EGFR through STAT3 modulates ΔN63α expression to sustain tumor‐initiating cell proliferation in squamous cell carcinomas

Many squamous cell carcinomas (SCCs) are characterized by high levels of EGFR and by overexpression of the ΔNp63α isoform. Here, we investigated the regulation of ΔNp63α expression upon EGFR activation and the role of the EGFR–ΔNp63α axis in proliferation of SCC tumor‐initiating cells (TICs). SCC cell lines A‐431, Cal‐27, and SCC‐25 treated with EGF showed a time‐dependent increase in ΔNp63α expression at the protein and mRNA levels, which was blocked by the tyrosine kinase inhibitor (TKI) Lapatinib. RNA interference experiments suggested the role of STAT3 in regulating ΔNp63α expression downstream of EGFR. Inactivation of EGFR by the monoclonal antibody Cetuximab and RNA interference against STAT3 or ΔNp63α impaired the TICs ability to grow under non‐differentiating conditions. Radiation treatment, which triggers EGFR activation, induced ΔNp63α accumulation without affecting TICs proliferation, whereas the combination Cetuximab plus radiation significantly reduced TICs growth under non‐differentiating conditions. Together, our findings provide evidence that ΔNp63α expression is regulated by EGFR activation through STAT3 and that the EGFR–ΔNp63α axis is crucial for proliferation of TICs present in SCCs. J. Cell. Physiol. 228: 871–878, 2013. © 2012 Wiley Periodicals, Inc.     

Molecular Evolution of Viruses of the Family Filoviridae Based on 97 Whole-Genome Sequences

Viruses in the Ebolavirus and Marburgvirus genera (family Filoviridae) have been associated with large outbreaks of hemorrhagic fever in human and nonhuman primates. The first documented cases occurred in primates over 45 years ago, but the amount of virus genetic diversity detected within bat populations, which have recently been identified as potential reservoir hosts, suggests that the filoviruses are much older. Here, detailed Bayesian coalescent phylogenetic analyses are performed on 97 whole-genome sequences, 55 of which are newly reported, to comprehensively examine molecular evolutionary rates and estimate dates of common ancestry for viruses within the family Filoviridae. Molecular evolutionary rates for viruses belonging to different species range from 0.46 × 10⁻⁴ nucleotide substitutions/site/year for Sudan ebolavirus to 8.21 × 10⁻⁴ nucleotide substitutions/site/year for Reston ebolavirus. Most recent common ancestry can be traced back only within the last 50 years for Reston ebolavirus and Zaire ebolavirus species and suggests that viruses within these species may have undergone recent genetic bottlenecks. Viruses within Marburg marburgvirus and Sudan ebolavirus species can be traced back further and share most recent common ancestors approximately 700 and 850 years before the present, respectively. Examination of the whole family suggests that members of the Filoviridae, including the recently described Lloviu virus, shared a most recent common ancestor approximately 10,000 years ago. These data will be valuable for understanding the evolution of filoviruses in the context of natural history as new reservoir hosts are identified and, further, for determining mechanisms of emergence, pathogenicity, and the ongoing threat to public health.     

Relationships between nutrient enrichment,pleurocerid snail density and trematode infection rate in streams

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A modified FCR test to evaluate pollen viability in Juniperus communis L.

Pollen viability of Juniperus communis L. and other gymnosperms with taxoid type pollen cannot be assessed with the more common viability tests because the thick sporoderm prevents reagents from penetrating into the cytoplasm. Here we describe a technique for pre‐hydration of pollen that overcomes this problem so that the common FCR test can be used to assess its viability. Pollen of J. communis must be re‐hydrated by suspending in water. This re‐hydration causes the splitting of the exine and a huge swelling of the intine. The sporoderm becomes permeable to fluoresceine diacetate and the FCR‐viability test can be applied. The FCR result is supported by scoring the germination percentage in vitro.     

New structure–activity relationship studies in a series of N,N-bis(cyclohexanol)amine aryl esters as potent reversers of P-glycoprotein-mediated multidrug resistance (MDR)

As a continuation of previous research on a new series of potent and efficacious P-gp-dependent multidrug resistant (MDR) reversers with a N,N-bis(cyclohexanol)amine scaffold, we have designed and synthesized several analogs by modulation of the two aromatic moieties linked through ester functions to the N,N-bis(cyclohexanol)amine, aiming to optimize activity and to extend structure–activity relationships (SAR) within the series. This scaffold, when esterified with two different aromatic carboxylic acids, gives origin to four geometric isomers (cis/trans, trans/trans, cis/cis and trans/cis).The new compounds were tested on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay. Most of them resulted in being potent modulators of the extrusion pump P-gp, showing potency values ([I]_0.5) in the submicromolar and nanomolar range. Of these, compounds 2b, 2c, 3d, 5a–d and 6d, showed excellent efficacy with a α_max close to 1. Selected compounds (2d, 3a, 3b, 5a–d) were further studied to evaluate their doxorubicin cytotoxicity potentiation (RF) on doxorubicin-resistant erythroleukemia K562 cells and were found able to enhance significantly doxorubicin cytotoxicity on K562/DOX cells.The results of both pirarubicin uptake and the cytotoxicity assay, indicate that the new compounds of the series are potent P-gp-mediated MDR reversers. They present a structure with a mix of flexible and rigid moieties, a property that seems critical to allow the molecules to choose the most productive of the several binding modes possible in the transporter recognition site.In particular, compounds 5c and 5d, similar to the already reported analogous isomers 1c and 1d,²⁹ are potent and efficacious modulators of P-gp-dependent MDR and may be promising leads for the development of MDR-reversal drugs.     

High genetic diversity is not essential for successful introduction

Some introduced populations thrive and evolve despite the presumed loss of diversity at introduction. We aimed to quantify the amount of genetic diversity retained at introduction in species that have shown evidence of adaptation to their introduced environments. Samples were taken from native and introduced ranges of Arctotheca populifolia and Petrorhagia nanteuilii. Using microsatellite data, we identified the source for each introduction, estimated genetic diversity in native and introduced populations, and calculated the amount of diversity retained in introduced populations. These values were compared to those from a literature review of diversity in native, confamilial populations and to estimates of genetic diversity retained at introduction. Gene diversity in the native range of both species was significantly lower than for confamilials. We found that, on average, introduced populations showing evidence of adaptation to their new environments retained 81% of the genetic diversity from the native range. Introduced populations of P. nanteuilii had higher genetic diversity than found in the native source populations, whereas introduced populations of A. populifolia retained only 14% of its native diversity in one introduction and 1% in another. Our literature review has shown that most introductions demonstrating adaptive ability have lost diversity upon introduction. The two species studied here had exceptionally low native range genetic diversity. Further, the two introductions of A. populifolia represent the largest percentage loss of genetic diversity in a species showing evidence of substantial morphological change in the introduced range. While high genetic diversity may increase the likelihood of invasion success, the species examined here adapted to their new environments with very little neutral genetic diversity. This finding suggests that even introductions founded by small numbers of individuals have the potential to become invasive.     

The SH2 Domain Interaction Landscape

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Highlights? The recognition specificity of 70 SH2 domains is probed ? Recognition specificity diverges faster than sequence ? PepspotDB is a database of protein interactions mediated by SH2 domains     

Legionella pneumophila Effector RomA Uniquely Modifies Host Chromatin to Repress Gene Expression and Promote Intracellular Bacterial Replication

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Highlights? Upon infection, L. pneumophila secretes RomA, a SET domain-containing methyltransferase ? RomA triggers H3K14 trimethylation, causing a switch from gene activation to repression ? ChIP-seq identified 4,870 H3K14 methylated promoter regions, including innate immune genes ? RomA SET domain is required for efficient intracellular replication of L. pneumophila