3,699 research outputs found

    An In Vivo Screen Identifies PYGO2 as a Driver for Metastatic Prostate Cancer

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    Advanced prostate cancer displays conspicuous chromosomal instability and rampant copy number aberrations, yet the identity of functional drivers resident in many amplicons remain elusive. Here, we implemented a functional genomics approach to identify new oncogenes involved in prostate cancer progression. Through integrated analyses of focal amplicons in large prostate cancer genomic and transcriptomic datasets as well as genes upregulated in metastasis, 276 putative oncogenes were enlisted into an in vivo gain-of-function tumorigenesis screen. Among the top positive hits, we conducted an in-depth functional analysis on Pygopus family PHD finger 2 (PYGO2), located in the amplicon at 1q21.3. PYGO2 overexpression enhances primary tumor growth and local invasion to draining lymph nodes. Conversely, PYGO2 depletion inhibits prostate cancer cell invasion in vitro and progression of primary tumor and metastasis in vivo In clinical samples, PYGO2 upregulation associated with higher Gleason score and metastasis to lymph nodes and bone. Silencing PYGO2 expression in patient-derived xenograft models impairs tumor progression. Finally, PYGO2 is necessary to enhance the transcriptional activation in response to ligand-induced Wnt/ÎČ-catenin signaling. Together, our results indicate that PYGO2 functions as a driver oncogene in the 1q21.3 amplicon and may serve as a potential prognostic biomarker and therapeutic target for metastatic prostate cancer.Significance: Amplification/overexpression of PYGO2 may serve as a biomarker for prostate cancer progression and metastasis. Cancer Res; 78(14); 3823-33. ©2018 AACR

    CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation

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    Runx2, an essential transactivator for osteoblast differentiation, is tightly regulated at both the transcriptional and posttranslational levels. In this paper, we report that CHIP (C terminus of Hsc70-interacting protein)/STUB1 regulates Runx2 protein stability via a ubiquitination-degradation mechanism. CHIP interacts with Runx2 in vitro and in vivo. In the presence of increased Runx2 protein levels, CHIP expression decreases, whereas the expression of other E3 ligases involved in Runx2 degradation, such as Smurf1 or WWP1, remains constant or increases during osteoblast differentiation. Depletion of CHIP results in the stabilization of Runx2, enhances Runx2-mediated transcriptional activation, and promotes osteoblast differentiation in primary calvarial cells. In contrast, CHIP overexpression in preosteoblasts causes Runx2 degradation, inhibits osteoblast differentiation, and instead enhances adipogenesis. Our data suggest that negative regulation of the Runx2 protein by CHIP is critical in the commitment of precursor cells to differentiate into the osteoblast lineage

    Understanding the DsJ+(2317)D^+_{sJ}(2317) and DsJ+(2460)D^+_{sJ}(2460) with Sum Rules in HQET

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    In the framework of heavy quark effective theory we use QCD sum rules to calculate the masses of the cˉs\bar c s (0+,1+)(0^+, 1^+) and (1+,2+)(1^+, 2^+) excited states. The results are consistent with that the states DsJ(2317)D_{sJ}(2317) and DsJ(2460)D_{sJ}(2460) observed by BABAR and CLEO are the 0+0^+ and 1+1^+ states in the jl=12+j_l={1\over 2}^+ doublet

    A search for pre-substellar cores and proto-brown dwarf candidates in Taurus: multiwavelength analysis in the B213-L1495 clouds

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    In an attempt to study whether the formation of brown dwarfs (BDs) takes place as a scaled-down version of low-mass stars, we conducted IRAM30m/MAMBO-II observations at 1.2 mm in a sample of 12 proto-BD candidates selected from Spitzer/IRAC data in the B213-L1495 clouds in Taurus. Subsequent observations with the CSO at 350 micron, VLA at 3.6 and 6 cm, and IRAM30m/EMIR in the 12CO(1-0), 13CO(1-0), and N2H+(1-0) transitions were carried out toward the two most promising Spitzer/IRAC source(s), J042118 and J041757. J042118 is associated with a compact (<10 arcsec or <1400 AU) and faint source at 350 micron, while J041757 is associated with a partially resolved (~16 arcsec or ~2000 AU) and stronger source emitting at centimetre wavelengths with a flat spectral index. The corresponding masses of the dust condensations are ~1 and ~5 Mjup for J042118 and J041757, respectively. In addition, about 40 arcsec to the northeast of J041757 we detect a strong and extended submillimetre source, J041757-NE, which is not associated with NIR/FIR emission down to our detection limits, but is clearly detected in 13CO and N2H+ at ~7 km/s, and for which we estimated a total mass of ~100 Mjup, close to the mass required to be gravitationally bound. In summary, our observational strategy has allowed us to find in B213-L1495 two proto-BD candidates and one pre-substellar core candidate, whose properties seem to be consistent with a scaled-down version of low-mass stars.Comment: MNRAS, 424, 2778; corrected typos, mass estimate refined in Section 3.2.1 and Section 5.3; conclusions unchange

    Modelling Herschel observations of hot molecular gas emission from embedded low-mass protostars

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    Aims. Young stars interact vigorously with their surroundings, as evident from the highly rotationally excited CO (up to Eup=4000 K) and H2O emission (up to 600 K) detected by the Herschel Space Observatory in embedded low-mass protostars. Our aim is to construct a model that reproduces the observations quantitatively, to investigate the origin of the emission, and to use the lines as probes of the various heating mechanisms. Methods. The model consists of a spherical envelope with a bipolar outflow cavity. Three heating mechanisms are considered: passive heating by the protostellar luminosity, UV irradiation of the outflow cavity walls, and C-type shocks along the cavity walls. Line fluxes are calculated for CO and H2O and compared to Herschel data and complementary ground-based data for the protostars NGC1333 IRAS2A, HH 46 and DK Cha. The three sources are selected to span a range of evolutionary phases and physical characteristics. Results. The passively heated gas in the envelope accounts for 3-10% of the CO luminosity summed over all rotational lines up to J=40-39; it is best probed by low-J CO isotopologue lines such as C18O 2-1 and 3-2. The UV-heated gas and the C-type shocks, probed by 12CO 10-9 and higher-J lines, contribute 20-80% each. The model fits show a tentative evolutionary trend: the CO emission is dominated by shocks in the youngest source and by UV-heated gas in the oldest one. This trend is mainly driven by the lower envelope density in more evolved sources. The total H2O line luminosity in all cases is dominated by shocks (>99%). The exact percentages for both species are uncertain by at least a factor of 2 due to uncertainties in the gas temperature as function of the incident UV flux. However, on a qualitative level, both UV-heated gas and C-type shocks are needed to reproduce the emission in far-infrared rotational lines of CO and H2O.Comment: 15 pages (+4 pages appendix), 20 figures, accepted by A&
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