins (iv): the conservation of mammalian granulin polypeptide sequences and how the conserved granulin amino acid sequences map to the known three dimensional structures of granulin modules. We report that progranulin-like proteins are present in unicellular eukaryotes that are closely related to metazoa suggesting that progranulin is among the earliest extracellular regulatory proteins still employed by multicellular animals. From the genomes of the elephant shark and coelacanth we identified contemporary representatives of a precursor for short-from <i>Grn</i> genes of ray-finned fish that is lost in tetrapods. In vertebrate <i>Grn</i>s pathways of exon duplication resulted in a conserved module architecture at the amino-terminus that is frequently accompanied by an unusual pattern of tandem nearly identical module repeats near the carboxyl-terminus. Polypeptide sequence conservation of mammalian granulin modules identified potential structure-activity relationships that may be informative in designing progranulin based therapeutics.</p></div

Annual census-count and demographic data for meerkat social groups

Comma separated data, from long-term monitoring of habituated meerkat social groups on and around the Kuruman River Reserve, Northern Cape Province, South Africa (26.978600°S, 21.832300°E). Columns represent variables of interest for unique group/year combinations (rows); see README file for details

Comparison of the spatial placement of conserved residues in GrnA and GrnF.

<p>The GrnA (right) and GrnF (left) modules are shown in two orientations comparing the conformation around the common tryptophan (Trp21, GrnA and Trp22, GrnF) is shown in brown tube style. The space fill side chains are those which show module-specific high conservation. Residues conserved in all granulin modules are shown only as tube backbones coloured yellow for cysteine and black for those highly conserved in all granulin modules. The most variable residues are coloured grey. The colour coding for the space filling side chains follows the conventions in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133749#pone.0133749.g008" target="_blank">Fig 8</a>. Red side-chains are basic, dark blue residues are acidic.</p

Consensus sequences for mammalian progranulin.

<p>The mammalian polypeptide sequences were aligned at five levels of identity form 100% to 50%. Cysteine residues are highlighted in yellow. Amino acids are in capital letters on a background colour. Other letters and symbols are the default Mview notation for residue categories, (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133749#sec002" target="_blank">methods</a> for details). The colour scheme was adjusted to facilitate coordination with colours used in 3D models. The signal peptide is underlined. J indicates a joining sequence between modules, the granulin modules are identified by number and letter designations and the positions of exon boundaries are indicated by arrowheads. Paragranulin is a half granulin module at the N-terminus of mammalian progranulin.</p

N-half module relationships illustrated by a DNA-based maximum likelihood tree.

<p>Letters and numbers are used to label some sub-trees and groups of sub-trees to facilitate reference from the text. Abbreviations for species and the specific Grn gene if there two or more are shown in the “species” boxes in the figure. In half-module labelling, this abbreviation is followed by a number based on the sequential numbering of whole modules encoded within the gene. For visual clarity, a "z" follows the number of the last module in a long-form of progranulin. When a repetitive module sequence or a lack of data make the number of modules uncertain, as in the lancelet (B_flo), the last letters of the alphabet replace numbering for the last sequential modules. N-half modules which are unpaired with C-half modules, paragranulins, are labeled "p", and followed by a number if there is more than one in the progranulin. An asterisk (*) indicates a 5-Cys form of half-module. (See also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133749#pone.0133749.g006" target="_blank">Fig 6</a> for a note on the cod module nomenclature). Bipartition support values of ≥20 are included. These were based upon data for trees from which rogue taxa had been pruned. The rogue taxa are indicated by red branches, and the support values for their placement in this topology are in red.</p