Cancer invasion and metastasis have been likened to wound healing gone awry. Despite parallels in cellular behavior between cancer progression and wound healing, the molecular relationships between these two processes and their prognostic implications are unclear. In this study, based on gene expression profiles of fibroblasts from ten anatomic sites, we identify a stereotyped gene expression program in response to serum exposure that appears to reflect the multifaceted role of fibroblasts in wound healing. The genes comprising this fibroblast common serum response are coordinately regulated in many human tumors, allowing us to identify tumors with gene expression signatures suggestive of active wounds. Genes induced in the fibroblast serum-response program are expressed in tumors by the tumor cells themselves, by tumor-associated fibroblasts, or both. The molecular features that define this wound-like phenotype are evident at an early clinical stage, persist during treatment, and predict increased risk of metastasis and death in breast, lung, and gastric carcinomas. Thus, the transcriptional signature of the response of fibroblasts to serum provides a possible link between cancer progression and wound healing, as well as a powerful predictor of the clinical course in several common carcinomas.

In response to various environmental stresses, eukaryotic cells down-regulate protein synthesis by phosphorylation of the ␣ subunit of eukaryotic translation initiation factor 2 (eIF-2␣). In mammals, the phosphorylation was shown to be carried out by eIF-2␣ kinases PKR and HRI. We report the identification and characterization of a cDNA from rat pancreatic islet cells that encodes a new related kinase, which we term pancreatic eIF-2␣ kinase, or PEK. In addition to a catalytic domain with sequence and structural features conserved among eIF-2␣ kinases, PEK contains a distinctive amino-terminal region 550 residues in length. Using recombinant PEK produced in Escherichia coli or Sf-9 insect cells, we demonstrate that PEK is autophosphorylated on both serine and threonine residues and that the recombinant enzyme can specifically phosphorylate eIF-2␣ on serine-51. Northern blot analyses indicate that PEK mRNA is expressed in all tissues examined, with highest levels in pancreas cells. Consistent with our mRNA assays, PEK activity was predominantly detected in pancreas and pancreatic islet cells. The regulatory role of PEK in protein synthesis was demonstrated both in vitro and in vivo. The addition of recombinant PEK to reticulocyte lysates caused a dose-dependent inhibition of translation. In the Saccharomyces model system, PEK functionally substituted for the endogenous yeast eIF-2␣ kinase, GCN2, by a process requiring the serine-51 phosphorylation site in eIF-2␣. We also identified PEK homologs from both Caenorhabditis elegans and the puffer fish Fugu rubripes, suggesting that this eIF-2␣ kinase plays an important role in translational control from nematodes to mammals.

The placenta is the principal metabolic, respiratory, excretory, and endocrine organ for the first 9 months of fetal life. Its role in fetal and maternal physiology is remarkably diverse. Because of the central role that the placenta has in fetal and maternal physiology and development, the possibility that variation in placental gene expression patterns might be linked to important abnormalities in maternal or fetal health, or even variations in later life, warrants investigation. As an initial step, we used DNA microarrays to analyze gene expression patterns in 72 samples of amnion, chorion, umbilical cord, and sections of villus parenchyma from 19 human placentas from successful full-term pregnancies. The umbilical cord, chorion, amnion, and villus parenchyma samples were readily distinguished by differences in their global gene-expression patterns, many of which seemed to be related to physiology and histology. Differentially expressed genes have roles that include placental trophoblast secretion, signal transduction, metabolism, immune regulation, cell adhesion, and structure. We found interindividual differences in expression patterns in villus parenchyma and systematic differences between the maternal, fetal, and intermediate layers. A group of genes that was expressed in both the maternal and fetal villus parenchyma sections of placenta included genes that may be associated with preeclampsia. We identified sets of genes whose expression in placenta was significantly correlated with the sex of the fetus. This study provides a rich and diverse picture of the molecular variation in the placenta from healthy pregnancies.microarray ͉ pregnancy ͉ transcriptome ͉ preeclampsia T he placenta is a temporary organ that performs the functions of several adult organs for the growing fetus. The placenta is designed uniquely for exchange of oxygen, nutrients, antibodies, hormones, and waste products between the mother and fetus and may carry valuable information about the pregnancy. Although a placenta after delivery is among the most easily accessible human tissues, it is usually discarded after a cursory evaluation (1). Several pregnancy disorders including preeclampsia (PE) and preterm labor are associated with placental pathology. Also, epidemiologic studies suggest that there are ''fetal origins'' that predispose adults to cardiovascular, metabolic, and endocrine diseases (2). Also, low-birth-weight fetuses associated with large placentas are associated with increased neonatal morbidity indicating abnormal placental activity in such scenarios (3, 4). The investigation of placenta may provide valuable insights into placental functions and help identify molecular mechanisms that have both immediate and long lasting effects on health of the fetus.A schematic representation of the placenta is given in Fig. 1, with both the placental disk proper and the reflected membranes. The placenta is a composite organ of trophectoderm-derived cells and cells that are derived from the inner cell mass (ICM)͞epiblast, and a minor co...

The anti-inflammatory effect of colchicine may be mediated not only through direct interaction with microtubules but also through changes at the transcriptional level. This latter effect apparently requires a higher concentration and a longer time to occur. This can explain the observation that colchicine does not have an immediate effect when given during an acute attack of FMF.

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