Identification of Essential Sequences for Cellular Localization in BRMS1 Metastasis Suppressor

10 páginas, 5 figuras. PMID: 19649328 [PubMed] PMCID: PMC2713406BACKGROUND: Breast cancer metastasis suppressor 1 (BRMS1) reduces the number and the size of secondary tumours in a mouse model without affecting the growth of the primary foci upon its re-expression. Knockdown of BRMS1 expression associates with metastasis. The molecular details on BRMS1 mechanism of action include its ability to function as a transcriptional co-repressor and consistently BRMS1 has been described as a predominantly nuclear protein. Since cellular distribution could represent a potential mechanism of regulation, we wanted to characterize BRMS1 sequence motifs that might regulate its cellular distribution. According to its amino acids sequence, BRMS1 contain two putative nuclear localization signals, however none of them has been proved to work so far. METHODOLOGY/PRINCIPAL FINDINGS: By using well known in vivo assays to detect both nuclear import and export signal, we have characterized, in the present study, one functional nuclear localisation signal as necessary and sufficient to promote nuclear transport. Additionally, the outcome of a directed yeast two-hybrid assay identify importin alpha6 as a specific partner of BRMS1 thus speculating that BRMS1 nuclear import could be specifically mediated by the reported nuclear transporter. Besides, the combination of a computational searching approach along the utilization of a nuclear export assay, identified a functional motif within the BRMS1 sequence responsible for its nuclear export, that resulted not affected by the highly specific CRM1 inhibitor Leptomycin-B. Interspecies heterokaryon assay demonstrate the capability of BRMS1 to shuttle between the nuclear and cytosolic compartments CONCLUSIONS/SIGNIFICANCE: Our results show for the first time that BRMS1 contains both nuclear import and export signals enabling its nucleo-cytoplasmic shuttling. These findings contributes new data for the understanding of the BRMS1 functions and allow us to speculate that this phenomenon could represent a novel mechanism for regulating the activity of BRMS1 or its associated cytosolic partnersThis work was supported by Spanish Ministerio de Ciencia y Tecnología (Grant SAF2006-10269), Ministerio de Ciencia e Innovación (Grant SAF2008-04048-E) and by a grant from Fundación Mutua Madrileña.Peer reviewe

Nuclear Import and Export Signals of Human Cohesins SA1/STAG1 and SA2/STAG2 Expressed in Saccharomyces cerevisiae

Abstract Background: Human SA/STAG proteins, homologues of the yeast Irr1/Scc3 cohesin, are the least studied constituents of the sister chromatid cohesion complex crucial for proper chromosome segregation. The two SA paralogues, SA1 and SA2, show some specificity towards the chromosome region they stabilize, and SA2, but not SA1, has been shown to participate in transcriptional regulation as well. The molecular basis of this functional divergence is unknown. Methodology/Principal Findings: In silico analysis indicates numerous putative nuclear localization (NLS) and export (NES) signals in the SA proteins, suggesting the possibility of their nucleocytoplasmic shuttling. We studied the functionality of those putative signals by expressing fluorescently tagged SA1 and SA2 in the yeast Saccharomyces cerevisiae. Only the Nterminal NLS turned out to be functional in SA1. In contrast, the SA2 protein has at least two functional NLS and also two functional NES. Depending on the balance between these opposing signals, SA2 resides in the nucleus or is distributed throughout the cell. Validation of the above conclusions in HeLa cells confirmed that the same N-terminal NLS of SA1 is functional in those cells. In contrast, in SA2 the principal NLS functioning in HeLa cells is different from that identified in yeast and is localized to the C-terminus. Conclusions/Significance: This is the first demonstration of the possibility of non-nuclear localization of an SA protein. The reported difference in the organization between the two SA homologues may also be relevant to their partially divergent functions. The mechanisms determining subcellular localization of cohesins are only partially conserved between yeast and human cells

State of the climate in 2017

In 2017, the dominant greenhouse gases released into Earth's atmosphere-carbon dioxide, methane, and nitrous oxide-reached new record highs. The annual global average carbon dioxide concentration at Earth's surface for 2017 was 405.0 ± 0.1 ppm, 2.2 ppm greater than for 2016 and the highest in the modern atmospheric measurement record and in ice core records dating back as far as 800 000 years. The global growth rate of CO2 has nearly quadrupled since the early 1960s. With ENSO-neutral conditions present in the central and eastern equatorial Pacific Ocean during most of the year and weak La Niña conditions notable at the start and end, the global temperature across land and ocean surfaces ranked as the second or third highest, depending on the dataset, since records began in the mid-to-late 1800s. Notably, it was the warmest non-El Niño year in the instrumental record. Above Earth's surface, the annual lower tropospheric temperature was also either second or third highest according to all datasets analyzed. The lower stratospheric temperature was about 0.2°C higher than the record cold temperature of 2016 according to most of the in situ and satellite datasets. Several countries, including Argentina, Uruguay, Spain, and Bulgaria, reported record high annual temperatures. Mexico broke its annual record for the fourth consecutive year. On 27 January, the temperature reached 43.4°C at Puerto Madryn, Argentina-the highest temperature recorded so far south (43°S) anywhere in the world. On 28 May in Turbat, western Pakistan, the high of 53.5°C tied Pakistan's all-time highest temperature and became the world-record highest temperature for May. In the Arctic, the 2017 land surface temperature was 1.6°C above the 1981-2010 average, the second highest since the record began in 1900, behind only 2016. The five highest annual Arctic temperatures have all occurred since 2007. Exceptionally high temperatures were observed in the permafrost across the Arctic, with record values reported in much of Alaska and northwestern Canada. In August, high sea surface temperature (SST) records were broken for the Chukchi Sea, with some regions as warm as +11°C, or 3° to 4°C warmer than the longterm mean (1982-present). According to paleoclimate studies, today's abnormally warm Arctic air and SSTs have not been observed in the last 2000 years. The increasing temperatures have led to decreasing Arctic sea ice extent and thickness. On 7 March, sea ice extent at the end of the growth season saw its lowest maximum in the 37-year satellite record, covering 8% less area than the 1981-2010 average. The Arctic sea ice minimum on 13 September was the eighth lowest on record and covered 25% less area than the long-term mean. Preliminary data indicate that glaciers across the world lost mass for the 38th consecutive year on record; the declines are remarkably consistent from region to region. Cumulatively since 1980, this loss is equivalent to slicing 22 meters off the top of the average glacier. Antarctic sea ice extent remained below average for all of 2017, with record lows during the first four months. Over the continent, the austral summer seasonal melt extent and melt index were the second highest since 2005, mostly due to strong positive anomalies of air temperature over most of the West Antarctic coast. In contrast, the East Antarctic Plateau saw record low mean temperatures in March. The year was also distinguished by the second smallest Antarctic ozone hole observed since 1988. Across the global oceans, the overall long-term SST warming trend remained strong. Although SST cooled slightly from 2016 to 2017, the last three years produced the three highest annual values observed; these high anomalies have been associated with widespread coral bleaching. The most recent global coral bleaching lasted three full years, June 2014 to May 2017, and was the longest, most widespread, and almost certainly most destructive such event on record. Global integrals of 0-700-m and 0-2000-m ocean heat content reached record highs in 2017, and global mean sea level during the year became the highest annual average in the 25-year satellite altimetry record, rising to 77 mm above the 1993 average. In the tropics, 2017 saw 85 named tropical storms, slightly above the 1981-2010 average of 82. The North Atlantic basin was the only basin that featured an above-normal season, its seventh most active in the 164-year record. Three hurricanes in the basin were especially notable. Harvey produced record rainfall totals in areas of Texas and Louisiana, including a storm total of 1538.7 mm near Beaumont, Texas, which far exceeds the previous known U.S. tropical cyclone record of 1320.8 mm. Irma was the strongest tropical cyclone globally in 2017 and the strongest Atlantic hurricane outside of the Gulf of Mexico and Caribbean on record with maximum winds of 295 km h-1. Maria caused catastrophic destruction across the Caribbean Islands, including devastating wind damage and flooding across Puerto Rico. Elsewhere, the western North Pacific, South Indian, and Australian basins were all particularly quiet. Precipitation over global land areas in 2017 was clearly above the long-term average. Among noteworthy regional precipitation records in 2017, Russia reported its second wettest year on record (after 2013) and Norway experienced its sixth wettest year since records began in 1900. Across India, heavy rain and flood-related incidents during the monsoon season claimed around 800 lives. In August and September, above-normal precipitation triggered the most devastating floods in more than a decade in the Venezuelan states of Bolívar and Delta Amacuro. In Nigeria, heavy rain during August and September caused the Niger and Benue Rivers to overflow, bringing floods that displaced more than 100 000 people. Global fire activity was the lowest since at least 2003; however, high activity occurred in parts of North America, South America, and Europe, with an unusually long season in Spain and Portugal, which had their second and third driest years on record, respectively. Devastating fires impacted British Columbia, destroying 1.2 million hectares of timber, bush, and grassland, due in part to the region's driest summer on record. In the United States, an extreme western wildfire season burned over 4 million hectares; the total costs of $18 billion tripled the previous U.S. annual wildfire cost record set in 1991

Social Relationships and Mortality Risk: A Meta-analytic Review

In a meta-analysis, Julianne Holt-Lunstad and colleagues find that individuals' social relationships have as much influence on mortality risk as other well-established risk factors for mortality, such as smoking