Nox2 regulates endothelial cell cycle arrest and apoptosis via p21 (cip1) and p53

Endothelial cells (EC) express constitutively two major isofonns (Nox2 and Nox4) of the catalytic subunit of NADPH oxidase, which is a major source of endothelial reactive oxygen species. However, the individual roles of these Noxes in endothelial function remain unclear. We have investigated the role of Nox2 in nutrient deprivation-induced cell cycle arrest and apoptosis. In proliferating human dermal microvascular EC, Nox2 mRNA expression was low relative to Nox4 (Nox2:Nox4 similar to 1:13), but was upregulated 24 It after starvation and increased to 8 +/- 3.5-fold at 36 h of starvation. Accompanying the upregulation of Nox2, there was a 2.28 +/- 0.18-fold increase in O-2(-); production, a dramatic induction of p21(cip1) and p53, cell cycle arrest, and the onset of apoptosis (all p < 0.05). All these changes were inhibited significantly by in vitro deletion of Nox2 expression and in coronary microvascular EC isolated from Nox2 knockout mice. In Nox2 knockout cells, although there was a 3.8 +/- 0.5fold increase in Nox4 mRNA expression after 36 h of starvation (p < 0.01), neither production nor the p21(cip1) or p53 expression was increased significantly and only 0.46% of cells were apoptotic. In conclusion, Nox2-derived O-2(-), through the modulation of p21(cip1) and p53 expression, participates in endothelial cell cycle regulation and apoptosis. (c) 2007 Elsevier Inc. All rights reserved.

Regulation of cell cycle and stress responses to hydrostatic pressure in fission yeast

We have investigated the cellular responses to hydrostatic pressure by using the fission yeast Schizosaccharomyces pombe as a model system. Exposure to sublethal levels of hydrostatic pressure resulted in G2 cell cycle delay. This delay resulted from Cdc2 tyrosine-15 (Y-15) phosphorylation, and it was abrogated by simultaneous disruption of the Cdc2 kinase regulators Cdc25 and Wee1. However, cell cycle delay was independent of the DNA damage, cytokinesis, and cell size checkpoints, suggesting a novel mechanism of Cdc2-Y15 phosphorylation in response to hydrostatic pressure. Spc1/Sty1 mitogen-activated protein (MAP) kinase, a conserved member of the eukaryotic stress-activated p38, mitogen-activated protein (MAP) kinase family, was rapidly activated after pressure stress, and it was required for cell cycle recovery under these conditions, in part through promoting polo kinase (Plo1) phosphorylation on serine 402. Moreover, the Spc1 MAP kinase pathway played a key role in maintaining cell viability under hydrostatic pressure stress through the bZip transcription factor, Atf1. Further analysis revealed that prestressing cells with heat increased barotolerance, suggesting adaptational cross-talk between these stress responses. These findings provide new insight into eukaryotic homeostasis after exposure to pressure stress.

Antarctic Peninsula ice sheet evolution during the Cenozoic Era

The Antarctic Peninsula region is currently undergoing rapid environmental change, resulting in the thinning, acceleration and recession of glaciers and the sequential collapse of ice shelves. It is important to view these changes in the context of long-term palaeoenvironmental complexity and to understand the key processes controlling ice sheet growth and recession. In addition, numerical ice sheet models require detailed geological data for tuning and testing. Therefore, this paper systematically and holistically reviews published geological evidence for Antarctic Peninsula Ice Sheet variability for each key locality throughout the Cenozoic, and brings together the prevailing consensus of the extent, character and behaviour of the glaciations of the Antarctic Peninsula region. Major contributions include a downloadable database of 186 terrestrial and marine calibrated dates; an original reconstruction of the LGM ice sheet; and a new series of isochrones detailing ice sheet retreat following the LGM. Glaciation of Antarctica was initiated around the Eocene/Oligocene transition in East Antarctica. Palaeogene records of Antarctic Peninsula glaciation are primarily restricted to King George Island, where glacigenic sediments provide a record of early East Antarctic glaciations, but with modification of far-travelled erratics by local South Shetland Island ice caps. Evidence for Neogene glaciation is derived primarily from King George Island and James Ross Island, where glaciovolcanic strata indicate that ice thicknesses reached 500–850 m during glacials. This suggests that the Antarctic Peninsula Ice Sheet draped, rather than drowned, the topography. Marine geophysical investigations indicate multiple ice sheet advances during this time. Seismic profiling of continental shelf-slope deposits indicates up to ten large advances of the Antarctic Peninsula Ice Sheet during the Early Pleistocene, when the ice sheet was dominated by 40 kyr cycles. Glacials became more pronounced, reaching the continental shelf edge, and of longer duration during the Middle Pleistocene. During the Late Pleistocene, repeated glacials reached the shelf edge, but ice shelves inhibited iceberg rafting. The Last Glacial Maximum (LGM) occurred at 18 ka BP, after which transitional glaciomarine sediments on the continental shelf indicate ice-sheet retreat. The continental shelf contains large bathymetric troughs, which were repeatedly occupied by large ice streams during Pleistocene glaciations. Retreat after the LGM was episodic in the Weddell Sea, with multiple readvances and changes in ice-flow direction, but rapid in the Bellingshausen Sea. The late Holocene Epoch was characterised by repeated fluctuations in palaeoenvironmental conditions, with associated glacial readvances. However, this has been subsumed by rapid warming and ice-shelf collapse during the twentieth century.