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1.
Drug Discov Today ; 9(22): 976-83, 2004 Nov 15.
Article in English | MEDLINE | ID: mdl-15539141

ABSTRACT

Arguably, the most immediately promising reverberation of the genomics era has been the application of biomarkers to drug development. The promise of applying biomarkers to early drug development is that they might aid in preclinical and early clinical decisions such as dose ranging, definition of treatment regimen, or even a preview of efficacy. Later in the clinic, biomarkers could be used to facilitate patient stratification, selection and the description of surrogate endpoints. Information derived from biomarkers should result in a better understanding of preclinical and clinical data, which ultimately benefits patients and drug developers. If the promise of biomarkers is realized, they will become a routine component of drug development and companions to newly discovered therapies.


Subject(s)
Biomarkers/analysis , Computational Biology , Drug Design , Gene Expression Profiling , Proteins/analysis , Animals , Drug Evaluation, Preclinical/methods , Genomics/methods , Humans , Nucleic Acids/analysis , Proteomics/methods
2.
Blood ; 104(1): 149-58, 2004 Jul 01.
Article in English | MEDLINE | ID: mdl-15016650

ABSTRACT

We conducted a genome-wide analysis of genes that are regulated by vascular endothelial growth factor (VEGF) in endothelial cells and identified DSCR1 to be most significantly induced. Consistent with an antagonistic function on calcineurin (CnA) signaling, expression of DSCR1 in endothelial cells blocked dephosphorylation, nuclear translocation, and activity of nuclear factor of activated T cell (NFAT), a transcription factor involved in mediating CnA signaling. DSCR1 was not only induced by VEGF, but also by other compounds activating CnA signaling, suggesting a more general role for DSCR1 in activated endothelial cells. Transient expression of DSCR1 attenuated inflammatory marker genes such as tissue factor (TF), E-selectin, and Cox-2, identifying a previously unknown regulatory role for DSCR1 in activated endothelial cells. In contrast, knock-down of endogenous DSCR1 increased NFAT activity and stimulated expression of inflammatory genes on activated endothelial cells. Thus, the negative regulatory feedback loop between DSCR1 and CnA signaling in endothelial cells identified may represent a potential molecular mechanism underlying the frequently transient expression of inflammatory genes following activation of endothelial cells.


Subject(s)
Endothelial Cells/physiology , Inflammation Mediators/metabolism , Muscle Proteins/physiology , Nuclear Proteins , Vascular Endothelial Growth Factors/genetics , Calcineurin/metabolism , Calcineurin Inhibitors , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , E-Selectin/biosynthesis , E-Selectin/genetics , Endothelial Cells/cytology , Endothelial Cells/metabolism , Endothelium, Vascular/cytology , Feedback, Physiological/physiology , Gene Expression Regulation/genetics , Gene Expression Regulation/physiology , Gene Targeting , Humans , Inflammation Mediators/physiology , Intercellular Adhesion Molecule-1/biosynthesis , Intercellular Adhesion Molecule-1/genetics , Intracellular Signaling Peptides and Proteins , Muscle Proteins/genetics , NFATC Transcription Factors , Phosphorylation , RNA, Small Interfering/pharmacology , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Thromboplastin/biosynthesis , Thromboplastin/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Transcription, Genetic , Umbilical Veins/cytology , Vascular Cell Adhesion Molecule-1/biosynthesis , Vascular Cell Adhesion Molecule-1/genetics , Vascular Endothelial Growth Factors/physiology
3.
Curr Opin Chem Biol ; 6(4): 418-26, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12133715

ABSTRACT

Recent advances in genomics include global assessment and classification of genome content, high-throughput biological pathway construction, systematic identification of previously unpredicted genes and the in vitro creation of novel motifs with biological function not found in nature (extra-genomic gene discovery). The ability to make global surveys of transcriptomes has given rise to fields such as pharmacogenomics and toxicogenomics. These applications of genomics technologies, with conventional drug assessment methodologies, will lead to more tolerable drugs and a better understanding of clinical populations. Integration of pathway mapping, using proteomics married to expression, will also significantly affect how new therapeutics are discovered as cross-biological cross-pathway interactions lead to novel drug targets and better predictions of drug tolerance.


Subject(s)
Databases, Nucleic Acid , Genomics/trends , Alternative Splicing , Animals , Base Sequence , Gene Expression Profiling , Genomics/methods , Humans , Polymorphism, Single Nucleotide , Sequence Homology
4.
J Biol Chem ; 277(16): 14255-65, 2002 Apr 19.
Article in English | MEDLINE | ID: mdl-11777915

ABSTRACT

The activation of the AKT/protein kinase B kinases by mutation of the PTEN lipid phosphatase results in enhanced survival of a diversity of tumors. This resistance to apoptosis is partly accomplished by the inhibition of genetic programs induced by a subfamily of forkhead transcription factors including AFX. Here we describe an AFX-regulated pathway that appears to account for at least part of this apoptotic regulatory system. Cells induced to synthesize an active form of AFX die by activating the apoptotic death pathway. An analysis of genes regulated by AFX demonstrated that BCL-6, a transcriptional repressor, is up-regulated approximately 4-7-fold. An examination of the BCL-6 promoter demonstrated that AFX bound to specific target sites that could activate transcription. BCL-X(L), an anti-apoptotic protein, contains potential BCL-6 target sites in its promoter. An analysis of endogenous BCL-X(L) levels in AFX-expressing cells revealed enhanced down-regulation of the transcript ( approximately 1.3-1.7-fold) and protein, and BCL-6 directly binds to and suppresses the BCL-X(L) promoter. Finally, macrophages isolated from BCL-6-/- mice show enhanced survival in vitro. These results suggest that AFX regulates apoptosis in part by suppressing the levels of anti-apoptotic BCL-XL through the transcriptional repressor BCL-6.


Subject(s)
Apoptosis , DNA-Binding Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Transcription Factors/metabolism , Animals , Base Sequence , Binding Sites , Blotting, Western , Cell Cycle Proteins , DNA/metabolism , Down-Regulation , Enzyme Activation , Forkhead Transcription Factors , Genetic Techniques , HeLa Cells , Humans , Luciferases/metabolism , Macrophages/metabolism , Mice , Mice, Transgenic , Models, Biological , Molecular Sequence Data , Mutation , Promoter Regions, Genetic , Protein Binding , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-6 , Time Factors , Transcription, Genetic , Up-Regulation , bcl-X Protein
5.
FASEB J ; 16(2): 155-68, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11818363

ABSTRACT

A survey of genes differentially expressed in the brown adipose tissue (BAT) of mice exposed to a range of environmental temperatures was carried out to identify novel genes and pathways associated with the transition of this tissue toward an amplified thermogenic state. The current report focuses on an analysis of the expression patterns of 50 metabolic genes in BAT under control conditions (22 degrees C), cold exposure (4 degrees C, 1 to 48 h), warm acclimation (33 degrees C, 3 wk), or food restriction/meal feeding (animals fed the same amount as warm mice). In general, expression of genes encoding proteins involving glucose uptake and catabolism was significantly elevated in the BAT of cold-exposed mice. The levels of mRNAs encoding proteins critical to de novo lipogenesis were also increased. Gene expression for enzymes associated with procurement and combustion of long chain fatty acids (LCFAs) was increased in the cold. Thus, a model was proposed in which coordinated activation of glucose uptake, fatty acid synthesis, and fatty acid combustion occurs as part of the adaptive thermogenic processes in BAT. Confirmation emerged from in vivo assessments of cold-induced changes in BAT 2-deoxyglucose uptake (increased 2.7-fold), BAT lipogenesis (2.8-fold higher), and incorporation of LCFA carboxyl-carbon into BAT water-soluble metabolites (elevated approximately twofold). It is proposed that temperature-sensitive regulation of distinct intracellular malonyl-CoA pool sizes plays an important role in driving this unique metabolic profile via maintenance of the lipogenic pool but diminution of the carnitine palmitoyltransferase 1 inhibitory pool under cold conditions.


Subject(s)
Adipose Tissue, Brown/metabolism , Cold Temperature , Fatty Acids/metabolism , Acclimatization , Acetyl-CoA Carboxylase/genetics , Animals , Carbohydrate Metabolism , Gene Expression Regulation , Lipid Metabolism , Male , Mice , Oxidation-Reduction , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Adrenergic, beta/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Stearoyl-CoA Desaturase/genetics , Transcription Factors/genetics
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