EMBO Molecular Medicine Research Articles

The emerging role of Nrf2 in dermatotoxicology

The nuclear factor erythroid 2-related factor 2 (Nrf2) is best known for its role in resistance to oxidant stress. In this issue of EMBO Molecular Medicine, Nrf2-prolonged genetic activation is shown with devastating effects on skin homeostasis. The study provides novel molecular insights into poison-induced chloracne and metabolizing acquired dioxin-induced skin hamartomas or MADISH.

Biophysical Characterization of the Potassium Channel Kv1.3 in B Cells from Patients Affected by Chronic Lymphocytic Leukemia

Recent discoveries identified ion channels as possible targets for cancer treatment. We have previously demonstrated that inhibition of the mitochondria-located potassium channel Kv1.3 (mtKv1.3) by membrane permeant inhibitors Psora-4, PAP-1 and clofazimine triggers cell death both in vitro and in vivo, resulting in reduction of tumor volume up to 90% (Leanza et al, 2012, EMBO Molecular Medicine). Importantly, these compounds are able to selectively kill pathological B cells from patients affected by chronic lymphocytic leukemia (B-CLL) (Leanza et al, 2013, Leukemia). Here, we determined the expression profile of Kv1.3 by western blot comparing B cells from healthy subjects and B-CLL patients in whole cell lysates as well as in purified mitochondria. An increased expression of the channel in pathological cells compared to normal ones was observed. To our knowledge, electrophysiological characterization of Kv1.3 in B-CLL cells has not been performed up to now. By measuring Kv1.3 current in patch clamp experiments, both at whole cell and at single channel levels, here we show that increased protein expression was correlated with enhanced channel activity. Biophysical and pharmacological properties of Kv1.3 from the two cells types are reported. Experiments with pathological B-cells cultured in the presence of cells mimicking bone marrow environment are in progress.

A new endeavour

Editorial7 January 2014free access A new endeavour The Editors The Editors [email protected] EMBO Reports, Heidelberg, Germany Search for more papers by this author The Editors The Editors [email protected] EMBO Reports, Heidelberg, Germany Search for more papers by this author Author Information 1 1EMBO Reports, Heidelberg, Germany EMBO Reports (2014)15:2-2https://doi.org/10.1002/embr.201338177 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Over the past 13 years, we have published more than a thousand scientific research articles. Many thousands of scientists have trusted us to manage the assessment of their work and, all being well, disseminate it to the scientific community. We have been supported in this endeavor by Nature Publishing Group, who have been our publishing partners for most of the journal's history. It has been a long and fruitful partnership, but the time for change has come. The scientific publishing landscape is shifting in many directions. New vistas are opening up and finding our way across them—as scientists and editors—requires a change in perspective and the independence to do new things. EMBO is therefore launching its own scientific publishing identity, EMBO Press, in partnership with Wiley and HighWire Press, who will help us to realize our vision of fair, transparent and data-enriched scientific publishing. EMBO Reports will be an integral part of this endeavor: we will continue to apply and improve the EMBO Press editorial policies, including transparent peer-review, scooping protection, referee cross-commenting and the source data initiative, and we will continue to provide a forum for discussing the wider impact of and issues surrounding the scientific endeavour. EMBO Press will be a shared identity for the four EMBO journals: EMBO Reports, The EMBO Journal, Molecular Systems Biology and EMBO Molecular Medicine. As such, it will serve as a platform for our policies and initiatives, guided by the scientific community at large and by our international advisory boards of leading scientific researchers. We hope that a single, strong voice that pushes for greater fairness and transparency in the interest of the scientific community will improve the way that science is communicated and used, and that scientists are assessed. We understand that the true driving force of science is not money, fame or fashion; it is curiosity. Scientists ask questions about the world and work carefully to discover answers. We would like to publish those answers in a way that is fair to authors and useful to our readers and those who will revisit these questions in the future. What does this mean for EMBO Reports? For more than a decade now, in addition to high-quality, short-format scientific reports and accessible reviews, EMBO Reports has published Science & Society articles on the broader impact and implications of scientific research. We hope that EMBO Press will become home to an active community of engaged scientists for discussing such issues, including science research, practice, policy and, of course, publishing. Ideas and conversations might evolve into ‘formally’ published content in the EMBO Press journals, whilst EMBO Reports’ thought-provoking articles and editorials will gain a new platform for dissemination and debate. The most obvious and immediate change, then, is the launch of the EMBO Reports website, alongside the new EMBO Press platform. This will not just be a cosmetic makeover: in the months to come, we will make significant enhancements to the way that we help scientists present their data, making it more accessible and reusable, improving the experience for both authors and readers. We will also continue to refine our editorial policies, based on community feedback, to ensure that the assessment and publishing experience at the EMBO Press family of journals is among the fairest and most transparent. Together, these improvements will allow EMBO Reports to continue its mission of publishing groundbreaking, relevant observations that are both exciting and reliable. EMBO Press stands for a better way of tackling the publication of science, backed up by some thoughtful editorial policies and innovative ideas for technologies. As such, EMBO Press is a compass pointing in the direction we think we should take across the changing publishing landscape. We hope that our authors and readers will agree with us on the direction and lead us onward. It is an ambitious goal, but EMBO has always been about setting high standards and good examples. EMBO Press is the next step on the journey, and the editors of EMBO Reports are excited to be along for the ride. Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 15,Issue 1,January 2014Cover picture: inspired by the Scientific Report p 62 | Illustration by Uta Mackensen. Volume 15Issue 11 January 2014In this issue RelatedDetailsLoading ...

Inhibition of a Mitochondrial Potassium Channel as a New Therapeutic Strategy for Chronic Lymphocytic Leukemia

Ion channels are involved in the regulation of proliferation and apoptosis and are emerging as promising oncological targets. We have recently identified three membrane-permeant inhibitors of the Kv1.3 potassium channel as inducers of apoptosis. These inhibitors induce mitochondrial membrane potential changes, increase of ROS release and opening of the permeability transition pore finally leading to cytochrome c release and cells death. Death occurs only when Kv1.3 is active in the inner mitochondrial membrane (mtKv1.3) and also in the absence of Bax and Bak. Efficiency of one of these inhibitors to reduce tumor volume in vivo was demonstrated in a melanoma orthotopic mouse model (Leanza, et al., 2012 EMBO Molecular Medicine). The same signaling pathway and a selective action of the Kv1.3 inhibitors was observed in B lymphocytes of patients suffering of Chronic lymphocytic leukemia (B-CLL) (Leanza, et al., 2013 Leukemia). Regarding the mechanism of selectivity, we defined that synergy between the level of Kv1.3 expression and an altered redox state in B-CLL cells determines the susceptibility of these cells. Since Kv1.3 inhibitors kill B-CLL by direct interference with mitochondrial functions, they act on these malignant cells independent of classic prognostic factors and Bcl-2 overexpression. To generalize our findings, in addition to melanoma and B-CLL cells, the effect of these inhibitors on cell survival was measured on different cancer cell lines expressing Kv1.3. A correlation between Kv1.3 expression and susceptibility to mtKv1.3 inhibitors was found.

EMBO Molecular Medicine: Fast Forward

These are exciting times for translational medicine as the convergence between fundamental and clinical research comes of age. The new EMBO Press publishing platform reinforces the standing of EMBO Molecular Medicine as the journal that matches high quality, novel research with rigorous editorial and ethical standards. It will also cement the journal's global reach and relevance - whether in highly active fields or explorative forays into emerging areas.

The ‘captain of the men of death’, Streptococcus pneumoniae , fights oxidative stress outside the ‘city wall’

We have come a long way since Streptococcus pneumoniae was first isolated in 1880. Over the years, the ability to combat this gram‐positive bacterium branded ‘captain of the men of death’ by William Osler in 1918 has been greatly enhanced by the development of vaccines and antibiotics. However, despite the existence of these therapeutic strategies, S. pneumoniae continues to kill to this day. The bacterium, which is usually found as a resident of the human naso‐oropharynx, causes indeed serious invasive diseases such as pneumonia, bacteraemia and meningitis, especially in young children, the elderly and immunocompromised individuals. Worldwide, it causes between 700,000 to 1 million child deaths every year (O'Brien et al, 2009). The limitations of existing vaccines, the emergence of antibiotic resistant clones, and the aging of the population will only make the problem worse, calling for new approaches against this pathogenic microorganism. S. pneumoniae is an anaerobic bacterium. However, it is tolerant to the oxygen (O2) present in the respiratory tract and is equipped with antioxidant systems to fight reactive oxygen species (ROS). ROS, such as superoxide (![Formula][1] ) and hydrogen peroxide (H2O2), are produced by transfer of electrons to O2 following metabolic reactions or through the oxidative burst in neutrophils and macrophages. Like many other bacteria, S. pneumoniae possesses specialized antioxidant enzymatic squads that are in the front line to convert ROS to innocuous products unable to damage cellular components. The ROS detoxifying proteins that have been described in S. pneumoniae include a superoxide dismutase (SodA), a thiol peroxidase (TpxD) and an alkyl hydroperoxidase … [1]: /embed/mml-math-1.gif

A new inducible model for t(8;21) AML

Faithful and tractable mouse models for t(8;21)‐associated human acute myeloid leukaemia (AML) have been difficult to develop, limiting insight into the malignancy associated with this frequent chromosomal translocation. In this issue of EMBO Molecular Medicine , Cabezas‐Wallscheid et al. bring us a step closer to this goal with an improved Tet‐inducible mouse model of t(8;21)‐associated AML (Cabezas‐Wallscheid et al, 2013). The t(8;21) is found in approximately 10% of human AML and encodes for the leukaemia fusion protein AML1‐ETO (RUNX1‐RUNX1T1) (Miyoshi et al, 1993). The translocation results in a fusion protein comprised of the amino‐terminal part of RUNX1, including the conserved RUNT domain that is critical for function, and nearly the entire coding region of the ETO (RUNX1T1) protein. RUNX1 forms a heterodimeric transcription factor complex with the CBFβ protein. This complex is known as core binding factor (CBF), and both the RUNX1 gene on chromosome 21 and the CBFβ gene on chromosome 16 are involved in chromosomal translocations in 15–20% of human AML. CBF is a master regulator of haematopoiesis and knockout of either RUNX1 or CBFβ results in embryonic lethality due to failure of definitive haematopoiesis (Chuang et al, 2013). The ETO protein is a transcriptional repressor that associates with nuclear co‐repressor proteins and histone deacetylase activity. Although the molecular mechanisms through which AML1‐ETO exerts its effects are unclear, it is likely that the strong repressor function contributed by ETO is critical. Repression of numerous genes involved in haematopoietic differentiation, including CEBPA and SPI1 (PU.1), likely plays an important role in the functional outcome upon expression of AML1‐ETO. However, it is clear from various studies that AML1‐ETO is not solely functioning as a strong transcriptional repressor of CBF activity. Many genes are directly up‐regulated by AML1‐ETO, and the molecular mechanisms involved in these processes are the subject of …

Gene therapy shows potential as Usher syndrome treatment

Gene therapy shows potential as Usher syndrome treatment

Cross‐presentation of malaria antigen by brain microvessels: why CD8+ T cells are critical for the pathogenesis of experimental cerebral malaria

Cross‐presentation of malaria antigen by brain microvessels: why <scp>CD</scp>8⁺ T cells are critical for the pathogenesis of experimental cerebral malaria

Farber disease: understanding a fatal childhood disorder and dissecting ceramide biology

Farber disease: understanding a fatal childhood disorder and dissecting ceramide biology

From Mutation Identification to Therapy: Discovery and Origins of the First Approved Gene Therapy in the Western World

On November 2, 2012, Glybera® (alipogene tipovarvec) was the first human gene therapy to receive long awaited market approval in the Western world. This important milestone is expected to open the door to additional gene therapies for the treatment of many diseases in the future. The development of this new gene therapy involved the dedicated contributions from many people from around the world

BiotecVisions 2013, February

BiotecVisions 2013, February

The stem and roots of Wilms' tumours

AbstractSee related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201201516

The cancer stem cell model: B cell acute lymphoblastic leukaemia breaks the mould

AbstractSee related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201201703

Asthma exacerbations: a molecular dichotomy between antiviral and pro-inflammatory responses revealed.

Acute exacerbations are the major cause of morbidity, mortality and healthcare costs for individuals with asthma. They are the main cause of hospitalizations and are poorly controlled by current medication. It is therefore disappointing that we still know so little about the mechanistic details of asthma exacerbations. In this issue of EMBO Molecular Medicine , Bartlett et al. suggest that the transcription factor NF‐κB, and specifically its subunit p65, is a key determinant of acute exacerbations of asthma, and propose a molecular dichotomy in the regulation of pro‐inflammatory versus antiviral responses in asthmatic individuals that is mediated by p65 NF‐κB and the type I interferon (IFN) system (Bartlett et al, 2012). Asthma exacerbations are mostly triggered by respiratory infections of which rhinoviruses (RV), ssRNA viruses of the Picornaviridae family that cause common cold, are the most frequent (Busse et al, 2010). Other respiratory tract infections that can also trigger exacerbations include influenza, parainfluenza and respiratory syncytial virus in children. Asthmatic patients have increased susceptibility to respiratory infections, especially of the lower respiratory tract, and respiratory infections cause in turn more severe episodes of dyspnoea and wheezing in these patients. Presence of allergic sensitization further increases the risk for infections, the severity of exacerbations and the chances for hospital admission compared to non‐sensitized asthmatic individuals. It is therefore essential to understand the complex interplay between sensitivity to infections, viral clearance and exacerbation of asthmatic inflammation in order to pave the way for the development of novel therapeutics.. . .it is possible to dissociate antiviral from pro‐inflammatory responses simply by inhibiting the p65 subunit of NF‐κB. . . To explain virus‐induced exacerbations, several hypotheses have been advanced that attribute asthma attacks to immune‐mediated exacerbations, direct viral injury, or both (Jackson et al, 2011). Virus infections can fuel innate and adaptive …

BiotecVisions 2012, November

BiotecVisions 2012, November

Back to the future: a new 'old' lead for tuberculosis.

See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201201689 ‘The Great White Plague, which only 10 years ago was thought to be immune to drug therapy, is gradually being eliminated. . . Streptomycin pointed a way. Later supplemented with PAS (para‐amino salicylic acid) and more recently with isoniazid, it has brought the control of this disease within sight’. Selman A. Waksman, Noble Prize Banquet Speech 1952. Despite the breakthroughs in management of tuberculosis noted by Waksman 8 years after his discovery of the first effective antitubercular drug, streptomycin (Schatz et al, 1944), the disease continues to infect, incapacitate and kill in the 21st century. Over 8.8 million are infected and 1.4 million die every year (www.who.int/mediacentre/factsheets/fs104/en/index.html). The organism that causes tuberculosis, Mycobacterium tuberculosis , has proven to be a formidable match for our ability to control disease. At the core of this challenge is the remarkable physiology and biochemistry of M. tuberculosis and its ability to reside in a dormant state within human macrophages. These unique characteristics necessitate multidrug therapy, typically ≥4 antibiotics, and extended periods of dosing (6–12 months). The rise of strains resistant to multiple drugs MDR (multi‐drug‐resistant) resistant to rifampin and isoniazid, XDR (extensive‐drug‐resistant) resistant to even more antibiotics, and now some strains totally impervious to all available drugs, TDR (totally drug‐resistant) raises the specter of the emergence of a global health care disaster and a return to a pre‐Waksman era of tuberculosis treatment (Zumla et al, 2012). The result is a great need for new therapies and a renewed effort to find new anti‐TB antibiotics. The result is a great need for new therapies …

Dendrimers branch out to support mucosal integrity

See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201201290 Dendritic polymer technology represents one of the most exciting areas at the interface of polymer chemistry and medical science. Dendritic polymers or dendrimers are symmetrical structurally perfect branching molecules synthesized from a central core molecule set, which are classified by the number of branching cycles or generations (Walter & Malkoch, 2012). Dendrimers typically contain a central cavity and beyond three generations, they adopt a spherical configuration. An increasing number of branching generations augment the number of functionalizable groups on the surface available to carry specific molecules or to directly interact with reaction partners. Dendritic polymers may have a range of functional properties including the capacity to function as catalysts, as biosensors or even as anti‐bacterial agents. Within biomedicine, dendrimers have been utilized as delivery systems for drugs and in particular hydrophobic agents, radioligands and other imaging molecules. Current research has also focused on dendrimers as vehicles for delivery of DNA with potential for gene therapy. They may be functionalized in a number of ways to improve cellular access through modification or coating of the dendrimer surface. In addition, dendrimers may have similar structural properties to molecules such as hemoglobin, porphyrins and others and have the potential to be modified to produce synthetic variants of naturally occurring biological molecules such as heme to be used as carriers for heme‐mimetics as potential blood substitutes (Palivan et al, 2012; Walter & Malkoch, 2012). The recent work by Teo et al in EMBO Molecular Medicine (Teo et al, 2012) has identified a further potential application for a surface‐modified dendrimer. These investigators identified a key interaction within the innate immune system as the target for the development of specific bioactive dendrimers. Bacteria, …

Novel non‐coding RNA‐based therapeutic approaches to prevent statin‐induced liver damage

See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201201228 MicroRNAs (miRNAs) are tiny non‐coding ribonucleic acids (RNAs) that control gene expression of target messenger RNA (mRNAs) at the posttranscriptional level by mRNA degradation or translational repression. Thus, miRNAs have emerged as critical regulators during physiological and pathological processes (Thum et al, 2007). Recently, several reports have revealed an important role for miRNAs in cholesterol and fatty acid homeostasis and also insulin signalling (Davalos et al, 2011; Marquart et al, 2010; Najafi‐Shoushtari et al, 2010; Rayner et al, 2010, 2011a). Cholesterol is a precursor in metabolic pathways and an important structural component in the cell membrane of most vertebrates. Notably, dysfunction in cholesterol homeostasis is linked to metabolic syndrome, atherosclerosis and type‐2 diabetes (Rayner et al, 2011b). In general, the cholesterol metabolism is a complex process which is regulated mainly by three transcription factors; sterol regulatory element binding protein (SREBP), liver X receptor (LXR) and Farnesoid X receptor (FXR) (Beaven & Tontonoz, 2006). Further, it has been recently shown that also miRNAs particularly miR‐33 posttranscriptionally control cholesterol metabolism (Marquart et al, 2010; Rayner et al, 2010, 2011a). MiR‐33 is an evolutionarily conserved miRNA that is located within intron 16 of the gene encoding sterol‐regulatory element‐binding protein‐2 (SREBP‐2) and is co‐transcribed with its host gene (Rayner et al, 2010). Moreover, miR‐33 targets the sterol transporters ABCG1 and ABCA1 (ATP‐binding cassette transporters) and decreases the efflux of cholesterol to high‐density lipoproteins (HDL) which are involved in the removal of excess cholesterol from the body (Horie et al, 2010; Rayner et al, 2010). Silencing of miR‐33 levels in vivo increased circulating HDL levels and promoted reverse cholesterol transport (RCT) suggesting a new therapy strategy to treat atherosclerosis and other metabolic diseases (Rayner et al, 2011a, …

IGF2: The Achilles' heel of p53‐deficiency?

See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201101105 There is growing evidence that inactivation of the p53 tumour suppressor pathway is required for full‐blown tumourigenesis (Levine, 1997). While half of human cancers harbour mutations or deletions of the p53 tumour suppressor locus, the remaining cancers employ alternative mechanisms to subvert the activity of wild‐type p53. This clinically relevant pathway has therefore logically become the target for the development of innovative avenues in cancer therapy. For instance, restoration of p53 function has been extensively pursued as a therapeutic modality in cancers in which p53 function is compromised although the TP53 locus remains intact (Brown et al, 2009). Such approach is, however, only applicable to tumours expressing wild‐type p53. Because alteration of p53 is so frequent in cancer, identification of synthetic lethal partners of p53 should lead to conceptually simple and attractive approaches to selective targeting of cancer cells (Kaelin, 2005). Inactivation of such a target would in theory be detrimental to virtually all cancer cells irrespective of the mechanisms that led to p53 inactivation. In the present issue, Haley and colleagues (Haley et al, 2012) provide evidence for a synthetic lethal interaction between the p53 and Igf2 pathways. IGF2 is a growth‐promoting hormone during gestation and commonly overexpressed in human cancer through re‐expression of the imprinted maternal allele by loss of imprinting (LOI). IGF‐2 exerts its effects by binding to the IGF‐1 receptor and activating both the PI3K‐AKT‐mTOR and RAS‐RAF‐MEK‐ERK downstream signalling pathways. Although previous in vitro studies highlighted several mechanistic pathway interactions between IGF2 and p53 signalling genetic evidence for such interactions was lacking. To search for such genetic links in vivo , Haley and colleagues engineered mice with varying allelic doses …