Growth factor receptors (GFRs) are often aberrantly expressed in tumor cells, and altered GFR expression and activity contribute to the pathogenesis of many types of cancer. A variety of mechanisms have been identified that result in enhanced GFR expression and activity in cancer cells. Defects in the pathways responsible for GFR internalization and intracellular trafficking are likely to be involved in altered GFR expression in a variety of cancers. The roles of GFR trafficking pathways in the regulation of GFR expression, in the pathogenesis of tumors, and in the response of tumors to treatment have not been fully delineated, but the likely contributions of GFR signaling to the development and progression of various malignancies suggest that therapies that modify GFR trafficking may be effective as anticancer treatments.

The intracellular trafficking of GFRs is regulated by a number of protein complexes and by protein ubiquitination. Many of the proteins required for this trafficking are products of tumor suppressor genes, and the expression and function of the protein machinery utilized for intracellular trafficking is frequently altered in tumor cells, consistent with the likely role of GFR trafficking in tumorigenesis. Many of the proteins involved in GFR trafficking have been identified as potential targets for anticancer treatment, and novel treatments directed against these targets are currently in preclinical development and in clinical trials. Ubiquitin ligases are critical for GFR trafficking and represent potentially important targets for the development of novel therapies.

The genes for the ubiquitin ligases c-Cbl and UBE4B are located in chromosome regions commonly altered in a variety of tumors and therefore are likely to be important for tumorigenesis. c-Cbl ubiquitinates a number of GFRs and directs them for degradation. Mutations in c-Cbl have been identified in cases of myeloid leukemia and myelodysplasia, providing a link between GFR ubiquitination and trafficking and leukemogenesis. We have shown that UBE4B plays a crucial role in GFR trafficking and degradation in tumor cells, suggesting a previously uncharacterized link between UBE4B and tumorigenesis. With the critical need for new and effective therapies for pediatric malignancies, the recently identified roles for the GFR trafficking pathway in the pathogenesis of various forms of cancer confirm the importance of the further development of novel therapies targeting this pathway in children with cancer.

Despite of several decades of efforts, lung cancer remains one of most deadly diseases, with a 5-year survival rate approximately 15% worldwide. In China, the situation is even worse. Although there is no official data released yet, the 5-year survival rate is estimated to be around 10%. In past 30 years, there was a dramatic increase of lung cancer related death about 465% in mainland China. Annually, about 400000 people die of lung cancer and the number is still climbing. At the same time, the number of new lung cancer cases also increase rapidly. The high mortality of lung cancer is mainly ascribed to two factors: the lack of effective ways to identify early diagnostic biomarkers and to treat metastatic cancer. Lung cancer can be pathologically divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), among which NSCLC accounts for about 80% of all cases. In this review, we will focus on the recent efforts and progress in finding biomarkers in NSCLC. Since biomarkers are derived from both invasive and non-invasive ways, we divide them into these two categories and review them separately. We hope the discovery of biomarkers will eventually change the current clinical practice in NSCLC patients and improve their quality of life.

The development of spinal cord is a precisely and sequentially regulated process, which is controlled by signaling pathways and transcription factors in each stage. Overwhelming data have shown the essential roles of BMP signaling in different stages of this developmental process. It is also clear that the proper functions of BMP signaling require its cross-talk with several other signaling pathways including Notch, Wnt and retinoic acid (RA) pathways. Here, we highlight the recent advancement in understanding the roles of BMP signaling during neurogenesis, neural tube patterning, axon development and glial differentiation in the spinal cord, and emphasize its integrations with other pathways during these processes.

Emerging research has suggested that inflammatory stress may play a role in the development of obesity. Both the leptin and insulin receptor are sensitive to intracellular inflammatory signaling that can be stimulated through toll-like receptor 4 activation by saturated fat. Pharmacological intervention within this cascade often protects animals from becoming obese, thus highlighting inflammatory pathways as a possible site of study in the prevention of pathologic weight gain. It has been well established in animal models that females display a marked reduction in the susceptibility to weight gain on high-fat diets compared to males. In addition, it has been widely accepted that females are partially protected from inflammatory-related diseases. At the molecular level, this reduction in disease susceptibility has been suggested to be due to the anti-inflammatory properties of 17 β-estradiol. Through direct free radical scavenging, transcriptional regulation, and protein interactions, chronic exposure to estradiol can reduce systemic inflammatory stress. As the knowledge base continues to grow on the etiology of obesity, further research is needed on the precise molecular pathways that can be inhibited by estradiol. Understanding of such pathways may provide a basis for the future use of estrogen and its related compounds (daidzein, genistein, resveratrol) to prevent weight gain in peri- and post-menopausal females.

Jasmonic acid (JA) is a natural hormone regulator involved in development, responses against wounding and pathogen attack. Upon perception of pathogens, JA is synthesized and mediates a signaling cascade initiating various defense responses. Traditionally, necrotrophic fungi have been shown to be the primary activators of JA-dependent defenses through the JA-receptor, COI1. Conversely, plants infected with biotrophic fungi have classically been associated with suppressing JA-mediated responses. However, recent evidence has shown that certain biotrophic fungal species also trigger activation of JA-mediated responses and mutants deficient in JA signaling show an increase in susceptibility to certain biotrophic fungal pathogens. These findings suggest a new role for JA in defense against fungal biotrophs. This review will focus on recent research advancing our knowledge of JA-dependant responses involved in defense against both biotrophic and necrotrophic fungi.

F?rster resonance energy transfer (FRET) techniques have been widely used in biological studies in vitro and in vivo and are powerful tools for elucidating protein interactions in many regulatory cascades. FRET occurs between oscillating dipoles of two fluorophores with overlapping emission and excitation wavelengths and is dependent on the spectroscopic and geometric properties of the donor-acceptor pair. Various efforts have been made to develop quantitative FRET methods to accurately determine the interaction affinity and kinetics parameters. SUMOylation is an important post-translational protein modification with key roles in multiple biological processes. Conjugating SUMO to substrates requires an enzymatic cascade. Sentrin/SUMO-specific proteases (SENP) act as endopeptidases to process the pre-SUMO or an isopeptidase to deconjugate SUMO from its substrate. Here we also summarize recent developments of theoretical and experimental procedures for determining the protein interaction dissociation constant, K_d, and protease kinetics parameters, k_cat and K_m, in the SUMOylation pathway. The general principles of these quantitative FRET-based measurements can be applied to other protein interactions and proteases.

Gene expression profiling of Drosophila melanogaster, an invertebrate model organism, applied to DNA microarray promises to provide novel insights into the important pathways and molecules that may contribute to the risk of alcohol abuse and addiction. Instead of studying one gene at a time, the technology provides a snapshot of transcriptional changes at once, and offers unprecedented opportunities to understand the molecular complexity of alcohol-seeking behavior including addiction and dependence.

During embryo development in many metazoan animals, the first differentiated cell type to form is an epithelial cell. This epithelial layer is modified by developmental cues of body axes formation to give rise to various tissues. The cells that arise are mesenchymal in nature and are a source of other tissue types. This epithelial to mesenchymal transition is used for tissue type formation and also seen in diseases such as cancer. Here we discuss recent findings on the cellular architecture formation in the Drosophila embryo and how it affects the developmental program of body axes formation. In particular these studies suggest the presence of compartments around each nucleus in a common syncytium. Despite the absence of plasma membrane boundaries, each nucleus not only has its own endoplasmic reticulum and Golgi complex but also its own compartmentalized plasma membrane domain above it. This architecture is potentially essential for morphogen gradient restriction in the syncytial Drosophila embryo. We discuss various properties of the dorso-ventral and the antero-posterior morphogen gradients in the Drosophila syncytium, which are likely to depend on the syncytial architecture of the embryo.

This article uses a real-life example to illustrate the concept and methodology of recombineering, a revolutionary genetic engineering technique based on phage-mediated homologous recombination. A step-by-step approach is presented along with a flow diagram, from obtaining gene-harboring BACs to the in vitro generation of a conditional null allele. This method can be used to target any gene at any position, without the knowledge or use of any restriction site. The extensive applicability of recombineering to gene manipulation is discussed.