Crucial function of histone deacetylase 1 for differentiation of teratomas in mice and humans

Although histone deacetylases are generally known as pro-tumourigenic factors, loss of HDAC1 is here shown to promote proliferation and inhibit differentiation in a mouse teratoma model, at least partly via regulation of the transcription factor SNAIL1

STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.Lukas Kenner and Jan Pencik are supported by FWF, P26011 and the Genome Research-Austria project “Inflammobiota” grants. Helmut Dolznig is supported by the Herzfelder Family Foundation and the Niederösterr. Forschungs-und Bildungsges.m.b.H (nfb). Richard Moriggl is supported by grant SFB-F2807 and SFB-F4707 from the Austrian Science Fund (FWF), Ali Moazzami is supported by Infrastructure for biosciences-Strategic fund, SciLifeLab and Formas, Zoran Culig is supported by FWF, P24428, Athena Chalaris and Stefan Rose-John are supported by the Deutsche Forschungsgemeinschaft (Grant SFB 877, Project A1and the Cluster of Excellence --“Inflammation at Interfaces”). Work of the Aberger lab was supported by the Austrian Science Fund FWF (Projects P25629 and W1213), the European FP7 Marie-Curie Initial Training Network HEALING and the priority program Biosciences and Health of the Paris-Lodron University of Salzburg. Valeria Poli is supported by the Italian Association for Cancer Research (AIRC, No IG13009). Richard Kennedy and Steven Walker are supported by the McClay Foundation and the Movember Centre of Excellence (PC-UK and Movember). Gerda Egger is supported by FWF, P27616. Tim Malcolm and Suzanne Turner are supported by Leukaemia and Lymphoma Research.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms873

Nuttalliella namaqua: A Living Fossil and Closest Relative to the Ancestral Tick Lineage: Implications for the Evolution of Blood-Feeding in Ticks

Ticks are monophyletic and composed of the hard (Ixodidae) and soft (Argasidae) tick families, as well as the Nuttalliellidae, a family with a single species, Nuttalliella namaqua. Significant biological differences in lifestyle strategies for hard and soft ticks suggest that various blood-feeding adaptations occurred after their divergence. The phylogenetic relationships between the tick families have not yet been resolved due to the lack of molecular data for N. namaqua. This tick possesses a pseudo-scutum and apical gnathostoma as observed for ixodids, has a leathery cuticle similar to argasids and has been considered the evolutionary missing link between the two families. Little knowledge exists with regard to its feeding biology or host preferences. Data on its biology and systematic relationship to the other tick families could therefore be crucial in understanding the evolution of blood-feeding behaviour in ticks. Live specimens were collected and blood meal analysis showed the presence of DNA for girdled lizards from the Cordylid family. Feeding of ticks on lizards showed that engorgement occurred rapidly, similar to argasids, but that blood meal concentration occurs via malpighian excretion of water. Phylogenetic analysis of the 18S nuclear and 16S mitochondrial genes indicate that N. namaqua grouped basal to the main tick families. The data supports the monophyly of all tick families and suggests the evolution of argasid-like blood-feeding behaviour in the ancestral tick lineage. Based on the data and considerations from literature we propose an origin for ticks in the Karoo basin of Gondwanaland during the late Permian. The nuttalliellid family almost became extinct during the End Permian event, leaving N. namaqua as the closest living relative to the ancestral tick lineage and the evolutionary missing link between the tick families

Simultaneous targeted exchange of two nucleotides by single-stranded oligonucleotides clusters within a region of about fourteen nucleotides-6

Rrows point to the position of the successfully exchanged nucleotides. The upper base code shows the sequence of the analyzed clones, the lower base code the original sequence of the transfected V79-151 cells.<p><b>Copyright information:</b></p><p>Taken from "Simultaneous targeted exchange of two nucleotides by single-stranded oligonucleotides clusters within a region of about fourteen nucleotides"</p><p>http://www.biomedcentral.com/1471-2199/9/14</p><p>BMC Molecular Biology 2008;9():14-14.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2266939.</p><p></p

Simultaneous targeted exchange of two nucleotides by single-stranded oligonucleotides clusters within a region of about fourteen nucleotides-5

E) ore 151 (dark blue) respectively. The possible positions for the second (silent) exchange are given in red. (B) Structure of the oligonucleotides showing the first mismatch at position 153 and the second mismatch at position 147 in various distance from the unmodified 3'-end. (C) Structure of the oligonucleotides with different length, modified with PTO and showing the first mismatch at position 151 and the second mismatch at position 159.<p><b>Copyright information:</b></p><p>Taken from "Simultaneous targeted exchange of two nucleotides by single-stranded oligonucleotides clusters within a region of about fourteen nucleotides"</p><p>http://www.biomedcentral.com/1471-2199/9/14</p><p>BMC Molecular Biology 2008;9():14-14.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2266939.</p><p></p

Simultaneous targeted exchange of two nucleotides by single-stranded oligonucleotides clusters within a region of about fourteen nucleotides-4

Is indicates the distance of the second mismatch (independent of its position in upstream or downstream direction) from the first exchange position. ● first mismatch at position 151, modified by TA-clamps. ◀ : first mismatch at position 153, modified by TA-clamps. ■ : first mismatch at position 151, modified by PTO. The black line shows the linear fit of the data points from the experiments with the three different kinds of oligonucleotides.<p><b>Copyright information:</b></p><p>Taken from "Simultaneous targeted exchange of two nucleotides by single-stranded oligonucleotides clusters within a region of about fourteen nucleotides"</p><p>http://www.biomedcentral.com/1471-2199/9/14</p><p>BMC Molecular Biology 2008;9():14-14.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2266939.</p><p></p

Simultaneous targeted exchange of two nucleotides by single-stranded oligonucleotides clusters within a region of about fourteen nucleotides-1

Rrows point to the position of the successfully exchanged nucleotides. The upper base code shows the sequence of the analyzed clones, the lower base code the original sequence of the transfected V79-151 cells.<p><b>Copyright information:</b></p><p>Taken from "Simultaneous targeted exchange of two nucleotides by single-stranded oligonucleotides clusters within a region of about fourteen nucleotides"</p><p>http://www.biomedcentral.com/1471-2199/9/14</p><p>BMC Molecular Biology 2008;9():14-14.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2266939.</p><p></p

Simultaneous targeted exchange of two nucleotides by single-stranded oligonucleotides clusters within a region of about fourteen nucleotides-0

E) ore 151 (dark blue) respectively. The possible positions for the second (silent) exchange are given in red. (B) Structure of the oligonucleotides showing the first mismatch at position 153 and the second mismatch at position 147 in various distance from the unmodified 3'-end. (C) Structure of the oligonucleotides with different length, modified with PTO and showing the first mismatch at position 151 and the second mismatch at position 159.<p><b>Copyright information:</b></p><p>Taken from "Simultaneous targeted exchange of two nucleotides by single-stranded oligonucleotides clusters within a region of about fourteen nucleotides"</p><p>http://www.biomedcentral.com/1471-2199/9/14</p><p>BMC Molecular Biology 2008;9():14-14.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2266939.</p><p></p