Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D

Medulloblastoma is the most common malignant brain tumor of childhood. Despite numerous advances, clinical challenges range from recurrent and progressive disease to long-term toxicities in survivors. The lack of more effective, less toxic therapies results from our limited understanding of medulloblastoma growth. Although TP53 is the most commonly altered gene in cancers, it is rarely mutated in medulloblastoma. Accumulating evidence, however, indicates that TP53 pathways are disrupted in medulloblastoma. Wild-typep53-induced phosphatase 1 (WIP1 or PPM1D) encodes a negative regulator of p53. WIP1 amplification (17q22-q23) and its overexpression have been reported in diverse cancer types. We examined primary medulloblastoma specimens and cell lines, and detected WIP1 copy gain and amplification prevalent among but not exclusively in the tumors with 17q gain and isochromosome 17q (i17q), which are among the most common cytogenetic lesions in medulloblastoma. WIP1 RNA levels were significantly higher in the tumors with 17q gain or i17q. Immunoblots confirmed significant WIP1 protein in primary tumors, generally higher in those with 17q gain or i17q. Under basal growth conditions and in response to the chemotherapeutic agent, etoposide, WIP1 antagonized p53-mediated apoptosis in medulloblastoma cell lines. These results indicate that medulloblastoma express significant levels of WIP1 that modulate genotoxic responsiveness by negatively regulating p53

The Caenorhabditis elegans Mucin-Like Protein OSM-8 Negatively Regulates Osmosensitive Physiology Via the Transmembrane Protein PTR-23

The molecular mechanisms of animal cell osmoregulation are poorly understood. Genetic studies of osmoregulation in yeast have identified mucin-like proteins as critical regulators of osmosensitive signaling and gene expression. Whether mucins play similar roles in higher organisms is not known. Here, we show that mutations in the Caenorhabditis elegans mucin-like gene osm-8 specifically disrupt osmoregulatory physiological processes. In osm-8 mutants, normal physiological responses to hypertonic stress, such as the accumulation of organic osmolytes and activation of osmoresponsive gene expression, are constitutively activated. As a result, osm-8 mutants exhibit resistance to normally lethal levels of hypertonic stress and have an osmotic stress resistance (Osr) phenotype. To identify genes required for Osm-8 phenotypes, we performed a genome-wide RNAi osm-8 suppressor screen. After screening ∼18,000 gene knockdowns, we identified 27 suppressors that specifically affect the constitutive osmosensitive gene expression and Osr phenotypes of osm-8 mutants. We found that one suppressor, the transmembrane protein PTR-23, is co-expressed with osm-8 in the hypodermis and strongly suppresses several Osm-8 phenotypes, including the transcriptional activation of many osmosensitive mRNAs, constitutive glycerol accumulation, and osmotic stress resistance. Our studies are the first to show that an extracellular mucin-like protein plays an important role in animal osmoregulation in a manner that requires the activity of a novel transmembrane protein. Given that mucins and transmembrane proteins play similar roles in yeast osmoregulation, our findings suggest a possible evolutionarily conserved role for the mucin-plasma membrane interface in eukaryotic osmoregulation

A microarray study of MPP(+)-treated PC12 Cells: Mechanisms of toxicity (MOT) analysis using bioinformatics tools

BACKGROUND: This paper describes a microarray study including data quality control, data analysis and the analysis of the mechanism of toxicity (MOT) induced by 1-methyl-4-phenylpyridinium (MPP(+)) in a rat adrenal pheochromocytoma cell line (PC12 cells) using bioinformatics tools. MPP(+ )depletes dopamine content and elicits cell death in PC12 cells. However, the mechanism of MPP(+)-induced neurotoxicity is still unclear. RESULTS: In this study, Agilent rat oligo 22K microarrays were used to examine alterations in gene expression of PC12 cells after 500 μM MPP(+ )treatment. Relative gene expression of control and treated cells represented by spot intensities on the array chips was analyzed using bioinformatics tools. Raw data from each array were input into the NCTR ArrayTrack database, and normalized using a Lowess normalization method. Data quality was monitored in ArrayTrack. The means of the averaged log ratio of the paired samples were used to identify the fold changes of gene expression in PC12 cells after MPP(+ )treatment. Our data showed that 106 genes and ESTs (Expressed Sequence Tags) were changed 2-fold and above with MPP(+ )treatment; among these, 75 genes had gene symbols and 59 genes had known functions according to the Agilent gene Refguide and ArrayTrack-linked gene library. The mechanism of MPP(+)-induced toxicity in PC12 cells was analyzed based on their genes functions, biological process, pathways and previous published literatures. CONCLUSION: Multiple pathways were suggested to be involved in the mechanism of MPP(+)-induced toxicity, including oxidative stress, DNA and protein damage, cell cycling arrest, and apoptosis

Sedimentary recycling in arc magmas: geochemical and U–Pb–Hf–O constraints on the Mesoproterozoic Suldal Arc, SW Norway

The Hardangervidda-Rogaland Block within southwest Norway is host to ~1.52 to 1.48 Ga continental building and variable reworking during the ~1.1 to 0.9 Ga Sveconorwegian orogeny. Due to the lack of geochronological and geochemical data, the timing and tectonic setting of early Mesoproterozoic magmatism has long been ambiguous. This paper presents zircon U–Pb–Hf–O isotope data combined with whole-rock geochemistry to address the age and petrogenesis of basement units within the Suldal region, located in the centre of the Hardangervidda-Rogaland Block. The basement comprises variably deformed grey gneisses and granitoids that petrologically and geochemically resemble mature volcanic arc lithologies. U–Pb ages confirm that magmatism occurred from ~1,521 to 1,485 Ma, and conspicuously lack any xenocrystic inheritance of distinctly older crust. Hafnium isotope data range from εHf(initial) +1 to +11, suggesting a rather juvenile magmatic source, but with possible involvement of late Palaeoproterozoic crust. Oxygen isotope data range from mantle-like (δ18O ~5 ‰) to elevated (~10 ‰) suggesting involvement of low-temperature altered material (e.g., supracrustal rocks) in the magma source. The Hf–O isotope array is compatible with mixing between mantle-derived material with young low-temperature altered material (oceanic crust/sediments) and older low-temperature altered material (continent-derived sediments). This, combined with a lack of xenoliths and xenocrysts, exposed older crust, AFC trends and S-type geochemistry, all point to mixing within a deep-crustal magma-generation zone. A proposed model comprises accretion of altered oceanic crust and the overlying sediments to a pre-existing continental margin, underthrusting to the magma-generation zone and remobilisation during arc magmatism. The geodynamic setting for this arc magmatism is comparable with that seen in the Phanerozoic (e.g., the Sierra Nevada and Coast Range batholiths), with compositions in the Suldal Sector reaching those of average upper continental crust. As within these younger examples, factors that drive magmatism towards the composition of the average continental crust include the addition of sedimentary material to magma source regions, and delamination of cumulate material. Underthrusting of sedimentary materials and their subsequent involvement in arc magmatism is perhaps a more widespread mechanism involved in continental growth than is currently recognised. Finally, the Suldal Arc magmatism represents a significant juvenile crustal addition to SW Fennoscandia

Mortgage Refinancing Activity: An Explanation [1990–2001]

Mortgage refinancing activity reached unprecedented high levels during 1990–2001. Using GARCH to control for heteroskedasticity and separating the data into regimes to control for potential structural changes over time, we estimate a model explaining changes in mortgage refinancing activity over the period studied. We find changes in refinancing activity to be negatively related to current as well as past changes in the 30-year mortgage rate with a declining significant lag over time. Similarly, there is a significant lagged dependent variable with a declining lag. Moreover, mortgage refinancing activity is a substitute for other investments during certain regimes. These results offer evidence that home owners cash out the mortgage for other investments. The lags suggest that the process is delayed for a variety of reasons. The declining lag signals a faster response by consumers. The reasons for a faster response include a consumer perception that interest rates have “bottomed out,” the presence of an increase in consumer sophistication, and improvements in technology and market coordination that facilitate and reduce the cost of the refinancing process. Copyright Springer Science + Business Media, LLC 2006Banking, Interest rates, Mortgages, Mortgage prepayment, Refinancing,