A large-scale effort, termed the Secreted Protein Discovery Initiative (SPDI), was undertaken to identify novel secreted and transmembrane proteins. In the first of several approaches, a biological signal sequence trap in yeast cells was utilized to identify cDNA clones encoding putative secreted proteins. A second strategy utilized various algorithms that recognize features such as the hydrophobic properties of signal sequences to identify putative proteins encoded by expressed sequence tags (ESTs) from human cDNA libraries. A third approach surveyed ESTs for protein sequence similarity to a set of known receptors and their ligands with the BLAST algorithm. Finally, both signal-sequence prediction algorithms and BLAST were used to identify single exons of potential genes from within human genomic sequence. The isolation of full-length cDNA clones for each of these candidate genes resulted in the identification of >1000 novel proteins. A total of 256 of these cDNAs are still novel, including variants and novel genes, per the most recent GenBank release version. The success of this large-scale effort was assessed by a bioinformatics analysis of the proteins through predictions of protein domains, subcellular localizations, and possible functional roles. The SPDI collection should facilitate efforts to better understand intercellular communication, may lead to new understandings of human diseases, and provides potential opportunities for the development of therapeutics.
Objective To observe the expression of CyclinD1 in the lung and the correlation between CyclinD1 and airway remodeling in asthmatic modeling rats.Methods Sixteen males SD rats were randomly assigned into control group and asthma group,each group had eight rats.The mice were sensitized and challenged with ovalbumin to establish the asthmatic model.The sections were stained with HE to assess the inflammatory cell infiltrates.Masson staining was used to detect the expression of collagen in the mice lungs.Western blot and Immunohistochemistry were applied to examine the expression of CyclinD1 in the lungs.Immunohistochemistry was used to detect the expression of α-SMA in the mice lungs.Results The deposition of collagen,the expression of CyclinD1 and α-SMA were obviously increased in asthmatic rats (P0.05). There were positive correlation between CyclinD1 with α-SMA.in asthmatic modeling rats (r1=0.20,P0.05,r2=0.53,P0.05).Conclusions CyclinD1 was playing an important role in airway remodeling.
<div>Abstract<p>To identify genes that could serve as targets for novel cancer therapeutics, we used a bioinformatic analysis of microarray data comparing gene expression between normal and tumor-derived primary human tissues. From this approach, we have found that <i>maternal embryonic leucine zipper kinase</i> (<i>Melk</i>), a member of the AMP serine/threonine kinase family, exhibits multiple features consistent with the potential utility of this gene as an anticancer target. An oligonucleotide microarray analysis of multiple human tumor samples and cell lines suggests that Melk expression is frequently elevated in cancer relative to normal tissues, a pattern confirmed by quantitative reverse transcription-PCR and Western blotting of selected primary tumor samples. <i>In situ</i> hybridization localized Melk expression to malignant epithelial cells in 96%, 23%, and 13% of colorectal, lung, and ovarian tissue tumor samples, respectively. Expression of this gene is also elevated in spontaneous tumors derived from the <i>Apc<sup>Min</sup></i> and <i>Apc<sup>1638N</sup></i> murine models of intestinal tumorigenesis. To begin addressing whether Melk is relevant for tumorigenesis, RNA interference–mediated silencing within human and murine tumor cell lines was done. We show that Melk knockdown decreases proliferation and anchorage-independent growth <i>in vitro</i> as well as tumor growth in a xenograft model. Together, these results suggest that Melk may provide a growth advantage for neoplastic cells and, therefore, inactivation may be therapeutically beneficial.</p></div>
<div>Abstract<p>The hepatocyte growth factor (HGF) and its receptor, c-Met, have been implicated in driving proliferation, invasion, and poor prognosis in pancreatic cancer. Here, we investigated the expression of HGF and c-Met in primary pancreatic cancers and described <i>in vitro</i> and <i>in vivo</i> models in which MetMAb, a monovalent antibody against c-Met, was evaluated. First, expression of <i>HGF</i> and <i>MET</i> mRNA was analyzed in 59 primary pancreatic cancers and 51 normal samples, showing that both factors are highly expressed in pancreatic cancer. We next examined HGF responsiveness in pancreatic cancer lines to select lines that proliferate in response to HGF. Based on these studies, two lines were selected for further <i>in vivo</i> model development: BxPC-3 (c-Met<sup>+</sup>, HGF<sup>−</sup>) and KP4 (c-Met<sup>+</sup>, HGF<sup>+</sup>) cells. As BxPC-3 cells are responsive to exogenous HGF, s.c. tumor xenografts were grown in a paracrine manner with purified human HGF provided by osmotic pumps, wherein MetMAb treatment significantly inhibited tumor growth. KP4 cells are autocrine for HGF and c-Met, and MetMAb strongly inhibited s.c. tumor growth. To better model pancreatic cancer and to enable long-term survival studies, an orthotopic model of KP4 was established. MetMAb significantly inhibited orthotopic KP4 tumor growth in 4-week studies monitored by ultrasound and also improved survival in 90-day studies. MetMAb significantly reduced c-Met phosphorylation in orthotopic KP4 tumors with a concomitant decrease in Ki-67 staining. These data suggest that the HGF/c-Met axis plays an important role in the progression of pancreatic cancer and that targeting c-Met therein may have therapeutic value. [Cancer Res 2008;68(11):4360–8]</p></div>
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