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Identification of hundreds of conserved and nonconserved human microRNAs 总被引:47,自引:0,他引:47
Bentwich I Avniel A Karov Y Aharonov R Gilad S Barad O Barzilai A Einat P Einav U Meiri E Sharon E Spector Y Bentwich Z 《Nature genetics》2005,37(7):766-770
MicroRNAs are noncoding RNAs of approximately 22 nucleotides that suppress translation of target genes by binding to their mRNA and thus have a central role in gene regulation in health and disease. To date, 222 human microRNAs have been identified, 86 by random cloning and sequencing, 43 by computational approaches and the rest as putative microRNAs homologous to microRNAs in other species. To prove our hypothesis that the total number of microRNAs may be much larger and that several have emerged only in primates, we developed an integrative approach combining bioinformatic predictions with microarray analysis and sequence-directed cloning. Here we report the use of this approach to clone and sequence 89 new human microRNAs (nearly doubling the current number of sequenced human microRNAs), 53 of which are not conserved beyond primates. These findings suggest that the total number of human microRNAs is at least 800. 相似文献
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A conserved microRNA module exerts homeotic control over Petunia hybrida and Antirrhinum majus floral organ identity 总被引:3,自引:0,他引:3
Cartolano M Castillo R Efremova N Kuckenberg M Zethof J Gerats T Schwarz-Sommer Z Vandenbussche M 《Nature genetics》2007,39(7):901-905
It is commonly thought that deep phylogenetic conservation of plant microRNAs (miRNAs) and their targets indicates conserved regulatory functions. We show that the blind (bl) mutant of Petunia hybrida and the fistulata (fis) mutant of Antirrhinum majus, which have similar homeotic phenotypes, are recessive alleles of two homologous miRNA-encoding genes. The BL and FIS genes control the spatial restriction of homeotic class C genes to the inner floral whorls, but their ubiquitous early floral expression patterns are in contradiction with a potential role in patterning C gene expression. We provide genetic evidence for the unexpected function of the MIRFIS and MIRBL genes in the center of the flower and propose a dynamic mechanism underlying their regulatory role. Notably, Arabidopsis thaliana, a more distantly related species, also contains this miRNA module but does not seem to use it to confine early C gene expression to the center of the flower. 相似文献
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Serena Stadler Chi Huu Nguyen Helga Schachner Daniela Milovanovic Silvio Holzner Stefan Brenner Julia Eichsteininger Mira Stadler Daniel Senfter Liselotte Krenn Wolfgang M. Schmidt Nicole Huttary Sigurd Krieger Oskar Koperek Zsuzsanna Bago-Horvath Konstantin Alexander Brendel Brigitte Marian Oliver de Wever Robert M. Mader Benedikt Giessrigl Walter Jäger Helmut Dolznig Georg Krupitza 《Cellular and molecular life sciences : CMLS》2017,74(10):1907-1921
Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro-invasive contributions of stromal cells in physiologically relevant three-dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca2+ levels were measured and pharmacological- or siRNA-based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca2+, Ca2+-calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca2+ release. Thus, Ca2+ signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour–stroma interaction. 相似文献
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Tóth DM Szoke E Bölcskei K Kvell K Bender B Bosze Z Szolcsányi J Sándor Z 《Cellular and molecular life sciences : CMLS》2011,68(15):2589-2601
Transgenic mice with a small hairpin RNA construct interfering with the expression of transient receptor potential vanilloid
1 (TRPV1) were created by lentiviral transgenesis. TRPV1 expression level in transgenic mice was reduced to 8% while the expression
of ankyrin repeat domain 1 (TRPA1) was unchanged. Ear oedema induced by topical application of TRPV1 agonist capsaicin was
completely absent in TRPV1 knockdown mice. Thermoregulatory behaviour in relation to environmental thermopreference (30 vs.
35°C) was slightly impaired in male knockdown mice, but the reduction of TRPV1 function was not associated with enhanced hyperthermia.
TRPV1 agonist resiniferatoxin induced hypothermia and tail vasodilatation was markedly inhibited in knockdown mice. In conclusion,
shRNA-mediated knock down of the TRPV1 receptor in mice induced robust inhibition of the responses to TRPV1 agonists without
altering the expression, gating function or neurogenic oedema provoked by TRPA1 activation. Thermoregulatory behaviour in
response to heat was inhibited, but enhanced hyperthermia was not observed. 相似文献
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Aitman TJ Critser JK Cuppen E Dominiczak A Fernandez-Suarez XM Flint J Gauguier D Geurts AM Gould M Harris PC Holmdahl R Hubner N Izsvák Z Jacob HJ Kuramoto T Kwitek AE Marrone A Mashimo T Moreno C Mullins J Mullins L Olsson T Pravenec M Riley L Saar K Serikawa T Shull JD Szpirer C Twigger SN Voigt B Worley K 《Nature genetics》2008,40(5):516-522
The rat is an important system for modeling human disease. Four years ago, the rich 150-year history of rat research was transformed by the sequencing of the rat genome, ushering in an era of exceptional opportunity for identifying genes and pathways underlying disease phenotypes. Genome-wide association studies in human populations have recently provided a direct approach for finding robust genetic associations in common diseases, but identifying the precise genes and their mechanisms of action remains problematic. In the context of significant progress in rat genomic resources over the past decade, we outline achievements in rat gene discovery to date, show how these findings have been translated to human disease, and document an increasing pace of discovery of new disease genes, pathways and mechanisms. Finally, we present a set of principles that justify continuing and strengthening genetic studies in the rat model, and further development of genomic infrastructure for rat research. 相似文献
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Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia 总被引:1,自引:0,他引:1
Grzeschik KH Bornholdt D Oeffner F König A del Carmen Boente M Enders H Fritz B Hertl M Grasshoff U Höfling K Oji V Paradisi M Schuchardt C Szalai Z Tadini G Traupe H Happle R 《Nature genetics》2007,39(7):833-835
Focal dermal hypoplasia (FDH) is an X-linked dominant multisystem birth defect affecting tissues of ectodermal and mesodermal origin. Using a stepwise approach of (i) genetic mapping of FDH, (ii) high-resolution comparative genome hybridization to seek deletions in candidate chromosome areas and (iii) point mutation analysis in candidate genes, we identified PORCN, encoding a putative O-acyltransferase and potentially crucial for cellular export of Wnt signaling proteins, as the gene mutated in FDH. The findings implicate FDH as a developmental disorder caused by a deficiency in PORCN. 相似文献