Disturbed balance of expression between XIAP and Smac/DIABLO during tumour progression in renal cell carcinomas

Dysregulation of apoptosis plays an important role in tumour progression and resistance to chemotherapy. The X-linked inhibitor of apoptosis ( XIAP) is considered to be the most potent caspase inhibitor of all known inhibitor of apoptosis-family members. Only recently, an antagonist of XIAP has been identified, termed Smac/DIABLO. To explore the relevance of antiapoptotic XIAP and proapoptotic Smac/DIABLO for tumour progression in renal cell carcinomas (RCCs), we analysed XIAP and Smac/DIABLO mRNA and protein expression in the primary tumour tissue from 66 RCCs of all major histological types by quantitative real-time PCR, Western blot and ELISA. X-linked inhibitor of apoptosis and Smac/DIABLO mRNA expression was found in all RCCs. Importantly, the relative XIAP mRNA expression levels significantly increased from early (pT1) to advanced (pT3) tumour stages ( P = 0.0002) and also with tumour dedifferentiation ( P = 0.04). Western blot analysis confirmed the tumour stage-dependent increase of XIAP expression on the protein level. In contrast, mRNA and protein expression levels of Smac/DIABLO did not significantly change between early and advanced tumour stages or between low and high tumour grades. Consequently, the mRNA expression ratio between antiapoptotic XIAP and proapoptotic Smac/DIABLO markedly increased during progression from early ( pT1) to advanced ( pT3) tumour stages. Moreover, RCCs confined within the organ capsule ( pT1 and pT2) exhibited a significantly lower XIAP to Smac/DIABLO expression ratio when compared with RCCs infiltrating beyond the kidney ( pT3; P = 0.01). Thus, our investigation demonstrates that the delicate balance between XIAP and Smac/DIABLO expression is gradually disturbed during progression of RCCs, resulting in a relative increase of antiapoptotic XIAP over proapoptotic Smac/DIABLO, thereby probably contributing to the marked apoptosis resistance of RCC.OncologySCI(E)46ARTICLE71349-13579

In vitro nuclear interactome of the HIV-1 Tat protein

<p>Abstract</p> <p>Background</p> <p>One facet of the complexity underlying the biology of HIV-1 resides not only in its limited number of viral proteins, but in the extensive repertoire of cellular proteins they interact with and their higher-order assembly. HIV-1 encodes the regulatory protein Tat (86–101aa), which is essential for HIV-1 replication and primarily orchestrates HIV-1 provirus transcriptional regulation. Previous studies have demonstrated that Tat function is highly dependent on specific interactions with a range of cellular proteins. However they can only partially account for the intricate molecular mechanisms underlying the dynamics of proviral gene expression. To obtain a comprehensive nuclear interaction map of Tat in T-cells, we have designed a proteomic strategy based on affinity chromatography coupled with mass spectrometry.</p> <p>Results</p> <p>Our approach resulted in the identification of a total of 183 candidates as Tat nuclear partners, 90% of which have not been previously characterised. Subsequently we applied <it>in silico </it>analysis, to validate and characterise our dataset which revealed that the Tat nuclear interactome exhibits unique signature(s). First, motif composition analysis highlighted that our dataset is enriched for domains mediating protein, RNA and DNA interactions, and helicase and ATPase activities. Secondly, functional classification and network reconstruction clearly depicted Tat as a polyvalent protein adaptor and positioned Tat at the nexus of a densely interconnected interaction network involved in a range of biological processes which included gene expression regulation, RNA biogenesis, chromatin structure, chromosome organisation, DNA replication and nuclear architecture.</p> <p>Conclusion</p> <p>We have completed the <it>in vitro </it>Tat nuclear interactome and have highlighted its modular network properties and particularly those involved in the coordination of gene expression by Tat. Ultimately, the highly specialised set of molecular interactions identified will provide a framework to further advance our understanding of the mechanisms of HIV-1 proviral gene silencing and activation.</p

Geomorphologic mapping of titan's polar terrains: Constraining surface processes and landscape evolution

We present a geomorphologic map of Titan's polar terrains. The map was generated from a combination of Cassini Synthetic Aperture Radar (SAR) and Imaging Science Subsystem imaging products, as well as altimetry, SARTopo and radargrammetry topographic datasets. In combining imagery with topographic data, our geomorphologic map reveals a stratigraphic sequence from which we infer process interactions between units. In mapping both polar regions with the same geomorphologic units, we conclude that processes that formed the terrains of the north polar region also acted to form the landscape we observe at the south. Uniform, SAR-dark plains are interpreted as sedimentary deposits, and are bounded by moderately dissected uplands. These plains contain the highest density of filled and empty lake depressions, and canyons. These units unconformably overlay a basement rock that outcrops as mountains and SAR-bright dissected terrains at various elevations across both poles. All these units are then superposed by surficial units that slope towards the seas, suggestive of subsequent overland transport of sediment. From estimates of the depths of the embedded empty depressions and canyons that drain into the seas, the SAR-dark plains must be &gt;600 m thick in places, though the thickness may vary across the poles. At the lowest elevations of each polar region, there are large seas, which are currently liquid methane/ethane filled at the north and empty at the south. The large plains deposits and the surrounding hillslopes may represent remnant landforms that are a result of previously vast polar oceans, where larger liquid bodies may have allowed for a sustained accumulation of soluble and insoluble sediments, potentially forming layered sedimentary deposits. Coupled with vertical crustal movements, the resulting layers would be of varying solubilities and erosional resistances, allowing formation of the complex landscape that we observe today

A rigid and weathered ice shell on Titan

Several lines of evidence suggest that Saturn's largest moon, Titan, has a global subsurface ocean beneath an outer ice shell 50 to 200 kilometres thick. If convection is occurring, the rigid portion of the shell is expected to be thin; similarly, a weak, isostatically compensated shell has been proposed to explain the observed topography. Here we report a strong inverse correlation between gravity and topography at long wavelengths that are not dominated by tides and rotation. We argue that negative gravity anomalies (mass deficits) produced by crustal thickening at the base of the ice shell overwhelm positive gravity anomalies (mass excesses) produced by the small surface topography, giving rise to this inverse correlation. We show that this situation requires a substantially rigid ice shell with an elastic thickness exceeding 40 kilometres, and hundreds of metres of surface erosion and deposition, consistent with recent estimates from local features. Our results are therefore not compatible with a geologically active, low-rigidity ice shell. After extrapolating to wavelengths that are controlled by tides and rotation, we suggest that Titan's moment of inertia may be even higher (that is, Titan may be even less centrally condensed) than is currently thought