Gain of function of mutant p53 by coaggregation with multiple tumor suppressors

Many p53 missense mutations possess dominant-negative activity and oncogenic gain of function. We report that for structurally destabilized p53 mutants, these effects result from mutant-induced coaggregation of wild-type p53 and its paralogs p63 and p73, thereby also inducing a heat-shock response. Aggregation of mutant p53 resulted from self-assembly of a conserved aggregation-nucleating sequence within the hydrophobic core of the DNA-binding domain, which becomes exposed after mutation. Suppressing the aggregation propensity of this sequence by mutagenesis abrogated gain of function and restored activity of wild-type p53 and its paralogs. In the p53 germline mutation database, tumors carrying aggregation-prone p53 mutations have a significantly lower frequency of wild-type allele loss as compared to tumors harboring nonaggregating mutations, suggesting a difference in clonal selection of aggregating mutants. Overall, our study reveals a novel disease mechanism for mutant p53 gain of function and suggests that, at least in some respects, cancer could be considered an aggregation-associated disease.     

Melatonin Prevents Oxidative Stress and Hepatocyte Cell Death Induced by Experimental Cholestasis

The induction of oxidative stress precedes liver injury during experimental obstructive jaundice (OJ). In this sense, different evidences suggest that melatonin (MEL), as antioxidant, may be useful in the protection against apoptosis and necrosis during experimental cholestasis. In addition, we will also assess if MEL-dependent protection is related to a recovery of antioxidant status disturbances induced by OJ. Cholestasis was achieved by double ligature and sectioning of the principal bile duct. MEL was injected intraperitoneally (500?μg/kg/day). Lipid peroxidation was evaluated by the measurement of malondialdehyde (MDA) content in liver. Different parameters related to antioxidant status, such as reduced glutathione (GSH), glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD) were determined in liver. Liver injury was assessed by alanine aminotransferase (ALT) in serum, histological examination, DNA fragmentation and TUNEL assay. The activation of perisinusoidal stellate cells was evaluated by immunohistochemical measurement of α-smooth muscle actin in liver sections. The induction of OJ increased all the parameters related to apoptosis and necrosis in liver. The induction of liver injury was associated with stellate cell activation, as well as an increase in MDA (p<0.0001) and a reduction in GSH, GPx, catalase and SOD content (p<0.0001) in liver. MEL reduced hepatic apoptosis and necrosis (p<0.004) with a significant improvement in all oxidative stress markers. In conclusion, our results showed that MEL recovered the antioxidant status and reduced apoptosis and necrosis induced by experimental cholestasis.     

Mapping and tissue mRNA expression analysis of the pig solute carrier 27A (SLC27A) multigene family

Solute-carrier family 27A molecules are integral transmembrane proteins that play a fundamental role in the uptake of long-chain fatty acids into mammalian cells. Our goal was to characterize this multigene family in pigs. Chromosomal location of the six porcine SLC27A genes was determined by radiation hybrid mapping and indicated that the six genes map to six different chromosomal locations. Moreover, we analyzed SLC27A mRNA expression in six pig tissues by quantitative RT-PCR. While SLC27A1, SLC27A3 and SLC27A4 were expressed in most, if not all, analyzed tissues, SLC27A2, SLC27A5 and SLC27A6 were predominantly expressed in the liver. In general, pig and human SLC27A mRNA expression profiles were remarkably concordant, although important differences were observed for SLC27A1 and SLC27A6 mRNAs. Discrepancies between mRNA expression profiles have been observed even in closely related primate species, and they might reflect the acquisition of regulatory changes promoting evolutionary adaptation.     

Desert travels in the Atacama: making place through movement (c. 2500-1500 cal BP)

Social worlds are constituted by movement. Mobility entails the circulation not only of people, but also of material goods, imaginaries, experiences, flows of information, and knowledge. In this article, we examine different forms of movement in the Atacama Desert during the Formative Period (c. 2500-1500 cal BP), such as pedestrian travels, llama caravans, and navigation on sea lion-skin vessels along the Pacific, incorporating various material means and encompassing a wide array of incentives. We present different case studies that challenge monolithic assumptions about mobility in the South-Central Andes, commonly understood through the lens of ecological complementarity and primarily driven by economic exchange. Extending Binford's classic distinction between residential and logistical mobility as two ideal types of hunter-gatherers’ settlement systems to include groups of early farmers, in combination with the territorial categories of local and extra-local, we interrogate the spatial and temporal scale of these journeys – from daily to seasonal, from short to long distance – and its materialization. In these examples, we approach movement and travel as a way of life, expanding the traditional view of mobility through an exploration of the varied ways in which it was practised and integrated into the social lives of desert dwellers.     

Proteomic analysis of arabidopsis seed germination and priming

To better understand seed germination, a complex developmental process, we developed a proteome analysis of the model plant Arabidopsis for which complete genome sequence is now available. Among about 1,300 total seed proteins resolved in two-dimensional gels, changes in the abundance (up- and down-regulation) of 74 proteins were observed during germination sensu stricto (i.e. prior to radicle emergence) and the radicle protrusion step. This approach was also used to analyze protein changes occurring during industrial seed pretreatments such as priming that accelerate seed germination and improve seedling uniformity. Several proteins were identified by matrix-assisted laser-desorption ionization time of flight mass spectrometry. Some of them had previously been shown to play a role during germination and/or priming in several plant species, a finding that underlines the usefulness of using Arabidopsis as a model system for molecular analysis of seed quality. Furthermore, the present study, carried out at the protein level, validates previous results obtained at the level of gene expression (e.g. from quantitation of differentially expressed mRNAs or analyses of promoter/reporter constructs). Finally, this approach revealed new proteins associated with the different phases of seed germination and priming. Some of them are involved either in the imbibition process of the seeds (such as an actin isoform or a WD-40 repeat protein) or in the seed dehydration process (e.g. cytosolic glyceraldehyde-3-phosphate dehydrogenase). These facts highlight the power of proteomics to unravel specific features of complex developmental processes such as germination and to detect protein markers that can be used to characterize seed vigor of commercial seed lots and to develop and monitor priming treatments.