Endosialin/TEM1 was originally discovered as a human embryonic fibroblast-specific antigen and was later found to be differentially expressed in tumor stroma and endothelium. Endosialin/TEM1 overexpression has been observed in many cancers of various tissue origin, including colon, breast, pancreatic, and lung. The knockout (KO) mouse model showed the absence of endosialin/TEM1 expression reduced growth, invasion, and metastasis of human tumor xenografts. In addition, lack of endosialin/TEM1 led to an increase in small immature blood vessels and decreased numbers of medium and large tumor vessels. This abnormal angiogenic response could be responsible for the reduced tumor growth and invasion observed in endosialin/TEM1 KO mice, suggesting a role for endosialin/TEM1 in controlling the interaction among tumor cells, endothelia, and stromal matrix. Here we report the identification of fibronectin (FN) and collagen types I and IV as specific ligands for endosialin/TEM1. More importantly, cells expressing endosialin/TEM1 exhibit enhanced adhesion to FN as well as enhanced migration through matrigel, although these properties could be blocked by a humanized antibody directed against human endosialin/TEM1. Our results pinpoint to a molecular mechanism by which expression of endosialin/TEM1 in the tumor stroma and endothelium may support tumor progression and invasion.CD248 ͉ fibronectin ͉ stroma ͉ collagen T he process of angiogenesis, which is critical for physiological tissue growth, wound healing, and embryonic development, also is required for the formation of large solid tumors (1). Within the developing capillary, extracellular matrix (ECM) proteins serve as a structural scaffold for proliferating endothelial and tumor tissues and, more important, provide support for the growth of tumor cells. Therefore, anticancer strategies aimed at disrupting these processes could result in effective therapies.Endosialin/TEM1 (CD248) originally discovered as a human embryonic fibroblast-specific antigen was later found to be differentially expressed in tumor stroma and endothelium. The monoclonal antibody FB5, generated through immunization of mice with human embryonic fibroblasts, was found to recognize an antigen, named endosialin, present on tumor stromal cells (2). Subsequently, examination of gene expression patterns in normal and neoplastic tissue indicated up-regulation of endosialin/TEM1 mRNA expression in tumor neovessels (3). Similar endosialin/TEM1 expression levels were noted in human colorectal cancer (4), breast cancer tissues (5), and histiocytomas (6). Moreover, human endosialin expression has been observed in highly invasive glioblastoma, anaplastic astrocytomas, and metastatic carcinomas, including melanomas (7,8).Tem1 knockout (KO) mice develop normally and exhibit normal wound healing, suggesting that endosialin/TEM1 is not required for neovascularization during fetal development or wound repair (9). However, when colorectal cancer cells were implanted in the abdominal sites of Tem1 KO mice, the loss of en...

Asthma is a complex heritable inf lammatory disorder of the airways associated with clinical signs of atopy and bronchial hyperresponsiveness. Recent studies localized a major gene for asthma to chromosome 5q31-q33 in humans. Thus, this segment of the genome represents a candidate region for genes that determine susceptibility to bronchial hyperresponsiveness and atopy in animal models. Homologs of candidate genes on human chromosome 5q31-q33 are found in four regions in the mouse genome, two on chromosome 18, and one each on chromosomes 11 and 13. We assessed bronchial responsiveness as a quantitative trait in mice and found it linked to chromosome 13. Interleukin 9 (IL-9) is located in the linked region and was analyzed as a gene candidate. The expression of IL-9 was markedly reduced in bronchial hyporesponsive mice, and the level of expression was determined by sequences within the qualitative trait locus (QTL). These data suggest a role for IL-9 in the complex pathogenesis of bronchial hyperresponsiveness as a risk factor for asthma.

B-MYB expression is associated with cell proliferation and recent studies have suggested that it promotes the S phase of mammalian cells. Based on its homology to the transcription factors c-MYB and A-MYB, B-MYB is thought to be involved in transcriptional regulation; however, its activity is not detectable in several cell lines. It was postulated that B-MYB function may depend on the presence of a cofactor, and recent studies suggested that B-MYB is phosphorylated specifically during S phase in murine fibroblasts. In this report we provide evidence that the product of the human B-myb gene can be activated in vivo by coexpression with cyclin A or cyclin E. Transfection studies showed that B-MYB was a weak transcriptional activator in SAOS-2 cells and was unable to promote their proliferation. In contrast, overexpression of both B-MYB and cyclin A or cyclin E caused a drastic increase in the number of SAOS-2 cells in S phase. Also, overexpression of cyclin A and cyclin E in SAOS-2 cells enhanced the ability of B-MYB, but not c-MYB, to transactivate various promoters, including the cdc2 promoter, the HIV-1-LTR, and the simian virus 40 minimal promoter. A direct role for cyclin-dependent activation of B-MYB was demonstrated using an in vitro transcription assay. These observations suggest that one mechanism by which cyclin A and E may promote the S phase is through modification and activation of B-MYB.B-MYB is a transcriptional regulator whose activity appears to be associated with cellular proliferation and differentiation (1-5). B-MYB is highly homologous to c-MYB within the DNA-binding domain region, and this correlates with a similar affinity displayed by both proteins for the myb-binding sequence (C͞T)AAC(G͞T)G (reviewed in ref. 6). A large body of evidence implicates B-MYB as a player in cell-cycle progression. First, although B-myb expression is ubiquitous, it is strictly regulated in cycling cells: B-myb transcription is downregulated in quiescent cells and expression is detected, upon reentry into the cell cycle, in late G 1 (7,8). Repression of B-myb transcription in G 0 ͞early G 1 is dependent upon an E2F binding site within the promoter and appears to involve negative regulation by the retinoblastoma-related proteins p107 and p130 (9, 10). B-MYB is a downstream target of growth suppressors such as p107 and p53 (5, 11) and its transcription is induced by E2F-1 (12), whose activity is associated with cell-cycle progression and, possibly, transformation. Overall, these data support the hypothesis that B-MYB may play a role in G 1 ͞S transition or during S phase itself. B-MYB can affect the growth rate of certain, but not all, cell lines, and it can activate or repress transcription depending on the promoter, cell type, and species. (13-15). The parameters regulating the specificity of B-MYB transcriptional activity have not been elucidated; however, there is evidence to suggest that the conserved region of B-MYB protein binds to a set of cellular factors that may be involved in cell-typedependent t...