2013 Vol. 4(9)

MED12 mutations in human diseases
Hua Wang, Qin Shen, Li-hua Ye, Jun Ye
2013, 4(9): 643-646. doi: 10.1007/s13238-013-3048-3
The Mediator Complex plays key roles in activating gene transcription in eukaryotes. Mediator of RNA polymerase Ⅱ transcription subunit 12 homolog (MED12) is a subunit of the Mediator Complex and regulates the activity of the complex. MED12 is involved in a variety of cellular activities, and mutations in MED12 gene impair MED12 activities and are associated with several diseases, including Opitz-Kaveggia syndrome, Lujan syndrome, uterine leiomyomas and prostate cancer. This review will discuss the biological function of MED12 and the relationship between MED12 mutations and diseases.
Reduced EGFR level potentially mediates the Aβ42-induced neuronal loss in transgenic fruit fly and mouse
Lei Wang, Bin Liang, Yi Zhong
2013, 4(9): 647-649. doi: 10.1007/s13238-013-3043-8
Hedgehog in the Drosophila testis niche: what does it do there?
Zhao Zhang, Chenyu Pan, Yun Zhao
2013, 4(9): 650-655. doi: 10.1007/s13238-013-3040-y
Stem cell niche is a specialized microenvironment crucial to self-renewal. The testis in Drosophila contains two different types of stem cells, the germline stem cells and the somatic cyst stem cells that are sustained by their respective niche signals, thus is a good system for studying the interaction between the stem cells and their hosting niche. The JAK-STAT and BMP pathways are known to play critical roles in the self-renewal of different kinds of stem cells, but the roles of several other pathways have emerged recently in a complex signaling network in the testis niche. Reports of independent observations from three research groups have uncovered an important role of Hedgehog (Hh) in the Drosophila testis niche. In this review, we summarize these recent findings and discuss the interplay between the Hh signaling mechanisms and those of the JAK-STAT and BMP pathways. We also discuss directions for further investigation.
siRNA-mediated DNA methylation and H3K9 dimethylation in plants
Chi Xu, Jing Tian, Beixin Mo
2013, 4(9): 656-663. doi: 10.1007/s13238-013-3052-7
Heterochromatic siRNAs regulate transcriptional gene silencing by inducing DNA methylation and histone H3K9 dimethylation. Recent advances have revealed the distinct phases involved in siRNA mediated silencing pathway, although the precise functions of a number of factors remain undesignated, putative mechanisms for the connection between DNA and histone methylation have been investigated, and much effort has been invested to understand the biological functions of siRNA-mediated epigenetic modification. In this review, we summarize the mechanism of siRNA-mediated epigenetic modification, which involves the production of siRNA and the recruitments of DNA and histone methytransferases to the target sequences assisted by complementary pairing between 24-nt siRNAs and nascent scaffold RNAs, the roles of siRNAmediated epigenetic modification in maintaining genome stability and regulating gene expression have been discussed, newly identified players of the siRNA mediated silencing pathway have also been introduced.
Romance of the three domains: how cladistics transformed the classification of cellular organisms
Chi-Chun Ho, Susanna K. P. Lau, Patrick C. Y. Woo
2013, 4(9): 664-676. doi: 10.1007/s13238-013-3050-9
Cladistics is a biological philosophy that uses genealogical relationship among species and an inferred sequence of divergence as the basis of classification. This review critically surveys the chronological development of biological classification from Aristotle through our postgenomic era with a central focus on cladistics. In 1957, Julian Huxley coined cladogenesis to denote splitting from subspeciation. In 1960, the English translation of Willi Hennig's 1950 work, Systematic Phylogenetics, was published, which received strong opposition from pheneticists, such as numerical taxonomists Peter Sneath and Robert Sokal, and evolutionary taxonomist, Ernst Mayr, and sparked acrimonious debates in 1960-1980. In 1977-1990, Carl Woese pioneered in using small subunit rRNA gene sequences to delimitate the three domains of cellular life and established major prokaryotic phyla. Cladistics has since dominated taxonomy. Despite being compatible with modern microbiological observations, i.e. organisms with unusual phenotypes, restricted expression of characteristics and occasionally being uncultivable, increasing recognition of pervasiveness and abundance of horizontal gene transfer has challenged relevance and validity of cladistics. The mosaic nature of eukaryotic and prokaryotic genomes was also gradually discovered. In the mid-2000s, high-throughput and whole-genome sequencing became routine and complex geneologies of organisms have led to the proposal of a reticulated web of life. While genomics only indirectly leads to understanding of functional adaptations to ecological niches, computational modeling of entire organisms is underway and the gap between genomics and phenetics may soon be bridged. Controversies are not expected to settle as taxonomic classifications shall remain subjective to serve the human scientist, not the classified.
Genome-wide association studies on prostate cancer: the end or the beginning?
Rui Chen, Shancheng Ren, Yinghao Sun
2013, 4(9): 677-686. doi: 10.1007/s13238-013-3055-4
Prostate cancer (PCa) is the second most frequently diagnosed malignancy in men. Genome-wide association studies (GWAS) has been highly successful in discovering susceptibility loci for prostate cancer. Currently, more than twenty GWAS have identified more than fifty common variants associated with susceptibility with PCa. Yet with the increase in loci, voices from the scientific society are calling for more. In this review, we summarize current findings, discuss the common problems troubling current studies and shed light upon possible breakthroughs in the future. GWAS is the beginning of something wonderful. Although we are quite near the end of the beginning, post-GWAS studies are just taking off and future studies are needed extensively. It is believed that in the future GWAS information will be helpful to build a comprehensive system intergraded with PCa prevention, diagnosis, molecular classification, personalized therapy.
Research articles
Structural biology study of human TNF receptor associated factor 4 TRAF domain
Fengfeng Niu, Heng Ru, Wei Ding, Songying Ouyang, Zhi-Jie Liu
2013, 4(9): 687-694. doi: 10.1007/s13238-013-3068-z
TRAF4 is a unique member of TRAF family, which is essential for innate immune response, nervous system and other systems. In addition to being an adaptor protein, TRAF4 was identified as a regulator protein in recent studies. We have determined the crystal structure of TRAF domain of TRAF4 (residues 292-466) at 2.60 Å resolution by X-ray crystallography method. The trimericly assembled TRAF4 resembles a mushroom shape, containing a super helical "stalk" which is made of three right-handed intertwined α helixes and a C-terminal "cap", which is divided at residue L302 as a boundary. Similar to other TRAFs, both intermolecular hydrophobic interaction in super helical "stalk" and hydrogen bonds in "cap" regions contribute directly to the formation of TRAF4 trimer. However, differing from other TRAFs, there is an additional flexible loop (residues 421-426), which contains a previously identified phosphorylated site S426 exposing on the surface. This S426 was reported to be phosphorylated by IKKα which is the pre-requisite for TRAF4-NOD2 complex formation and thus to inhibit NOD2-induced NF-κB activation. Therefore, the crystal structure of TRAF4-TRAF is valuable for understanding its molecular basis for its special function and provides structural information for further studies.
Tip-to-tip interaction in the crystal packing of PACSIN 2 is important in regulating tubulation activity
Xiaoyun Bai, Xiaofeng Zheng
2013, 4(9): 695-701. doi: 10.1007/s13238-013-3041-x
The F-BAR domain containing proteins PACSINs are cytoplasmic phosphoproteins involved in various membrane deformations, such as actin reorganization, vesicle transport and microtubule movement. Our previous study shows that all PACSINs are composed of crescent shaped dimers with two wedge loops, and the wedge loopmediated lateral interaction between neighboring dimers is important for protein packing and tubulation activity. Here, from the crystal packing of PACSIN 2, we observed a tight tip-to-tip interaction, in addition to the wedge loopmediated lateral interaction. With this tip-to-tip interaction, the whole packing of PACSIN 2 shows a spiral-like assembly with a central hole from the top view. Elimination of this tip-to-tip connection inhibited the tubulation function of PACSIN 2, indicating that tip-to-tip interaction plays an important role in membrane deformation activity. Together with our previous study, we proposed a packing model for the assembly of PACSIN 2 on membrane, where the proteins are connected by tip-to-tip and wedge loop-mediated lateral interactions on the surface of membrane to generate various diameter tubules.
Inhibition of SIRT6 in prostate cancer reduces cell viability and increases sensitivity to chemotherapeutics
Yewei Liu, Qian Reuben Xie, Boshi Wang, Jiaxiang Shao, Tingting Zhang, Tengyuan Liu, Gang Huang, Weiliang Xia
2013, 4(9): 702-710. doi: 10.1007/s13238-013-3054-5
SIRT6 is an important histone modifying protein that regulates DNA repair, telomere maintenance, energy metabolism, and target gene expression. Recently SIRT6 has been identified as a tumor suppressor and is downregulated in certain cancer types, but not in other cancers. From deposited gene profiling studies we found that SIRT6 was overexpressed in prostate tumors, compared with normal or paratumor prostate tissues. Tissue microarray studies confirmed the higher levels of SIRT6 in both prostate tumor tissues and prostate cancer cells than in their normal counterparts. Knockdown of SIRT6 in human prostate cancer cells led to sub-G1 phase arrest of cell cycle, increased apoptosis, elevated DNA damage level and decrease in BCL2 gene expression. Moreover, SIRT6-deficiency reduced cell viability and enhanced chemotherapeutics sensitivity. Taken together, this study provides the first evidence of SIRT6 overexpression in human prostate cancer, and SIRT6 regulation could be exploited for prostate cancer therapy.
ULK1 and JNK are involved in mitophagy incurred by LRRK2 G2019S expression
Yuangang Zhu, Chunyan Wang, Mei Yu, Jie Cui, Liang Liu, Zhiheng Xu
2013, 4(9): 711-721. doi: 10.1007/s13238-013-3910-3
Mutations in LRRK2 (Leucine rich repeat kinase 2) are a major cause of Parkinson's disease (PD). We and others reported recently that expression of the pathogenic gainof-function mutant form of LRRK2, LRRK2 G2019S, induces mitochondrial fission in neurons through DLP1. Here we provide evidence that expression of LRRK2 G219S stimulates mitochondria loss or mitophagy. We have characterized several LRRK2 interacting proteins and found that LRRK2 interacts with ULK1 which plays an essential role in autophagy. Knockdown of either ULK1 or DLP1 expression with shRNAs suppresses LRRK2 G2019S expression-induced mitochondrial clearance, suggesting that LRRK2 G2019S expression induces mitochondrial fission through DLP1 followed by mitophagy via an ULK1 dependent pathway. In addition to ULK1, we found that LRRK2 interacts with the endogenous MKK4/7, JIP3 and coordinates with them in the activation of JNK signaling. Interestingly, LRRK2 G2019S-induced loss of mitochondria can also be suppressed by 3 different JNK inhibitors, implying the involvement of the JNK pathway in the pathogenic mechanism of mutated LRRK2. Thus our findings may provide an insight into the complicated pathogenesis of PD as well as some clues to the development of novel therapeutic strategies.

Current Issue

March, 2019

Volume 10, Issue 3

Pages 157-233

About the cover

Metastasis is the leading cause of human cancer deaths.Unfortunately, no approved drugs are available for antimetastatic treatment. In this study, high-throughputsequencing-based high-throughput screening (HTS2) anda breast cancer lung metastasis (BCLM)-associated genesignature were combined to discover anti-metastatic drugs.After screening of thousands of compounds, Shao et al.identifed Ponatinib as a BCLM inhibitor. Ponatinib signifcantlyinhibited the migration and mammosphere formation of breastcancer cells in vitro and blocked BCLM in multiple mousemodels. This study may facilitate the therapeutic treatment ofBCLM as well as other metastases.

Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang Beijing 100101, China

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