miRNAs

The evolution of complex animals such as insects and mammals is achieved with surprisingly few additions in protein coding genes. MicroRNAs (miRNAs), a class of non-coding RNAs, have emerged as important regulators of organogenesis in insects, fish and mammals. The microRNA repertoire of animals has expanded significantly during evolution especially in vertebrates, insects and nematodes, accompanying the appearance of complex body plans. MicroRNAs therefore have gained enormous interest in recent years. They are now regarded as key modulators of gene expression in many tissues during embryogenesis, in adult organisms and in disease processes. Therefore, these small RNA molecules have entered the center stage of molecular biology and are promising candidates not only for the regulation of key biological processes such as proliferation and apoptosis, but also for therapy of human diseases.     

Direct immunosuppressive effects of EBV-encoded latent membrane protein 1

In neoplastic cells of EBV-positive lymphoid malignancies latent membrane protein (LMP1) is expressed. Because no adequate cellular immune response can be detected against LMP1, we investigated whether LMP1 had a direct effect on T lymphocyte activation. In this study we show that nanogram amounts of purified recombinant LMP1 (rLMP1) strongly suppresses activation of T cells. By sequence alignment two sequences (LALLFWL and LLLLAL) in the first transmembrane domain of LMP1 were identified showing strong homology to the immunosuppressive domain (LDLLFL) of the retrovirus-encoded transmembrane protein p15E. The effects of rLMP1 and LMP1-derived peptides were tested in T cell proliferation and NK cytotoxicity assays and an Ag-induced IFN-gamma release enzyme-linked immunospot assay. LMP1 derived LALLFWL peptides showed strong inhibition of T cell proliferation and NK cytotoxicity, while acetylated LALLFWL peptides had an even stronger effect. In addition, Ag-specific IFN-gamma release was severely inhibited. To exert immunosuppressive effects in vivo, LMP1 has to be excreted from the cells. Indeed, LMP1 was detected in supernatant of EBV-positive B cell lines (LCL), and differential centrifugation in combination with Western blot analysis of the pellets indicated that LMP1 is probably secreted by LCL in the form of exosomes. The amount of secreted LMP1 in B cell cultures is well below the immunosuppressive level observed with rLMP1. Our results demonstrate direct immunosuppressive properties of LMP1 (fragments) and suggest that EBV-positive tumor cells may actively secrete LMP1 and thus mediate immunosuppressive effects on tumor-infiltrating lymphocytes. Moreover, we demonstrate, for the first time, that transmembrane protein-mediated immunosuppression is not solely restricted to RNA tumor viruses, but can also be found in DNA tumor viruses.     

植物 miRNA

植物RNA家族中最近发现和研究的一个新种类miRNA,它与动物体内的miRNA有相似点,但也有不同。它参与指导mRNA的剪切,影响转座子,目前在拟南芥中发现了19种miRNA,由Dicer酶和Argonaute蛋白作用下产生的,通过与目标序列的互补影响mRNA剪切和DNA甲基化,引起相关生理过程的发生。     

miRNAs got rhythm

Despite significant advances in treatments, cardiovascular disease (CVD) remains the leading cause of human morbidity and mortality in developed countries. The development of novel and efficient treatment strategies requires an understanding of the basic molecular mechanisms underlying cardiac function. MicroRNAs (miRNAs) are a family of small nonprotein-coding RNAs that have emerged as important regulators in cardiac and vascular developmental and pathological processes, including cardiac arrhythmia, fibrosis, hypertrophy and ischemia, heart failure and vascular atherosclerosis. The miRNA acts as an adaptor for the miRNA-induced silencing complex (miRISC) to specifically recognize and regulate particular mRNAs. Mature miRNAs recognize their target mRNAs by base-pairing interactions between nucleotides 2 and 8 of the miRNA (the seed region) and complementary nucleotides in the 3'-untranslated region (3'-UTR) of mRNAs and miRISCs subsequently inhibit gene expression by targeting mRNAs for translational repression or cleavage. In this review we summarize the basic mechanisms of action of miRNAs as they are related to cardiac arrhythmia and address the potential for miRNAs to be therapeutically manipulated in the treatment of arrhythmias.     

Adenovirus and miRNAs

Adenovirus infection has a tremendous impact on the cellular silencing machinery. Adenoviruses express high amounts of non-coding virus associated (VA) RNAs able to saturate key factors of the RNA interference (RNAi) processing pathway, such as Exportin 5 and Dicer. Furthermore, a proportion of VA RNAs is cleaved by Dicer into viral microRNAs (mivaRNAs) that can saturate Argonaute, an essential protein for miRNA function. Thus, processing and function of cellular miRNAs is blocked in adenoviral-infected cells. However, viral miRNAs actively target the expression of cellular genes involved in relevant functions such as cell proliferation, DNA repair or RNA regulation. Interestingly, the cellular silencing machinery is active at early times post-infection and can be used to control the adenovirus cell cycle. This is relevant for therapeutic purposes against adenoviral infections or when recombinant adenoviruses are used as vectors for gene therapy. Manipulation of the viral genome allows the use of adenoviral vectors to express therapeutic miRNAs or to be silenced by the RNAi machinery leading to safer vectors with a specific tropism. This article is part of a "Special Issue entitled:MicroRNAs in viral gene regulation".     

miRNAs play a tune

Two new studies describe functionally relevant interactions between microRNAs (miRNAs) and their targets in the immune system and the brain (Xiao et al., 2007; Karres et al., 2007). Furthermore, these studies illustrate the involvement of miRNAs in tuning the expression of target genes to physiologically relevant levels.     

鼻咽癌与miRNAs

鼻咽癌（nasopharyngeal carcinoma, NPC）是一种多基因遗传性疾病,好发生于我国华南、东南亚及部分非洲地区。近年来随着分子生物学及其技术的迅速发展,人们对鼻咽癌发生、发展及其生物学行为的研究已进入基因水平。microRNA（miRNA）是一类广泛存在于动植物体内的非编码小RNA,主要参与基因转录后水平调控。随着对miRNA研究的深入,发现肿瘤的细胞分化障碍、增殖失控、细胞永生化与miRNA密切相关。人类肿瘤组织与正常细胞组织间的miRNA表达水平和类型存在明显差异,提示miRNA可能是一类新的参与肿瘤发生的重要分子。本文就鼻咽癌与miRNA相关的研究进展作一综述。     

miRNAs and morphogen gradients

Morphogens induce biological diversity by operating in a dose-dependent manner. Here we review recent evidences indicating that microRNAs (miRNAs) are ideally suited to serve the morphogen cause. miRNAs regulate the establishment of morphogen gradients, including TGFβ, Wnt and other growth factors by acting on their secretion, distribution and clearance. miRNA are also critical in receiving cells, establishing context-dependency and threshold responses. Moreover, miRNAs contributes to gene networks that transform the graded activity of a morphogen into robust cell fate decisions. Finally, we discuss in the perspective section the implication of the new ceRNA hypothesis for morphogen biology.     

Secreted miRNAs suppress atherogenesis

Endothelial-vascular smooth muscle cell communication has a critical role in cardiovascular homeostasis and the pathogenesis of atherosclerosis. A study now demonstrates extracellular-vesicle-mediated transfer of the atheroprotective microRNAs miR-143/145 between endothelial and vascular smooth muscle cells, providing compelling evidence that intercellular transport of miRNAs can influence a pathological process, namely atherosclerosis.     

Tissue-dependent paired expression of miRNAs

It is believed that depending on the thermodynamic stability of the 5′-strand and the 3′-strand in the stem-loop structure of a precursor microRNA (pre-miRNA), cells preferentially select the less stable one (called the miRNA or guide strand) and destroy the other one (called the miRNA* or passenger strand). However, our expression profiling analyses revealed that both strands could be co-accumulated as miRNA pairs in some tissues while being subjected to strand selection in other tissues. Our target prediction and validation assays demonstrated that both strands of a miRNA pair could target equal numbers of genes and that both were able to suppress the expression of their target genes. Our finding not only suggests that the numbers of miRNAs and their targets are much greater than what we previously thought, but also implies that novel mechanisms are involved in the tissue-dependent miRNA biogenesis and target selection process.     

miRNAs, 'stemness' and skin

The epidermis and its appendages provide organisms with protection from the environment, keeping pathogens out and preventing the loss of essential body fluids. To perform both functions, the skin has elaborated a complex differentiation process known as cornification. The renewal capacity of the skin, which is responsible for maintaining tissue homeostasis, regenerating hair and repairing the epidermis after injury, resides in the basal proliferating compartment in which epidermal stem cells are located. These cells possess the remarkable capacity to both self-perpetuate and give rise to the differentiating cells that form mature tissues. Recent findings indicate that microRNAs have an essential role in orchestrating the formation of epidermis and skin appendages, in particular, at the interface between stemness and differentiation.