Mutant Ras and inflammation-driven skin tumorigenesis is suppressed via a JNK-iASPP-AP1 axis

Concurrent mutation of a RAS oncogene and the tumor suppressor p53 is common in tumorigenesis, and inflammation can promote RAS-driven tumorigenesis without the need to mutate p53. Here, we show, using a well-established mutant RAS and an inflammation-driven mouse skin tumor model, that loss of the p53 inhibitor iASPP facilitates tumorigenesis. Specifically, iASPP regulates expression of a subset of p63 and AP1 targets, including genes involved in skin differentiation and inflammation, suggesting that loss of iASPP in keratinocytes supports a tumor-promoting inflammatory microenvironment. Mechanistically, JNK-mediated phosphorylation regulates iASPP function and inhibits iASPP binding with AP1 components, such as JUND, via PXXP/SH3 domain-mediated interaction. Our results uncover a JNK-iASPP-AP1 regulatory axis that is crucial for tissue homeostasis. We show that iASPP is a tumor suppressor and an AP1 coregulator

Analysis of Large Phenotypic Variability of EEC and SHFM4 Syndromes Caused by K193E Mutation of the TP63 Gene

EEC (ectrodactyly, ectodermal dysplasia, clefting; OMIM 604292) is an autosomal dominant developmental disorder resulting mainly from pathogenic mutations of the DNA-binding domain (DBD) of the TP63 gene. In this study, we showed that K193E mutation in nine affected individuals of a four-generation kindred with a large degree of phenotypic variability causes four different syndromes or TP63-related disorders: EEC, Ectrodactyly-ectodermal dysplasia (EE), isolated ectodermal dysplasia, and isolated Split Hand/Foot Malformation type 4 (SHFM4). Genotype-phenotype and DBD structural modeling analysis showed that the K193-located loop L2-A is associated with R280 through hydrogen bonding interactions, while R280 mutations also often cause large phenotypic variability of EEC and SHFM4. Thus, we speculate that K193 and several other DBD mutation-associated syndromes may share similar pathogenic mechanisms, particularly in the case of the same mutation with different phenotypes. Our study and others also suggest that the phenotypic variability of EEC is attributed, at least partially, to genetic and/or epigenetic modifiers

Sp6 and Sp8 transcription factors control AER formation and dorsal-ventral patterning in limb development

The formation and maintenance of the apical ectodermal ridge (AER) is critical for the outgrowth and patterning of the vertebrate limb. The induction of the AER is a complex process that relies on integrated interactions among the Fgf, Wnt, and Bmp signaling pathways that operate within the ectoderm and between the ectoderm and the mesoderm of the early limb bud. The transcription factors Sp6 and Sp8 are expressed in the limb ectoderm and AER during limb development. Sp6 mutant mice display a mild syndactyly phenotype while Sp8 mutants exhibit severe limb truncations. Both mutants show defects in AER maturation and in dorsal-ventral patterning. To gain further insights into the role Sp6 and Sp8 play in limb development, we have produced mice lacking both Sp6 and Sp8 activity in the limb ectoderm. Remarkably, the elimination or significant reduction in Sp6;Sp8 gene dosage leads to tetra-amelia; initial budding occurs, but neither Fgf8 nor En1 are activated. Mutants bearing a single functional allele of Sp8 (Sp6-/-;Sp8+/-) exhibit a split-hand/foot malformation phenotype with double dorsal digit tips probably due to an irregular and immature AER that is not maintained in the center of the bud and on the abnormal expansion of Wnt7a expression to the ventral ectoderm. Our data are compatible with Sp6 and Sp8 working together and in a dose-dependent manner as indispensable mediators of Wnt/βcatenin and Bmp signaling in the limb ectoderm. We suggest that the function of these factors links proximal-distal and dorsal-ventral patterning

Values of time and reliability in passenger and freight transport in The Netherlands

New values of time (VOTs) and of travel time reliability (VORs) for passenger and freight transport have been established for use in cost-benefit analysis (CBA) of transport projects in The Netherlands. This was the first national study in The Netherlands and one of the first world-wide that empirically investigated these topics in a joint framework. Stated preference (SP) questionnaires were designed for interviewing travellers, shippers and carriers. The hypothetical alternatives were described in terms of travel time, travel costs and reliability, where reliability was presented to the respondents in the form of five possible travel times which are equally likely to happen. For passenger transport (comprising car, train, bus/tram/metro, plane and recreational navigation), we first collected interviews using an existing internet panel. In an additional data collection, recruitment was done by asking travellers at petrol stations/service areas, parking garages, stations, bus stops, airports and ports to participate in the survey. One important conclusion is that the SP survey using members of an internet panel leads to substantially lower VOTs than the SP survey with en-route recruitment, because of self-selection bias in the internet panel. For freight transport, shippers and carriers were interviewed using computer-assisted personal interviews We estimated discrete choice models on the passenger SP data in which the values of time differ between trips with different time and costs levels, different time and costs changes offered in the SP, and different characteristics of the respondents (e.g. education, income, age, household composition). By using a panel latent class model, we also account for unobserved differences between respondents in the value of time and for repeated measurements/panel effects. The reference values of time and the reference reliability ratios were estimated on the 2011 sample only, but the effect of time and cost level, time and cost changes offered and socio-economic attributes was estimated on both the 2009 and 2011 samples. For freight transport, we used relative models for rail, inland waterways, air and sea transport, in which the attributes are measured relative to the observed levels, and an absolute model for road transport. The final outcome of the project consists of recommended VOTs and VORs for use in cost-benefit analysis of transport projects in the Netherlands

Zinc incorporation via the vapor−liquid−solid mechanism into InP nanowires

We report the incorporation of zinc atoms into vapor−liquid−solid grown indium phosphide nanowires via a gold catalyst particle. We demonstrate this by synthesizing axial pn-junctions, chemically etching them, and fabricating electrical contacts in a vertical configuration. Electrical measurements show clear diode behavior. Control of dopant incorporation is crucial for future applications and will eventually lead to full freedom of design

ΔNp63α Transcriptionally Regulates the Expression of CTEN That Is Associated with Prostate Cell Adhesion

<div><p>p63 is a member of the p53 transcription factor family and a linchpin of epithelial development and homeostasis. p63 drives the expression of many target genes involved in cell survival, adhesion, migration and cancer. In this study, we identify C-terminal tensin-like (CTEN) molecule as a downstream target of ΔNp63α, the predominant p63 isoform expressed in epithelium. CTEN belongs to the tensin family and is mainly localized to focal adhesions, which mediate many biological events such as cell adhesion, migration, proliferation and gene expression. Our study demonstrate that ΔNp63 and CTEN are both highly expressed in normal prostate epithelial cells and are down-regulated in prostate cancer. In addition, reduced expression of <i>CTEN</i> and <i>ΔNp63</i> is correlated with prostate cancer progression from primary tumors to metastatic lesions. Silencing of ΔNp63 leads to decreased mRNA and protein levels of CTEN. ΔNp63α induces transcriptional activity of the <i>CTEN</i> promoter and a 140-bp fragment upstream of the transcription initiation site is the minimal promoter region required for activation. A putative binding site for p63 is located between -61 and -36 within the <i>CTEN</i> promoter and mutations of the critical nucleotides in this region abolish ΔNp63α-induced promoter activity. The direct interaction of ΔNp63α with the <i>CTEN</i> promoter was demonstrated using a chromatin immunoprecipitation (ChIP) assay. Moreover, impaired cell adhesion caused by ΔNp63α depletion is rescued by over-expression of CTEN, suggesting that CTEN is a downstream effector of ΔNp63α-mediated cell adhesion. In summary, our findings demonstrate that ΔNp63α functions as a trans-activation factor of <i>CTEN</i> promoter and regulates cell adhesion through modulating CTEN. Our study further contributes to the potential regulatory mechanisms of CTEN in prostate cancer progression.</p></div