Showing papers in "Signal Transduction and Targeted Therapy in 2016"

The role of MicroRNAs in human cancer

Abstract: MicroRNAs (miRNAs) are endogenous, small non-coding RNAs that function in regulation of gene expression. Compelling evidences have demonstrated that miRNA expression is dysregulated in human cancer through various mechanisms, including amplification or deletion of miRNA genes, abnormal transcriptional control of miRNAs, dysregulated epigenetic changes and defects in the miRNA biogenesis machinery. MiRNAs may function as either oncogenes or tumor suppressors under certain conditions. The dysregulated miRNAs have been shown to affect the hallmarks of cancer, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, activating invasion and metastasis, and inducing angiogenesis. An increasing number of studies have identified miRNAs as potential biomarkers for human cancer diagnosis, prognosis and therapeutic targets or tools, which needs further investigation and validation. In this review, we focus on how miRNAs regulate the development of human tumors by acting as tumor suppressors or oncogenes.

Treatment of CD20-directed Chimeric Antigen Receptor-modified T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an early phase IIa trial report.

Abstract: Patients with relapsed or refractory non-Hodgkin lymphoma have a dismal prognosis. Chimeric Antigen Receptor (CAR)-modified T cells (CART cells) that targeted CD20 were effective in a phase I clinical trial for patients with advanced B-cell lymphomas. We performed a phase IIa trial to further assess the safety and efficacy of administering autologous anti-CD20 CART (CART-20) cells to patients with refractory or relapsed CD20+ B-cell lymphoma. Eleven patients were enrolled, and seven patients underwent cytoreductive chemotherapy to debulk the tumors and deplete the lymphocytes before receiving T-cell infusions. The overall objective response rate was 9 of 11 (81.8%), with 6 complete remissions (CRs) and 3 partial remissions; no severe toxicity was observed. The median progression-free survival lasted for >6 months, and 1 patient had a 27-month continuous CR. A significant inverse correlation between the levels of the CAR gene and disease recurrence or progression was observed. Clinically, the lesions in special sites, specifically the spleen and testicle, were refractory to CART-20 treatment. Collectively, these results together with our data from phase I strongly demonstrated the feasibility and efficacy of CART-20 treatment in lymphomas and suggest large-scale patient recruitment in a future study. This study was registered at www.clinicaltrials.org as NCT01735604.

Inhibiting cancer cell hallmark features through nuclear export inhibition.

Abstract: Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. Nuclear export factor chromosomal region maintenance 1 (CRM1; Xpo1 and exportin-1) controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials (phase I-III) on both advanced-stage solid and hematological tumors. In this review, we compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy.

Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer

Abstract: As tumor PD-L1 provides signals to anti-tumor PD-1+ T cells that blunt their functions, αPD-1 and αPD-L1 antibodies have been developed as anti-cancer immunotherapies based on interrupting this signaling axis. However, tumor cell-intrinsic PD-L1 signals also regulate immune-independent tumor cell proliferation and mTOR signals, among other important effects. Tumor-initiating cells (TICs) generate carcinomas, resist treatments and promote relapse. We show here that in murine B16 melanoma and ID8agg ovarian carcinoma cells, TICs express more PD-L1 versus non-TICs. Silencing PD-L1 in B16 and ID8agg cells by shRNA (‘PD-L1lo’) reduced TIC numbers, the canonical TIC genes nanog and pou5f1 (oct4), and functions as assessed by tumorosphere development, immune-dependent and immune-independent tumorigenesis, and serial transplantability in vivo. Strikingly, tumor PD-L1 sensitized TIC to interferon-γ and rapamycin in vitro. Cell-intrinsic PD-L1 similarly drove functional TIC generation, canonical TIC gene expression and sensitivity to interferon-γ and rapamycin in human ES2 ovarian cancer cells. Thus, tumor-intrinsic PD-L1 signals promote TIC generation and virulence, possibly by promoting canonical TIC gene expression, suggesting that PD-L1 has novel signaling effects on cancer pathogenesis and treatment responses. The tumor-cell signaling molecule PD-L1 promotes self-renewal tumor initiating cells (TICs) in melanoma and ovarian cancer. PD-L1 is known to help cancer cells evade the immune response by inhibiting T-cell activity. Now, Tyler Curiel at the University of Texas Health Science Center at San Antonio and colleagues show that PD-L1 has important effects on cancer cells themselves. They found that PD-L1 increases the number of treatment-resistant TICs in mouse and human cancer cell lines by stimulating the expression of genes associated with long-term self-renewal. Interestingly, it also sensitizes these cells to the anti-cancer action of interferon-? and rapamycin. These findings highlight differences between TICs and differentiated tumor cells, which could explain their distinct responses to treatment. Further understanding the effects of PD-L1 signaling will contribute to the development of more effective therapeutic strategies.

Seeing is believing: anti-PD-1/PD-L1 monoclonal antibodies in action for checkpoint blockade tumor immunotherapy

Abstract: Structural immunology, focusing on structures of host immune related molecules, enables the immunologists to see what the molecules look like, and more importantly, how they work together. Antibody-based PD-1/PD-L1 blockade therapy has achieved brilliant successes in clinical applications. The recent breakthrough of the complex structures of checkpoint blockade antibodies with their counterparts, pembrolizumab with PD-1 and avelumab with PD-L1, have made it clear how these monoclonal antibodies compete the binding of PD-1/PD-L1 and function to blockade the receptor-ligand interaction. Herein, we summarize the structural findings of these two reports and look into the future for how this information would facilitate the development of more efficient PD-1/PD-L1 targeting antibodies, small molecule drugs, and other protein or non-protein inhibitors.

USP21 deubiquitylates Nanog to regulate protein stability and stem cell pluripotency

Abstract: The homeobox transcription factor Nanog has a vital role in maintaining pluripotency and self-renewal of embryonic stem cells (ESCs). Stabilization of Nanog proteins is essential for ESCs. The ubiquitin-proteasome pathway mediated by E3 ubiquitin ligases and deubiquitylases is one of the key ways to regulate protein levels and functions. Although ubiquitylation of Nanog catalyzed by the ligase FBXW8 has been demonstrated, the deubiquitylase that maintains the protein levels of Nanog in ESCs yet to be defined. In this study, we identify the ubiquitin-specific peptidase 21 (USP21) as a deubiquitylase for Nanog, but not for Oct4 or Sox2. USP21 interacts with Nanog protein in ESCs in vivo and in vitro. The C-terminal USP domain of USP21 and the C-domain of Nanog are responsible for this interaction. USP21 deubiquitylates the K48-type linkage of the ubiquitin chain of Nanog, stabilizing Nanog. USP21-mediated Nanog stabilization is enhanced in mouse ESCs and this stabilization is required to maintain the pluripotential state of the ESCs. Depletion of USP21 in mouse ESCs leads to Nanog degradation and ESC differentiation. Overall, our results demonstrate that USP21 maintains the stemness of mouse ESCs through deubiquitylating and stabilizing Nanog.

Human IgG1 antibodies suppress angiogenesis in a target-independent manner.

Abstract: Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world's population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab's Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.

TIFA suppresses hepatocellular carcinoma progression via MALT1-dependent and -independent signaling pathways

Abstract: Research elucidating how a protein suppresses the progression of liver cancer could provide new therapeutic targets, say researchers in China. A team led by Rong Xiang and Na Luo at Nankai University examined liver biopsies of patients with hepatocellular carcinoma (HCC), the third most common cause of cancer-related death worldwide. They also grafted HCC cells under the skin of mice. They found that a protein, called TIFA, suppresses the progression of HCC via one of three pathways. One involves competition with another protein, MALT1, to bind with the protein TRAF6, signaling pathways that induce cancer cell death. TIFA-induced cell death also results from suppressing MALT1. Finally, TIFA expression can also activate two genes, JNK and p38, which signal cell death and cell cycle arrest, respectively. The research may provide insights into drug targets that could affect HCC progression.

A novel cancer vaccine with the ability to simultaneously produce anti-PD-1 antibody and GM-CSF in cancer cells and enhance Th1-biased antitumor immunity

Abstract: Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T-cell activation. A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as program death-1 (PD-1/PD-L1) pathway in the tumor environment. However, the determinants of response to anti-PD-1 monoclonal antibodies (mAbs) treatment remain incompletely understood. In murine models, PD-1 blockade alone fails to induce effective immune responses to poorly immunogenic tumors, but is successful when combined with additional interventions, such as cancer vaccines. Novel cancer vaccines combined with antibody may offer promising control of cancer development and progression. In this investigation, we generated a novel tumor cell vaccine simultaneously expressing anti-PD-1 mAbs and granulocyte-macrophage colony stimulating factor (GM-CSF) in CT26 colon cancer and B16-F10 melanoma. The antitumor effect of the vaccine was verified by therapeutic and adoptive animal experiments in vivo. The antitumor mechanism was analyzed using Flow cytometry, Elispot and in vivo intervention approaches. The results showed that tumor cell vaccine secreting PD-1 neutralizing antibodies and GM-CSF induced remarkable antitumor immune effects and prolonged the survival of tumor-bearing animals compared with animals treated with either PD-1 mAbs or GM-CSF alone. Antitumor effects and prolonged survival correlated with strong antigen-specific T-cell responses by analyzing CD11c+CD86+ DC, CD11b+F4/80+ MΦ cells, increased ratio of Teff/Treg in the tumor microenvironment, and higher secretion levels of Th1 proinflammatory cytokines in serum. Furthermore, the results of ELISPOT and in vivo blocking strategies further confirmed that the antitumor immune response is acquired by CD4 and CD8 T immune responses, primarily dependent on CD4 Th1 immune response, not NK innate immune response. The combination of PD-1 blockade with GM-CSF secretion potency creates a novel tumor cell vaccine immunotherapy, affording significantly improved antitumor responses by releasing the state of immunosuppressive microenvironment and augmenting the tumor-reactive T-cell responses.

Osteosarcoma: prognosis plateau warrants retinoblastoma pathway targeted therapy.

Abstract: Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents, affecting ~560 young patients in the United States annually. The term OS describes a diverse array of subtypes with varying prognoses, but the majority of tumors are high grade and aggressive. Perhaps because the true etiology of these aggressive tumors remains unknown, advances in OS treatment have reached a discouraging plateau, with only incremental improvements over the past 40 years. Thus, research surrounding the pathogenesis of OS is essential, as it promises to unveil novel therapeutic targets that can attack tumor cells with greater specificity and lower toxicity. Among the candidate molecular targets in OS, the retinoblastoma (RB) pathway demonstrates the highest frequency of inactivation and thus represents a particularly promising avenue for molecular targeted therapy. This review examines the present thinking and practices in OS treatment and specifically highlights the relevance of the RB pathway in osteosarcomagenesis. Through further investigation into RB pathway-related novel therapeutic targets, we believe that a near-term breakthrough in improved OS prognosis is possible.

Transferrin protects against Parkinsonian neurotoxicity and is deficient in Parkinson's substantia nigra.

Abstract: Iron deposition in Parkinson's disease (PD) is a potential disease-modifying target. We previously showed that supplementation of the iron-exporter, ceruloplasmin, selectively corrected nigral iron elevation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Ceruloplasmin delivers iron to transferrin (Tf), the extracellular iron-transporting protein. We show that Tf protein levels are decreased in the nigra of post-mortem PD brains compared with controls (-35%; n=10 each). Because Tf traffics iron away from iron-replete tissues, we hypothesized that Tf supplementation could selectively facilitate iron export from the nigra in PD. In cultured neurons, Tf treatment corrected iron accumulation, and subcutaneous Tf to mice ameliorated iron accumulation and motor deficits in the MPTP model of PD. Although these data support a role for Tf in the disease mechanism for PD, and its potential use for correcting disorders of iron overload, Tf therapy also caused systemic iron depletion, which could limit its application for PD.

Targeting duplex DNA with the reversible reactivity of quinone methides.

Abstract: DNA alkylation and crosslinking remains a common and effective strategy for anticancer chemotherapy despite its infamous lack of specificity. Coupling a reactive group to a sequence-directing component has the potential to enhance target selectivity but may suffer from premature degradation or the need for an external signal for activation. Alternatively, quinone methide conjugates may be employed if they form covalent but reversible adducts with their sequence directing component. The resulting self-adducts transfer their quinone methide to a chosen target without an external signal and avoid off-target reactions by alternative intramolecular self-trapping. Efficient transfer is shown to depend on the nature of the quinone methide and the sequence-directing ligand in applications involving alkylation of duplex DNA through a triplex recognition motif. Success required an electron-rich derivative that enhanced the stability of the transient quinone methide intermediate and a polypyrimidine strand of DNA to associate with its cognate polypurine/polypyrimidine target. Related quinone methide conjugates with peptide nucleic acids were capable of quinone methide transfer from their initial precursor but not from their corresponding self-adduct. The active peptide nucleic acid derivatives were highly selective for their complementary target. Chemical agents that bind and reversibly modify specific DNA sequences could provide the foundation for safer anticancer treatments. Seeing that many current chemotherapy agents kill cancer cells by introducing irreversible modifications at any site in the genome—damaging non-target cells while also depleting the amount of drug available to fight cancer—Steven Rokita at the University of Maryland, along with colleagues in China, sought a more selective and safer approach to treatment. They combined DNA-modifying compounds known as quinone methides with nucleic acid constructs that specifically bind particular gene sequences, allowing for targeted treatment. Importantly, these chemical modifications are potentially reversible, minimizing the damage that occurs if the quinone methide-nucleic acid conjugates briefly bind the wrong DNA sequence. This could open doors for the development of less toxic, targeted chemotherapies that are effective at lower doses.

Intravenous immune globulin suppresses angiogenesis in mice and humans

Abstract: Human intravenous immune globulin (IVIg), a purified IgG fraction composed of ~ 60% IgG1 and obtained from the pooled plasma of thousands of donors, is clinically used for a wide range of diseases. The biological actions of IVIg are incompletely understood and have been attributed both to the polyclonal antibodies therein and also to their IgG (IgG) Fc regions. Recently, we demonstrated that multiple therapeutic human IgG1 antibodies suppress angiogenesis in a target-independent manner via FcγRI, a high-affinity receptor for IgG1. Here we show that IVIg possesses similar anti-angiogenic activity and inhibited blood vessel growth in five different mouse models of prevalent human diseases, namely, neovascular age-related macular degeneration, corneal neovascularization, colorectal cancer, fibrosarcoma and peripheral arterial ischemic disease. Angioinhibition was mediated by the Fc region of IVIg, required FcγRI and had similar potency in transgenic mice expressing human FcγRs. Finally, IVIg therapy administered to humans for the treatment of inflammatory or autoimmune diseases reduced kidney and muscle blood vessel densities. These data place IVIg, an agent approved by the US Food and Drug Administration, as a novel angioinhibitory drug in doses that are currently administered in the clinical setting. In addition, they raise the possibility of an unintended effect of IVIg on blood vessels.

Neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy

Abstract: Diabetic retinopathy (DR) affects approximately one-third of diabetic patients and, if left untreated, progresses to proliferative DR (PDR) with associated vitreous hemorrhage, retinal detachment, iris neovascularization, glaucoma and irreversible blindness. In vitreous samples of human patients with PDR, we found elevated levels of hypoxia inducible factor 1 alpha (HIF1α). HIFs are transcription factors that promote hypoxia adaptation and have important functional roles in a wide range of ischemic and inflammatory diseases. To recreate the human PDR phenotype for a preclinical animal model, we generated a mouse with neuroretinal-specific loss of the von Hippel Lindau tumor suppressor protein, a protein that targets HIF1α for ubiquitination. We found that the neuroretinal cells in these mice overexpressed HIF1α and developed severe, irreversible ischemic retinopathy that has features of human PDR. Rapid progression of retinopathy in these mutant mice should facilitate the evaluation of therapeutic agents for ischemic and inflammatory blinding disorders. In addition, this model system can be used to manipulate the modulation of the hypoxia signaling pathways, for the treatment of non-ocular ischemic and inflammatory disorders. Scientists in the USA have developed a mouse model to study blindness in humans. Stephen Tsang at Columbia University Medical Center, together with collaborators across the country, aimed to clarify the mechanisms of the key symptoms of proliferative diabetic retinopathy (PDR), the leading cause of blindness in Americans aged 20 to 64. Vinit Mahajan at the University of Iowa discovered high levels of a transcription factor in samples from the eyes of PDR patients but not in those who had been successfully treated. To create a useful animal model, the scientists genetically engineered mice to inactivate the repressor of the transcription factor in retinal neurons. The mice developed a retinal disease that advances in the same way as PDR in humans. This animal model is expected to improve understanding of PDR and other diseases.

Lyn prevents aberrant inflammatory responses to Pseudomonas infection in mammalian systems by repressing a SHIP-1-associated signaling cluster

Abstract: The pleiotropic Src kinase Lyn has critical roles in host defense in alveolar macrophages against bacterial infection, but the underlying mechanism for Lyn-mediated inflammatory response remains largely elusive. Using mouse Pseudomonas aeruginosa infection models, we observed that Lyn−/− mice manifest severe lung injury and enhanced inflammatory responses, compared with wild-type littermates. We demonstrate that Lyn exerts this immune function through interaction with IL-6 receptor and cytoskeletal protein Ezrin via its SH2 and SH3 domains. Depletion of Lyn results in excessive STAT3 activation, and enhanced the Src homology 2-containing inositol-5-phopsphatase 1 (SHIP-1) expression. Deletion of SHIP-1 in Lyn−/− mice (double knockout) promotes mouse survival and reduces inflammatory responses during P. aeruginosa infection, revealing the rescue of the deadly infectious phenotype in Lyn deficiency. Mechanistically, loss of SHIP-1 reduces NF-κB-dependent cytokine production and dampens MAP kinase activation through a TLR4-independent PI3K/Akt pathway. These findings reveal Lyn as a regulator for host immune response against P. aeruginosa infection through SHIP-1 and IL-6/STAT3 signaling pathway in alveolar macrophages. A protein that constrains the immune response plays a critical role in minimizing the damage inflicted by bacterial lung infections. An overreaction by a patient’s immune defenses can be just as deadly as an under-reaction. A protein called Lyn helps maintain an appropriate balance. Now, researchers led by Min Wu of the University of North Dakota have discovered how Lyn helps prevent respiratory infection by the pathogen Pseudomonas aeruginosa from turning fatal. They found that Lyn-deficient mice are far more likely to die from exposure to this bacterium, suffering extensive lung tissue damage. Closer examination revealed that this damage results from an uncontrolled inflammatory response, which is normally constrained by Lyn. Wu and colleagues also identified proteins that Lyn interacts with to exert this control, revealing cellular pathways that could be manipulated to fight infection.

G-protein-coupled receptors mediate 14-3-3 signal transduction.

Abstract: G-protein-coupled receptor (GPCR)-interacting proteins likely participate in regulating GPCR signaling by eliciting specific signal transduction cascades, inducing cross-talk with other pathways, and fine tuning the signal. However, except for G-proteins and β-arrestins, other GPCR-interacting proteins are poorly characterized. 14-3-3 proteins are signal adaptors, and their participation in GPCR signaling is not well understood or recognized. Here we demonstrate that GPCR-mediated 14-3-3 signaling is ligand-regulated and is likely to be a more general phenomenon than suggested by the previous reports of 14-3-3 involvement with a few GPCRs. For the first time, we can pharmacologically characterize GPCR/14-3-3 signaling. We have shown that GPCR-mediated 14-3-3 signaling is phosphorylation-dependent, and that the GPCR/14-3-3 interaction likely occurs later than receptor desensitization and internalization. GPCR-mediated 14-3-3 signaling can be β-arrestin-independent, and individual agonists can have different potencies on 14-3-3 and β-arrestin signaling. GPCRs can also mediate the interaction between 14-3-3 and Raf-1. Our work opens up a new broad realm of previously unappreciated GPCR signal transduction. Linking GPCRs to 14-3-3 signal transduction creates the potential for the development of new research directions and provides a new signaling pathway for drug discovery.

Genetic and environmental factors strongly influence risk, severity and progression of age-related macular degeneration

Abstract: Age-related macular degeneration (AMD) is characterized by complex interactions between genetic and environmental factors. Here we genotyped the selected 25 single-nucleotide polymorphisms (SNPs) in 983 cases with advanced AMD and 271 cases with intermediate AMD and build an AMD life-risk score model for assessment of progression from intermediate to advanced AMD. We analyzed the performance of the prediction model for geographic atrophy progressors or choroidal neovascularization progressors versus non-progressors based on the 25 SNPs plus body mass index and smoking status. Our results suggest that a class prediction algorithm can be used for the risk assessment of progression from intermediate to late AMD stages. The algorithm could also be potentially applied for therapeutic response, and toward personalized care and precision medicine.

The competing mini-dumbbell mechanism: new insights into CCTG repeat expansion

Abstract: CCTG repeat expansions in intron 1 of the cellular nucleic acid-binding protein gene are associated with myotonic dystrophy type 2. Recently, we have reported a novel mini-dumbbell (MDB) structure formed by two CCTG or TTTA repeats, which potentially has a critical role in repeat expansions. Here we present a mechanism, called the competing MDB mechanism, to explain how the formation of MDB can lead to efficient mismatch repair (MMR) escape and thus CCTG repeat expansions during DNA replication. In a long tract of CCTG repeats, two competing MDBs can be formed in any segment of three repeats. Fast exchange between these MDBs will make the commonly occupied repeat behave like a mini-loop. Further participations of the 5'- or 3'-flanking repeat in forming competing MDBs will make the mini-loop shift in the 5'- or 3'-direction, thereby providing a pathway for the mini-loop to escape from MMR. To avoid the complications due to the formation of hairpin conformers in longer CCTG repeats, we made use of TTTA repeats as model sequences to demonstrate the formation of competing MDBs and shifting of mini-loop in a long tract of repeating sequence.

From a retrovirus infection of mice to a long noncoding RNA that induces proto-oncogene transcription and oncogenesis via an epigenetic transcription switch.

Abstract: Here I review the properties of the mouse retroelement VL30-1, which apparently derived from retrotranspostions of a founder VL30 retrovirus that infected the mouse germline after the mouse-human speciation. The VL30-1 gene is transcribed as a long noncoding RNA (lncRNA) with an essential host function in an epigenetic transcription switch (ETS) that regulates transcription of multiple genes, including proto-oncogenes that control cell proliferation and oncogenesis. The ETS involves the tumor suppressor protein PSF that has a DNA-binding domain (DBD) and two RNA-binding domains (RBDs). The DBD binds to promoters that have a DBD-binding sequence and switches off transcription, and the RBDs bind lncRNAs that have a RBD-binding sequence, releasing PSF and switching on transcription. VL30-1 lncRNA has two RBD-binding sequences, apparently acquired by mutations during retrotranspositions of the founder retrovirus, which drive proto-oncogene transcription and oncogenesis via the ETS. VL30-1 lncRNA is a seminal example of the key role of endogenous retroviruses (ERVs) and their retroelements in the evolution of transcription regulatory systems.

Peptide-substituted Oligonucleotide Synthesis and Non-Toxic, Passive Cell Delivery

Abstract: Chemically modified oligodeoxynucleotides (ODNs) are known to modulate gene expression by interacting with RNA. An efficient approach for synthesizing amino acid- or peptide-substituted triazolylphosphonate analogs (TP ODNs) has been developed to provide improved stability and cell uptake. The chemistry is quite general, as peptides can be introduced throughout the TP ODN at any preselected internucleotide linkage. These synthetic TP ODNs enter cells through endocytosis in the absence of transfection reagents and localize into perinuclear organelles. The entrapped ODNs are released into the cytoplasm by treatment with endosomal-releasing agents and several are then active as microRNA inhibitors.

Announcing Signal Transduction and Targeted Therapy .

Abstract: Since the concept of signal transduction was introduced in the 1970s, various signal transduction pathways and signaling molecules have been identified. A major driving force in this field is the potential for signaling pathway-targeted therapy in clinical applications. Indeed, the fundamental research in cell signal transduction has led to the success of targeted therapies, such as imatinib (Gleevec; Novartis, Basel, Switzerland), for the treatment of chronic myelogenous leukemia, and trastuzumab (Herceptin; Roche/Genentech, South San Francisco, CA, USA), for the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer, which, in turn, has further stimulated basic research in signal transduction. Despite advances in our understanding of signal transduction and signaling pathway-targeted therapies, there are still many challenges to be faced. The cell signaling network and its regulation are more complicated than previously anticipated. Signal transduction between cells and between tissues is still far from understood. Constantly emerging gene mutations and drug resistance to targeted therapies indicate unmet clinical needs. Furthermore, the growing publication record indicates the field is rapidly expanding. Based on a PubMed Advanced Keyword Search—‘signal transduction and/or targeted therapy’—the total number of papers published in 1990 was just 3674, which has since risen to 15 225 in 2000, and 47 730 in 2013. However, high-impact professional journals related to this field are lacking, and, as a result, the published literature is vastly decentralized. Furthermore, governments around the world are increasing funding for research in Signal Transduction and Targeted Therapy, including basic science research, targeted drug research and development, and the clinical application of targeted drugs. Undoubtedly, there will be new and exciting discoveries in this field in the near future, and the limited capacity of existing journals cannot ensure the timely publication of relevant works that will emerge. In this light, we are establishing Signal Transduction and Targeted Therapy to consolidate and advance the growing body of knowledge in this field. The scope of Signal Transduction and Targeted Therapy encompasses signal transduction in physiological and pathological processes, as well as signaling pathway-targeted therapies, including biological agents and small molecular drugs used in the management of human diseases. Areas of interest also include basic and translational research in molecular pharmacology and chemotherapy, drug sensitivity and resistance, tumor immunology and immunotherapy, biomarkers and prognostic indicators, gene therapy, cell adhesion, invasion and metastasis, differentiation and cell death, clinical genetics, medicinal chemistry, systems biology, pharmacy, nanometer materials, computational chemistry, and computational biology. The disease types span all the major human diseases, including cancer, immune disorders, diabetes, cardiovascular diseases, inflammation, central nervous system diseases and other pathologies. A notable feature of Signal Transduction and Targeted Therapy is that it is a multidisciplinary journal, covering topics including but not limited to molecular biology, cell biology, pathology, medicinal chemistry, computational chemistry, systems biology, bioinformatics, pharmacology, pharmaceutics and clinical medicine. It has a wide range of authors and readership, including researchers engaged in basic research and applied research related to signal transduction and signaling pathway-targeted therapy, as well as clinicians. We aim to be the leading forum for research on cell signal regulation, molecular abnormalities that predict incidence, response to therapy, and outcome; targeted drug discovery and preclinical studies of new drugs; and clinical trials evaluating new treatments for various diseases. In addition to original research articles and review articles related to Signal Transduction and Targeted Therapy, invited viewpoint articles may be aperiodically published, which address timely and controversial topics in cell signal regulation and targeted therapy. Researchers are welcome to contribute valuable work to Signal Transduction and Targeted Therapy. We promise fast review followed by fair and prompt decisions. Once a manuscript is accepted, the outstanding editorial staff of the journal will provide high-quality support to ensure your article is the best that it can be. We have entered an unprecedented era, in which the essence of life is increasingly understood at the molecular level, and our ability to treat disease is being improved by precision-targeted therapy. With advances in DNA-sequencing and gene-editing technologies (for example, CRISPR/Cas9), new signaling pathways and biomarkers are identified quickly, followed by the emergence of new targeted drugs and clinical treatments. Signal Transduction and Targeted Therapy provides a platform for basic research scientists and clinicians to share their discoveries in this field. We are committed to making the journal innovative and timely, and to providing important and valuable information to you and the community.