arrow encodes an LDL-receptor-related protein essential for Wingless signalling

The Wnt family of secreted molecules functions in cell-fate determination and morphogenesis during development in both vertebrates and invertebrates (reviewed in ref. 1). Drosophila Wingless is a founding member of this family, and many components of its signal transduction cascade have been identified, including the Frizzled class of receptor. But the mechanism by which the Wingless signal is received and transduced across the membrane is not completely understood. Here we describe a gene that is necessary for all Wingless signalling events in Drosophila. We show that arrow gene function is essential in cells receiving Wingless input and that it acts upstream of Dishevelled. arrow encodes a single-pass transmembrane protein, indicating that it may be part of a receptor complex with Frizzled class proteins. Arrow is a low-density lipoprotein (LDL)-receptor-related protein (LRP), strikingly homologous to murine and human LRP5 and LRP6. Thus, our data suggests a new and conserved function for this LRP subfamily in Wingless/Wnt signal reception.     

Subduction and collision processes in the Central Andes constrained by converted seismic phases

The Central Andes are the Earth's highest mountain belt formed by ocean-continent collision. Most of this uplift is thought to have occurred in the past 20 Myr, owing mainly to thickening of the continental crust, dominated by tectonic shortening. Here we use P-to-S (compressional-to-shear) converted teleseismic waves observed on several temporary networks in the Central Andes to image the deep structure associated with these tectonic processes. We find that the Moho (the Mohorovici? discontinuity--generally thought to separate crust from mantle) ranges from a depth of 75 km under the Altiplano plateau to 50 km beneath the 4-km-high Puna plateau. This relatively thin crust below such a high-elevation region indicates that thinning of the lithospheric mantle may have contributed to the uplift of the Puna plateau. We have also imaged the subducted crust of the Nazca oceanic plate down to 120 km depth, where it becomes invisible to converted teleseismic waves, probably owing to completion of the gabbro-eclogite transformation; this is direct evidence for the presence of kinetically delayed metamorphic reactions in subducting plates. Most of the intermediate-depth seismicity in the subducting plate stops at 120 km depth as well, suggesting a relation with this transformation. We see an intracrustal low-velocity zone, 10-20 km thick, below the entire Altiplano and Puna plateaux, which we interpret as a zone of continuing metamorphism and partial melting that decouples upper-crustal imbrication from lower-crustal thickening.     

Resveratrol-type oligostilbenes from Iris clarkei antagonize 20-hydroxyecdysone action in the Drosophila melanogaster B(II) cell line

Bioassay-guided high-performance liquid chromatography analysis of a MeOH extract of Iris clarkei seeds yielded the resveratrol-type oligomeric stilbenes, ampelopsin B and α-viniferin, which antagonize the action of 20-hydroxyecdysone; with a 20-hydroxyecdysone concentration of 50 nM, the ED₅₀ values were 33 μM and 10 μM, respectively. The structures of these compounds were determined by spectroscopic analysis, notably ultraviolet, liquid secondary ion mass spectrometry and modern one- and two-dimensional nuclear magnetic resonance techniques. Received 4 November 1999; accepted 13 December 1999     

MDR1, cholesterol certification and cell growth: a comparative study in normal and multidrug-resistant KB cell lines

The product of the MDR1 gene (P-gp) has been implicated in the transport of cholesterol from plasma membrane to endoplasmic reticulum for esterification. In previous studies on leukemia cell lines, we suggested that cholesterol esterification may regulate the rate of cell growth and that the MDR1 gene might be involved in this process by modulating intracellular cholesterol esters levels. To further investigate this matter, the rate of cell growth, cholesterol metabolism, expression of the MDR1 gene, and P-gp activity were compared in KB cell lines displaying differences in expression and function of P-gp (drug-sensitive phenotype versus MDR phenotype). The rate of cell growth correlated with cholesterol esterification in all KB cell lines, whereas the over-expression of MDR1 observed in the MDR cell lines was not always associated with an increased capacity of cells to esterify cholesterol. Two known inhibitors of P-gp activity, progesterone and verapamil, strongly inhibited both cholesterol esterification and cell proliferation in all KB cell lines, but they affected intracellular accumulation of labeled vinblastine only in MDR cell lines. These results further support a role for cholesterol esters in the regulation of cell growth and suggest that the P-gp expressed in MDR KB cells is not involved in the general process leading to cholesterol esterification. Received 14 February 2000; received after revision 10 April 2000; accepted 8 May 2000     

The role of ras and other low molecular weight guanine nucleotide (GTP)-binding proteins during hematopoietic cell differentiation

Recent progress in the understanding of signal transduction and gene regulation in hematopoietic cells has shown that many intracellular signalling pathways are modulated by low molecular weight guanine nucleotide (GTP)-binding proteins (LMWGs). LMWGs act as molecular switches for regulating a wide range of signal-transduction pathways in virtually all cells. In hematopoietic cells, LMWGs have been shown to participate in essential functions such as growth control, differentiation, cytoskeletal organization, cytokine and chemoattractant-induced signalling events, reduced nicotinamide adenine dinucleotide phosphate oxidase activity, intracellular vesicle transport and secretion. In human leukemias, myelodysplastic syndromes and myeloproliferative disorders, Ras activation occurs by point mutations, overexpression or by alteration of NF-1 Ras-GTPase activating protein (GAP). These are postinitiation events in leukemia but may modulate growth-factor-dependent and independent leukemic growth. Two animal models of mutated N-ras expression resulting in myelodysplastic and myeloproliferative features are discussed. The role of Ras in organ development is discussed in the context of transgenic knockout mice. More LMWG functions will certainly be identified as we gain a better understanding of regulatory pathways modulating myeloid signal transduction. This review will summarize our current understanding of this rapidly advancing area of research.     

The Ras family of GTPases in cancer cell invasion

The ability of tumoral cells to invade surrounding tissues is a prerequisite for metastasis. This is the most life-threatening event of tumor progression, and so research is intensely focused on elucidating the mechanisms responsible for invasion and metastasis. The Ras superfamily of GTPases comprises several subfamilies of small GTP-binding proteins whose functions include the control of proliferation, differentiation, and apoptosis, as well as cytoskeleton organization. The development of metastasis is a multistep process that requires coordinated activation of proliferation, motility, changes in normal cell-to-cell and cell-to-substrate contacts, degradation of extracellular matrix, inhibition of apoptosis, and adaptation to an inappropriate tissue environment. Several members of the Ras superfamily of proteins have been implicated in these processes. The present review summarizes the current knowledge in this field.