2011 Vol. 2, No. 11

News and views
Progress in targeted delivery of siRNA to combat Coxsackievirus
Anju Gautam
2011, 2(11): 855-857. doi: 10.1007/s13238-011-1124-0
Secondary metabolism in simulated microgravity and space flight
Hong Gao, Zhiheng Liu, Lixin Zhang
2011, 2(11): 858-861. doi: 10.1007/s13238-011-1125-z
Space flight experiments have suggested that microgravity can affect cellular processes in microorganisms. To simulate the microgravity environment on earth, several models have been developed and applied to examine the effect of microgravity on secondary metabolism. In this paper, studies of effects of space flight on secondary metabolism are exemplified and reviewed along with the advantages and disadvantages of the current models used for simulating microgravity. This discussion is both significant and timely to researchers considering the use of simulated microgravity or space flight to explore effects of weightlessness on secondary metabolism.
Behind the Artemisinin, efforts and persistence from numerous scientists
Ming Li
2011, 2(11): 862-863. doi: 10.1007/s13238-011-1131-1
Conserved RB functions in development and tumor suppression
Gabriel M. Gordon, Wei Du
2011, 2(11): 864-878. doi: 10.1007/s13238-011-1117-z
The variety of human cancers in which the retinoblastoma protein pRb is inactivated reflects both its broad importance for tumor suppression and its multitude of cellular functions. Accumulating evidence indicates that pRb contributes to a diversity of cellular functions, including cell proliferation, differentiation, cell death, and genome stability. pRb performs these diverse functions through the formation of large complexes that include E2F transcription factors and chromatin regulators. In this review we will discuss some of the recent advances made in understanding the structure and function of pRb as they relate to tumor suppression, and highlight research using Drosophila melanogaster that reveals important, evolutionarily conserved functions of the RB family.
Transcriptional activators and activation mechanisms
Jun Ma
2011, 2(11): 879-888. doi: 10.1007/s13238-011-1101-7
Transcriptional activators are required to turn on the expression of genes in a eukaryotic cell. Activators bound to the enhancer can facilitate either the recruitment of RNA polymerase Ⅱ to the promoter or its elongation. This article examines a few selected issues in understanding activator functions and activation mechanisms.
c-Jun, at the crossroad of the signaling network
Qinghang Meng, Ying Xia
2011, 2(11): 889-898. doi: 10.1007/s13238-011-1113-3
c-Jun, the most extensively studied protein of the activator protein-1 (AP-1) complex, is involved in numerous cell activities, such as proliferation, apoptosis, survival, tumorigenesis and tissue morphogenesis. Earlier studies focused on the structure and function have led to the identification of c-Jun as a basic leucine zipper (bZIP) transcription factor that acts as homo-or heterodimer, binding to DNA and regulating gene transcription. Later on, it was shown that extracellular signals can induce post-translational modifications of c-Jun, resulting in altered transcriptional activity and target gene expression. More recent work has uncovered multiple layers of a complex regulatory scheme in which c-Jun is able to crosstalk, amplify and integrate different signals for tissue development and disease. One example of such scheme is the autocrine amplification loop, in which signal-induced AP-1 activates the c-Jun gene promoter, while increased c-Jun expression feedbacks to potentiate AP-1 activity. Another example of such scheme, based on recent characterization of gene knockout mice, is that c-Jun integrates signals of several developmental pathways, including EGFR-ERK, EGFR-RhoA-ROCK, and activin B-MAP3K1-JNK for embryonic eyelid closure. After more than two decades of extensive research, c-Jun remains at the center stage of a molecular network with mysterious functional properties, some of which are yet to be discovered. In this article, we will provide a brief historical overview of studies on c-Jun regulation and function, and use eyelid development as an example to illustrate the complexity of c-Jun crosstalking with signaling pathways.
Parkinson disease drug screening based on the interaction between D2 dopamine receptor and beta-arrestin 2 detected by capillary zone electrophoresis
Zheng Zhou, Jun-Ming Liao, Peng Zhang, Jun-Bao Fan, Jie Chen, Yi Liang
2011, 2(11): 899-905. doi: 10.1007/s13238-011-1096-0
Parkinson's disease is the second most common neurodegenerative disease in the world. Beta-arrestin-2 has been reported to be an important protein involved in D2 dopamine receptor desensitization, which is essential to Parkinson's disease. Moreover, the potential value of pharmacological inactivation of G protein-coupled receptor kinase or arrestin in the treatment of patients with Parkinson's disease has recently been shown. We studied the interaction between D2 dopamine receptor and beta-arrestin-2 and the pharmacological regulation of chemical compounds on such interaction using capillary zone electrophoresis. The results from screening more than 40 compounds revealed three compounds that remarkably inhibit the beta-arrestin-2/D2 dopamine receptor interaction among them. These compounds are promising therapies for Parkinson's disease, and the method used in this study has great potential for application in large-scale drug screening and evaluation.
Research articles
Mechanism involved in the modulation of photoreceptor-specific cyclic nucleotidegated channel by the tyrosine kinase adapter protein Grb14
Vivek K. Gupta, Ammaji Rajala, Karla K. Rodgers, Raju V. S. Rajala
2011, 2(11): 906-917. doi: 10.1007/s13238-011-1115-1
We recently found that growth factor receptor-bound (Grb) protein 14 is a novel physiological modulator of photoreceptor specific cyclic nucleotide-gated channel alpha subunit (CNGA1). Grb14 promotes the CNG channel closure through its Ras-associating (RA) domain. In the current study we show that this RA domain-mediated inhibition of rod CNG channel is electrostatic in nature. Grb14 competes with cGMP for the CNGA1 binding pocket and electrostatically interacts with Arg559 through a negatively charged β-turn at its RA domain. Moreover, the three Glu residues (180-182) in Grb14 are absolutely critical for electrostatic interaction with the cGMP binding pocket and resultant inhibition. Our study also demonstrates that substitution of Lys140 for Ala or in combination with polyglutamte mutants of Grb14 results in a significantly reduced binding with CNGA1. These results suggest that in addition to Glu180-182 and Lys140, other residues in Grb14 may be involved in the electrostatic interaction with CNGA1. The RA domain is highly conserved among the members of Grb7 family of proteins, which includes Grb7, Grb10 and Grb14. Further, only Grb14 is able to modulate the channel activity, but not Grb7 and Grb10. All together, it suggests the existence of a divergence in RA domains among the members of the Grb7 family.
A genome-wide RNAi screen identifies genes regulating the formation of P bodies in C. elegans and their functions in NMD and RNAi
Yinyan Sun, Peiguo Yang, Yuxia Zhang, Xin Bao, Jun Li, Wenru Hou, Xiangyu Yao, Jinghua Han, Hong Zhang
2011, 2(11): 918-939. doi: 10.1007/s13238-011-1119-x
Cytoplasmic processing bodies, termed P bodies, are involved in diverse post-transcriptional processes including mRNA decay, nonsense-mediated RNA decay (NMD), RNAi, miRNA-mediated translational repression and storage of translationally silenced mRNAs. Regulation of the formation of P bodies in the context of multicellular organisms is poorly understood. Here we describe a systematic RNAi screen in C. elegans that identified 224 genes with diverse cellular functions whose inactivations result in a dramatic increase in the number of P bodies. 83 of these genes form a complex functional interaction network regulating NMD. We demonstrate that NMD interfaces with many cellular processes including translation, ubiquitin-mediated protein degradation, intracellular trafficking and cytoskeleton structure. We also uncover an extensive link between translation and RNAi, with different steps in protein synthesis appearing to have distinct effects on RNAi efficiency. Moreover, the intracellular vesicular trafficking network plays an important role in the regulation of RNAi. A subset of genes enhancing P body formation also regulate the formation of stress granules in C. elegans. Our study offers insights into the cellular mechanisms that regulate the formation of P bodies and also provides a framework for system-level understanding of NMD and RNAi in the context of the development of multicellular organisms.