Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia, a common consequence of solid tumor growth in breast cancer or other cancers, serves to propagate a cascade of molecular pathways which include angiogenesis, glycolysis, and various cell-cycle control proteins. As we have shown previously, hypoxia activates STAT5 (signal transducer and activator of transcription 5) and increases its binding activity to the GAS element in mammary epithelial cells. In this study we attempted to elucidate the mechanism by which cyclin D1 is regulated by the STAT5 protein under hypoxic conditions. Our data demonstrate that hypoxia (2% O(2)) or desferrioxamine (DFO) induces tyrosine and serine phosphorylation of STAT5 in human breast cancer cells (MCF-7) and mammary epithelial cells (HC11). Imunoprecipitation and subsequent Western analysis showed that Jak2 leads to the tyrosine phosphorylation and activation of STAT5a or STAT5b under hypoxic conditions. Using a transfected COS-7 cell model system, we demonstrate that the activity of a cyclin D1 promoter-luciferase construct increased under hypoxic conditions or DFO treatment. The activity of the STAT5b/cyclin D1 promoter increased significantly by 12 h of hypoxia, whereas the activity of the STAT5a/cyclin D1 promoter was unaffected under hypoxic conditions. These increases in promoter activity are predominantly mediated by the Jak2/STAT5b signaling pathway. We have shown by EMSA that hypoxia induces STAT5 to bind to the cyclin D1 promoter (GAS-1) in MCF-7 and HC11 cells. These data suggest that STAT5b may mediate the transcriptional activation of cyclin D1 after hypoxic stimulation.
Exp Mol Med 2005 Aug 31
PMID:Hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells. 1615 12

Numerous human tumor lines fail to induce major histocompatibility (MHC) class II expression following interferon-gamma (IFN-gamma) treatment, a response that is considered to be a normal function for almost all human parenchymal and connective tissue cell-types. The effect of MHC class II non-inducibility on solid tumor growth is controversial, but an extensive body of literature indicates that tumor cell MHC class II expression can lead to an antitumor response or tumor tolerance, depending on a number of variables. Thus, understanding the molecular basis for MHC class II induction failures in solid tumor cells will likely lead to ideas for manipulating the antitumor immune response. To date, a handful of tumor associated molecular anomalies have accounted for all the known failures of MHC class II inducibility. In particular, lack of the retinoblastoma tumor suppressor protein (Rb) has been shown in both human and mouse cells to be strongly associated with failure to induce MHC class II. The basis for this relationship is traceable to, among other things, high level Oct-1 DNA binding activity in Rb-defective cells, which represses the prototypical human MHC class II gene, HLA-DRA. Ordinarily, re-establishment of Rb expression leads to elimination of, or substantially reduced Oct-1 DNA binding activity and to rescue of HLA-DRA inducibility. However, in the case of one non-small cell lung carcinoma line (NSCLC), Rb re-expression failed to rescue HLA-DRA inducibility despite successful re-establishment of Rb-function. We now report that this failure is traceable to the failure of Rb to rescue normal Oct-1 function. Furthermore, histone deacetylase inhibitor treatment allows a bypass of the Rb requirement and facilitates the MHC class II induction in this NSCLC line.
Mol Immunol 2006 Feb
PMID:Oct-1 DNA binding activity unresponsive to retinoblastoma protein expression prevents MHC class II induction in a non-small cell lung carcinoma cell line. 1636 16

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting to detect proteins and glycoproteins is one of the most widely used and broadly useful techniques in cancer research, allowing the proteins in a complex sample--such as a blood sample, aspirate, or solid tumor homogenate--to be separated according to molecular weight and visualized within a gel matrix and/or, once separated, transferred onto a supporting membrane, where they may be probed for the binding of antibodies or lectins. In this chapter, the theory and principles of SDS-PAGE and Western blotting are briefly outlined, and basic methods are given that can be applied to investigate virtually any (glyco)protein of interest in breast cancer research.
Methods Mol Med 2006
PMID:SDS-PAGE and Western blotting to detect proteins and glycoproteins of interest in breast cancer research. 1649 4

It is widely recognized that the vasculature of the tumor is inadequate to meet the demands of the growing mass. The malformed vasculature is at least in part responsible for regions of the tumor that are hypoxic, acidotic, and exposed to increased interstitial fluid pressure. These unique aspects of the tumor microenvironment have been shown to act as barriers to conventional chemotherapy or radiation-based therapies. It now seems that while the vasculature initiates these tumor-specific conditions, the cells within the tumor respond to these stresses and add to the unique solid tumor physiology. Gene expression changes have been reported in the tumor for vascular endothelial growth factor, carbonic anhydrase IX, and pyruvate dehydrogenase kinase 1. The activity of these gene products then influences the tumor physiology through alterations in vascular permeability and interstitial fluid pressure, extracellular acidosis, and mitochondrial oxygen consumption and hypoxia, respectively. Novel molecular strategies designed to interfere with the activities of these gene products are being devised as ways to overcome the physiologic barriers in the tumor to standard anticancer therapies.
Mol Cancer Res 2006 Feb
PMID:Overcoming physiologic barriers to cancer treatment by molecularly targeting the tumor microenvironment. 1651 37

Serum peptidomics is a special form of functional proteomics. The small number of blood proteins that are the source of most prominent peptides in human serum serve as a substrate pool for commonly occurring and/or cancer-derived proteases. Exoprotease activities in particular, when superimposed on the ex vivo coagulation and complement degradation pathways, contribute to generation of not only cancer-specific but also "cancer type"-specific serum peptides. Following development of a unique, semiautomated serum peptide profiling platform and after completing investigations to eliminate common experimental bias, we have now studied possible effects of gender and age on serum peptidomes of 200 healthy men and women, ages 20-80, and of 60 patients (30 men and 30 women) with metastatic thyroid carcinomas. Extensive MALDI-TOF MS and data analysis suggested negligible contributions of both age and gender to the serum peptidome patterns except that healthy men and women under 35 years, but not older individuals, could be distinguished with approximately 70% accuracy. Considering the more advanced age of most patients, this finding is unlikely to interfere with peptidomics analysis of most cancers. By examining patient samples and age/gender-matched controls followed by variability analysis of either demographic or disease (versus control) groups, we could conclusively rule out demographic bias. An optimized, 12-peptide ion thyroid cancer signature was then developed, enabling classification of an independent validation set with 95% sensitivity and 95% specificity (binomial confidence intervals, 75.1-99.9%). Ten of these peptides had previously been assigned to signature patterns of other solid tumor cancers. One of the two newly discovered peptides was dehydro-Ala(3)-fibrinopeptide A. As we expand this study to include hundreds of thyroid cancer patients, the peptide signature will be adjusted, further validated, and then evaluated in a clinical setting used either independently or in combination with existing markers.
Mol Cell Proteomics 2006 Oct
PMID:Serum peptidome patterns that distinguish metastatic thyroid carcinoma from cancer-free controls are unbiased by gender and age. 1689 61

Novel therapies and delivery methods directed against malignancies such as melanoma, and particularly metastatic melanoma, are needed. The HIV-1 accessory protein Vpr (viral protein R) has previously been demonstrated to induce G2 cell cycle arrest as well as in vitro growth inhibition/killing of a number of tumor cells by apoptosis. In vivo electroporation has been utilized as an effective delivery method for pharmacologic agents and DNA plasmids that express "therapeutic" proteins and has been targeted to various tissues, including malignant tumors. For the study reported here, we hypothesized that intratumoral delivery of a Vpr expression plasmid through in vivo electroporation would induce apoptosis and growth attenuation or regression of melanoma tumors. Established subcutaneous B16.F10 melanoma tumors were injected intratumorally with a Vpr-expressing (either 25 or 100 microg) plasmid, followed by electroporation, on day 0 (i.e., when tumors had attained an appropriate size) and day 4. Treatment with 25 or 100 microg of the Vpr-expressing plasmid resulted in complete tumor regression with long-term survival in 14.3 and 7.1% of the mice, respectively. In addition, electroporative delivery of the Vpr-expressing plasmid was shown to induce apoptosis in tumors after intratumoral injection. This is the first report demonstrating the ability of Vpr, when delivered as a DNA expression plasmid with in vivo electroporation, to attenuate melanoma lesion growth and induce complete tumor regression coupled with long-term survival of mice in a highly aggressive and metastatic solid tumor model.
Mol Ther 2006 Nov
PMID:Complete regression of established subcutaneous B16 murine melanoma tumors after delivery of an HIV-1 Vpr-expressing plasmid by in vivo electroporation. 1695 Jun 55

This study was undertaken to characterize preclinical cytotoxic interactions for human malignancies between the multikinase inhibitor sorafenib (BAY 43-9006) and proteasome inhibitors bortezomib or MG132. Multiple tumor cell lines of varying histiotypes, including A549 (lung adenocarcinoma), 786-O (renal cell carcinoma), HeLa (cervical carcinoma), MDA-MB-231 (breast), K562 (chronic myelogenous leukemia), Jurkat (acute T-cell leukemia), MEC-2 (B-chronic lymphocytic leukemia), and U251 and D37 (glioma), as well as cells derived from primary human glioma tumors that are likely a more clinically relevant model were treated with sorafenib or bortezomib alone or in combination. Sorafenib and bortezomib synergistically induced a marked increase in mitochondrial injury and apoptosis, reflected by cytochrome c release, caspase-3 cleavage, and poly(ADP-ribose) polymerase degradation in a broad range of solid tumor and leukemia cell lines. These findings were accompanied by several biochemical changes, including decreased phosphorylation of vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-beta, and Akt and increased phosphorylation of stress-related c-Jun NH2-terminal kinase (JNK). Inhibition of Akt was required for synergism, as a constitutively active Akt protected cells against apoptosis induced by the combination. Alternatively, the JNK inhibitor SP600125 could also protect cells from apoptosis induced by the combination, indicating that both inhibition of Akt and activation of JNK were required for the synergism. These findings show that sorafenib interacts synergistically with bortezomib to induce apoptosis in a broad spectrum of neoplastic cell lines and show an important role for the Akt and JNK pathways in mediating synergism. Further clinical development of this combination seems warranted.
Mol Cancer Ther 2006 Sep
PMID:Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. 1698 72

Reverse genetics is one strategy that is currently used to establish a link between a target gene and a disease phenotype. In this process, the function of a gene is inhibited and the consequence of its loss on a desired biological function, such as tumor growth and metastasis, is monitored. RNA interference (RNAi) has been found to be the most effective method to specifically inhibit gene expression. Notably, interactions between cancer cells, stromal cells, and the extracellular matrix (ECM) are crucial to angiogenesis and tumorigenesis. Tumor cells and the surrounding stroma are the principle source of growth factors and cytokines, which induce remodeling of the ECM mediated by metalloproteases (MMPs) secreted by macrophages. The production of macrophages is regulated by colony-stimulating factor (CSF)-1, which is overexpressed in several tumors. When short-interfering RNAs (siRNAs) targeting either the CSF-1 or its receptors were delivered into colon and breast cancer xenografts in mice, tumor growth was inhibited. Associated with this suppression, we observed decreased tumor vascularity, reduced expression of angiogenic factors and MMPs, and decreased macrophage recruitment to the tumors. The suppression of CSF-1 by RNA interference is therefore a powerful tool to block gene function and influence tumor-stroma interactions in solid tumor development.
Methods Mol Biol 2007
PMID:Target validation using RNA interference in solid tumors. 1717 15

Mutations in the BRAF oncogene at amino acid 600 have been reported in 40 to 70% of human metastatic melanoma tissues, and the critical role of BRAF in the biology of melanoma has been established. Sampling the blood compartment to detect the mutational status of a solid tumor represents a highly innovative advance in cancer medicine, and such an approach could have advantages over tissue-based techniques. We report the development of a fluorescence-based polymerase chain reaction (PCR) assay to detect mutant BRAF alleles in plasma. A mutant-specific PCR assay was optimized to specifically amplify the mutant BRAF allele without amplifying the wild-type allele. Experiments mixing DNA from a BRAF mutant melanoma cell line with wild-type human placental DNA in varying proportions were performed to determine the threshold of this assay and to compare it with routine DNA sequencing. The assay was then applied to tissue and plasma specimens from patients with metastatic melanoma. The assay detected 0.1 ng of mutant DNA mixed in 100 ng of wild-type DNA and was 500-fold more sensitive than DNA sequencing. The assay detected mutant BRAF alleles in plasma samples from 14 of 26 (54%) metastatic melanoma patients. These data demonstrate the feasibility of blood-based testing for BRAF mutations in metastatic melanoma patients.
J Mol Diagn 2007 Apr
PMID:Detection of mutant BRAF alleles in the plasma of patients with metastatic melanoma. 1738 9

A dual probe with fluorescent and magnetic reporter groups was constructed by linkage of the near-infrared (NIR) fluorescent transferrin conjugate (Tf(NIR)) on the surface of contrast agent-encapsulated cationic liposome (Lip-CA). This probe was used for magnetic resonance imaging (MRI) and optical imaging of MDA-MB-231-luc breast cancer cells grown as a monolayer in vitro and as solid tumor xenografts in nude mice. Confocal microscopy, optical imaging, and MRI showed a dramatic increase of in vitro cellular uptake of the fluorescent and magnetic reporter groups from the probe compared with the uptake of contrast agent or Lip-CA alone. Pretreatment with transferrin (Tf) blocked uptake of the probe reporters, indicating the importance and specificity of the Tf moiety for targeting. Intravenous administration of the dual probe to nude mice significantly enhanced the tumor contrast in MRI, and preferential accumulation of the fluorescent signal was clearly seen in NIR-based optical images. More interestingly, the contrast enhancement in MRI showed a heterogeneous pattern within tumors, which reflected the tumor's morphologic heterogeneity. These results indicate that the newly developed dual probe enhances the tumor image contrast and is superior to contrast agent alone for identifying the tumor pathologic features on the basis of MRI but also is suitable for NIR-based optical imaging.
Mol Imaging
PMID:Dual probe with fluorescent and magnetic properties for imaging solid tumor xenografts. 1744 3


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