SNAI2/Slug promotes growth and invasion in human gliomas

<p>Abstract</p> <p>Background</p> <p>Numerous factors that contribute to malignant glioma invasion have been identified, but the upstream genes coordinating this process are poorly known.</p> <p>Methods</p> <p>To identify genes controlling glioma invasion, we used genome-wide mRNA expression profiles of primary human glioblastomas to develop an expression-based rank ordering of 30 transcription factors that have previously been implicated in the regulation of invasion and metastasis in cancer.</p> <p>Results</p> <p>Using this approach, we identified the oncogenic transcriptional repressor, <it>SNAI2</it>/Slug, among the upper tenth percentile of invasion-related transcription factors overexpressed in glioblastomas. <it>SNAI2 </it>mRNA expression correlated with histologic grade and invasive phenotype in primary human glioma specimens, and was induced by EGF receptor activation in human glioblastoma cells. Overexpression of <it>SNAI2/</it>Slug increased glioblastoma cell proliferation and invasion <it>in vitro </it>and promoted angiogenesis and glioblastoma growth <it>in vivo</it>. Importantly, knockdown of endogenous <it>SNAI2</it>/Slug in glioblastoma cells decreased invasion and increased survival in a mouse intracranial human glioblastoma transplantation model.</p> <p>Conclusion</p> <p>This genome-scale approach has thus identified <it>SNAI2</it>/Slug as a regulator of growth and invasion in human gliomas.</p

IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction

Myocardial contractile dysfunction accompanies both systemic and cardiac insults. Septic shock and burn trauma can lead to reversible contractile deficits, whereas ischemia and direct inflammation of the heart can precipitate transient or permanent impairments in contractility. Many of the insults that trigger contractile dysfunction also activate the innate immune system. Activation of the innate immune response to infection is coordinated by the conserved Toll/interleukin-1 (IL-1) signal transduction pathway. Interestingly, components of this pathway are also expressed in normal and failing hearts, although their function is unknown. The hypotheses that Toll/IL-1 signaling occurs in the heart and that intact pathway function is required for contractile dysfunction after different insults were tested. Results from these experiments demonstrate that lipopolysaccharides (LPS) activate Toll/IL-1 signaling and IL-1 receptor-associated kinase-1 (IRAK1), a critical pathway intermediate in the heart, indicating that the function of this pathway is not limited to immune system tissues. Moreover, hearts lacking IRAK1 exhibit impaired LPS-triggered downstream signal transduction. Hearts from IRAK1-deficient mice also resist acute LPS-induced contractile dysfunction. Finally, IRAK1 inactivation enhances survival of transgenic mice that develop severe myocarditis and lethal heart failure. Thus the Toll/IL-1 pathway is active in myocardial tissue and interference with pathway function, through IRAK1 inactivation, may represent a novel strategy to protect against cardiac contractile dysfunction

Evolution of mammalian CD1: marsupial CD1 is not orthologous to the eutherian isoforms and is a pseudogene in the opossum Monodelphis domestica

CD1 is a member of the major histocompatibility complex (MHC) class I family of proteins that present lipid antigens to T cells and natural killer (NK) T cells; it is found in both eutherian mammals and birds. In eutherians, duplication of the CD1 gene has resulted in multiple isoforms. A marsupial CD1 homologue was identified in a set of expressed sequence tags from the thymus of the bandicoot Isoodon macrourus. Southern blot and genomic sequence analyses revealed that CD1 is a single copy gene in both I. macrourus and a distantly related marsupial, the opossum Monodelphis domestica, which is currently the only marsupial species for which a whole genome sequence is available. We found that the opossum CD1 is located in a genomic region with a high degree of conserved synteny to the chromosomal regions containing human and mouse CD1. A phylogenetic analysis of mammalian CD1 revealed that marsupial CD1 is not orthologous to the eutherian CD1 isoforms, consistent with the latter having emerged by duplication after the separation of marsupials and eutherians 170–180 million years ago. The I. macrourus CD1 gene is actively transcribed and appears to encode a functional protein. In contrast, transcription of the M. domestica CD1 was not detected in any tissue and the predicted CD1 gene sequence contains a number of deletions that appear to render the locus a pseudogene