Ral GTPases contribute to regulation of cyclin D1 through activation of NF-kappaB.

Ral GTPases have been implicated as mediators of Ras-induced signal transduction from observations that Ral-specific guanine nucleotide exchange factors associate with Ras and are activated by Ras. The cellular role of Ral family proteins is unclear, as is the contribution that Ral may make to Ras-dependent signaling. Here we show that expression of activated Ral in quiescent rodent fibroblasts is sufficient to induce activation of NF-kappaB-dependent gene expression and cyclin D1 transcription, two key convergence points for mitogenic and survival signaling. The regulation of cyclin D1 transcription by Ral is dependent on NF-kappaB activation and is mediated through an NF-kappaB binding site in the cyclin D1 promoter. Ral activation of these responses is likely through an as yet uncharacterized effector pathway, as we find activation of NF-kappaB and the cyclin D1 promoter by Ral is independent of association of Ral with active phospholipase D1 or Ral-binding protein 1, two proteins proposed to mediate Ral function in cells.

Uncoupling Raf1 from MEK1/2 impairs only a subset of cellular responses to Raf activation.

The Raf family of serine/threonine protein kinases is intimately involved in the transmission of cell regulatory signals controlling proliferation and differentiation. The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. However, accumulating evidence suggests that there are additional Raf substrates and that subsets of Raf-induced regulatory events are mediated independently of Raf activation of MEK1/2. To examine the possibility that there is bifurcation at the level of Raf in activation of MEK1/2-dependent and MEK1/2-independent cell regulatory events, we engineered a kinase-active Raf1 variant (RafBXB(T481A)) with an amino acid substitution that disrupts MEK1 binding. We find that disruption of MEK1/2 association uncouples Raf from activation of ERK1/2, induction of serum-response element-dependent gene expression, and induction of growth and morphological transformation. However, activation of NF-kappaB-dependent gene expression and induction of neurite differentiation were unimpaired. In addition, Raf-dependent activation of p90 ribosomal S6 kinase was only slightly impaired. These results support the hypothesis that Raf kinases utilize multiple downstream effectors to regulate distinct cellular activities.

Prehistoric cultural ecology in southern jordan.

Research in the mountains of southern Jordan resulted in the discovery of 109 archaeological sites that are from the Lower Paleolithic to the Chalcolithic period [150 to 6 thousand years ago (ka)]. Beginning with the Middle Paleolithic (70 ka) two site types (long-term and ephemeral camps) are recognized. Long-term sites have larger areas, thicker deposits, higher artifact densities, and more abundant archaeological features than ephemeral sites. Their natural settings (elevation and exposure) and associated seasonal evidence (phytolith and cementum increment data) indicate that long-term sites were occupied during the winter, wet season and ephemeral sites during the warm, dry season. These differences in site use and seasonality likely reflect an adaptive strategy of transhumance that persisted to modern Bedouin times. At the end of the Pleistocene, the onset of warmer, drier conditions induced a shift of the long-term winter camps from relatively low (800 to 1000 meters above sea level) to high (1000 to 1250 meters above sea level) elevations and largely reversed the earlier transhumant pattern.