@article {2131, title = {Direct, androgen receptor-mediated regulation of the FKBP5 gene via a distal enhancer element.}, journal = {Endocrinology}, volume = {147}, year = {2006}, month = {2006 Jan 6}, pages = {590-8}, abstract = {

Androgen signaling via the androgen receptor (AR) transcription factor is crucial to normal prostate homeostasis and prostate tumorigenesis. Current models of AR function are predominantly based on studies of prostate-specific antigen regulation in androgen-responsive cell lines. To expand on these in vitro paradigms, we used the mouse prostate to elucidate the mechanisms through which AR regulates another direct target, FKBP5, in vivo. FKBP5 encodes an immunophilin that has been previously implicated in glucocorticoid and progestin signaling pathways and that likely influences prostate physiology in the presence of androgens. In this work, we show that androgens directly regulate FKBP5 via an interaction between the AR and a distal enhancer located 65 kb downstream of the transcription start site in the fifth intron of the FKBP5 gene. We have found that AR selectively recruits cAMP response element-binding protein to this enhancer. These interactions, in turn, result in chromatin remodeling that affects the enhancer proper but not the FKBP5 locus as a whole. Furthermore, in contrast to prostate-specific antigen-regulatory mechanisms, we show that transactivation of the FKBP5 gene does not rely on a single looping complex to mediate communication between the distal enhancer and proximal promoter. Rather, the distal enhancer complex and basal transcription apparatus communicate indirectly with one another, implicating a regulatory mechanism that has not been previously appreciated for AR target genes.

}, keywords = {Androgen, Animals, Base Sequence, Chromosome Mapping, Conserved Sequence, Enhancer Elements, Gene Expression Regulation, Genetic, Humans, Introns, Male, Mice, Molecular Sequence Data, Nucleic Acid, Orchiectomy, Prostate, Receptors, Reverse Transcriptase Polymerase Chain Reaction, Sequence Alignment, Sequence Homology, Tacrolimus Binding Proteins, Transcription}, issn = {0013-7227}, doi = {10.1002/cbic.201000254}, author = {Magee, Jeffrey A and Chang, Li-Wei and Stormo, Gary D and Milbrandt, Jeffrey} } @article {2129, title = {A systematic model to predict transcriptional regulatory mechanisms based on overrepresentation of transcription factor binding profiles.}, journal = {Genome Research}, volume = {16}, year = {2006}, month = {2006 Mar}, pages = {405-13}, abstract = {

An important aspect of understanding a biological pathway is to delineate the transcriptional regulatory mechanisms of the genes involved. Two important tasks are often encountered when studying transcription regulation, i.e., (1) the identification of common transcriptional regulators of a set of coexpressed genes; (2) the identification of genes that are regulated by one or several transcription factors. In this study, a systematic and statistical approach was taken to accomplish these tasks by establishing an integrated model considering all of the promoters and characterized transcription factors (TFs) in the genome. A promoter analysis pipeline (PAP) was developed to implement this approach. PAP was tested using coregulated gene clusters collected from the literature. In most test cases, PAP identified the transcription regulators of the input genes accurately. When compared with chromatin immunoprecipitation experiment data, PAP{\textquoteright}s predictions are consistent with the experimental observations. When PAP was used to analyze one published expression-profiling data set and two novel coregulated gene sets, PAP was able to generate biologically meaningful hypotheses. Therefore, by taking a systematic approach of considering all promoters and characterized TFs in our model, we were able to make more reliable predictions about the regulation of gene expression in mammalian organisms.

}, keywords = {Animals, Cell Proliferation, Cholesterol, Chromatin Immunoprecipitation, Computational Biology, Conserved Sequence, Gene Expression Profiling, Gene Expression Regulation, Genetic, Humans, Mice, Models, Promoter Regions, Protein Binding, Transcription Factors}, issn = {1088-9051}, doi = {10.1002/cbic.201000254}, author = {Chang, Li-Wei and Nagarajan, Rakesh and Magee, Jeffrey A and Milbrandt, Jeffrey and Stormo, Gary D} } @article {2139, title = {Haploinsufficiency at the Nkx3.1 locus. A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation.}, journal = {Cancer Cell}, volume = {3}, year = {2003}, month = {2003 Mar}, pages = {273-83}, abstract = {

Tumorigenesis requires sequential accumulation of multiple genetic lesions. In the prostate, tumor initiation is often linked to loss of heterozygosity at the Nkx3.1 locus. In mice, loss of even one Nkx3.1 allele causes prostatic epithelial hyperplasia and eventual prostatic intraepithelial neoplasia (PIN) formation. Here we demonstrate that Nkx3.1 allelic loss extends the proliferative stage of regenerating luminal cells, leading to epithelial hyperplasia. Microarray analysis identified Nkx3.1 target genes, many of which show exquisite dosage sensitivity. The number of Nkx3.1 alleles determines the relative probabilities of stochastic activation or inactivation of a given target gene. Thus, loss of a single Nkx3.1 allele likely results in hyperplasia and PIN by increasing the probability of completely inactivating select Nkx3.1-regulated pathways within a subset of affected cells.

}, keywords = {Alleles, Animals, Biological, Cell Division, Gene Deletion, Gene Dosage, Gene Expression Profiling, Gene Expression Regulation, Gene Targeting, Genes, Genetic Predisposition to Disease, Loss of Heterozygosity, Male, Mice, Models, Mutant Strains, Neoplastic, Orchiectomy, Prostatic Intraepithelial Neoplasia, Prostatic Neoplasms, Testosterone, Tumor Suppressor}, issn = {1535-6108}, doi = {10.1002/cbic.201000254}, author = {Magee, Jeffrey A and Abdulkadir, Sarki A and Milbrandt, Jeffrey} } @article {2143, title = {Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia.}, journal = {Molecular and Cellular Biology}, volume = {22}, year = {2002}, month = {2002 Mar}, pages = {1495-503}, abstract = {

The homeodomain-containing transcription factor NKX3.1 is a putative prostate tumor suppressor that is expressed in a largely prostate-specific and androgen-regulated manner. Loss of NKX3.1 protein expression is common in human prostate carcinomas and prostatic intraepithelial neoplasia (PIN) lesions and correlates with tumor progression. Disruption of the murine Nkx3.1 gene results in defects in prostate branching morphogenesis, secretions, and growth. To more closely mimic the pattern of NKX3.1 loss that occurs in human prostate tumors, we have used Cre- and loxP-mediated recombination to delete the Nkx3.1 gene in the prostates of adult transgenic mice. Conditional deletion of one or both alleles of Nkx3.1 leads to the development of preinvasive lesions that resemble PIN. The pattern of expression of several biomarkers (Ki-67, E-cadherin, and high-molecular-weight cytokeratins) in these PIN lesions resembled that observed in human cases of PIN. Furthermore, PIN foci in mice with conditional deletion of a single Nkx3.1 allele lose expression of the wild-type allele. Our results support the role of NKX3.1 as a prostate tumor suppressor and indicate a role for this gene in tumor initiation.

}, keywords = {Animals, Gene Deletion, Genes, Genetic Predisposition to Disease, Homeodomain Proteins, Homozygote, Hyperplasia, Integrases, Male, Mice, Prostate, Prostatic Intraepithelial Neoplasia, Prostatic Neoplasms, Transcription Factors, Transgenic, Tumor Suppressor, Viral Proteins}, issn = {0270-7306}, doi = {10.1002/cbic.201000254}, author = {Abdulkadir, Sarki A and Magee, Jeffrey A and Peters, Thomas J and Kaleem, Zahid and Naughton, Cathy K and Humphrey, Peter A and Milbrandt, Jeffrey} }