Recent progress in hormone research最新文献

{"title":"Overlapping but distinct profiles of gene expression elicited by glucocorticoids and progestins.","authors":"Yihong Wan,&nbsp;Steven K Nordeen","doi":"10.1210/rp.58.1.199","DOIUrl":"https://doi.org/10.1210/rp.58.1.199","url":null,"abstract":"<p><p>Glucocorticoids and progestins bind to receptors that share many structural and functional similarities, including virtually identical DNA recognition specificity. Nonetheless, the two hormones mediate very distinct biological functions. For example, progestins are associated with the incidence and progression of breast cancer, whereas glucocorticoids are growth suppressive in mammary cancer cells. To understand the mechanisms that engender biological specificity, we have employed two systematic approaches to identify genes that are differentially regulated by the two hormones. The first strategy is to utilize Affymetrix oligonucleotide arrays to compare glucocorticoid- and progestin-regulated gene expression in a human breast cancer cell line. This global analysis reveals that the two hormones regulate overlapping but distinct sets of genes, including 31 genes that are differentially regulated. Surprisingly, the set of differentially regulated genes was almost as large as the set of genes regulated by both hormones. Examination of the set of differentially regulated genes suggests mechanisms behind the distinct growth effects of the two hormones in breast cancer. The differential regulation of four genes representing different regulatory patterns was confirmed by reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analyses. Treatment with cycloheximide or mifepristone (RU486) indicates that the regulation is a primary, receptor-mediated event. The second strategy is to employ a retroviral promoter trap and Cre/loxP-mediated, site-specific recombination to identify genes that are differentially regulated by glucocorticoids and progestins. A mouse fibroblast cell line (4F) stably expressing both glucocorticoid receptor (GR) and progesterone receptor (PR) and containing a single copy of a multifunctional selection plasmid was generated. This line was transduced with a self-inactivating retroviral promoter trap vector carrying coding sequences for Cre-recombinase (Cre) in the U3 region. Integration of the provirus places Cre expression under the control of genomic flanking sequence. Activation of Cre expression from integration into active genes results in a permanent switch between the selectable marker genes that convert the cells from neomycin resistant to hygromycin resistant. Selection for hygromycin resistance after hormone treatment yields recombinants in which Cre sequences in the U3 region are expressed from hormone-inducible, upstream cellular promoters. Because Cre-mediated recombination is a permanent event, the expression of the selectable marker genes is independent of ongoing Cre expression. Thus, this system permits the identification of genes that are transiently or weakly induced by hormone. Detailed analyses of genes identified in these studies will furnish a mechanistic understanding of differential regulation by glucocorticoids and progestins.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"58 ","pages":"199-226"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22426616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of gene expression in the normal and malignant cerebellum.","authors":"Robert J Wechsler-Reya","doi":"10.1210/rp.58.1.227","DOIUrl":"https://doi.org/10.1210/rp.58.1.227","url":null,"abstract":"<p><p>The developing nervous system consists of a small number of multipotent precursors that undergo extensive proliferation to generate the neurons and glia that make up the adult brain. Elucidating the mechanisms that control the growth and differentiation of these cells is important not only for understanding normal neural development but also for understanding the etiology of central nervous system tumors. A particularly striking example of this is in the cerebellum. Recent studies have suggested that the Sonic hedgehog-Patched signaling pathway plays a critical role in regulating the proliferation of cerebellar granule cell precursors and is also a major target of mutation in the cerebellar tumor medulloblastoma. In light of these observations, identification of additional genes that control cerebellar growth and differentiation is likely to provide important insight into the basis of cerebellar tumors. Similarly, analysis of gene expression in medulloblastoma will no doubt shed light on previously unknown signaling pathways that regulate normal cerebellar development. The advent of high-throughput gene expression analysis techniques--such as adapter-tagged competitive polymerase chain reaction (ATAC-PCR), serial analysis of gene expression (SAGE), and DNA microarrays--makes identification of such genes faster and easier than ever before. This review summarizes recent studies of gene expression in the cerebellum and discusses the value of such approaches for understanding development and tumorigenesis in this tissue.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"58 ","pages":"227-48"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22426617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microarray analysis and identification of novel molecules involved in insulin-like growth factor-1 receptor signaling and gene expression.","authors":"Joelle Dupont,&nbsp;Sandra E Dunn,&nbsp;J Carl Barrett,&nbsp;Derek LeRoith","doi":"10.1210/rp.58.1.325","DOIUrl":"https://doi.org/10.1210/rp.58.1.325","url":null,"abstract":"<p><p>The insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF-1R) are members of the same subfamily of receptor tyrosine kinases. The two receptors phosphorylate many of the same substrates and activate the same signaling modules, including the mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3' kinase (PI3K) signaling pathways. Although the IR and IGF-1R share some redundant functions in metabolism, cell growth, differentiation, and apoptosis, they also exhibit distinct physiological roles. Some of these may be due to differences in tissue distribution, receptor structure, formation of hybrid receptors, or mechanisms of ligand binding. However, the divergent effects of insulin and IGF-1 also may be explained by specificity in the intracellular signals generated by insulin and IGF-1. In particular, the IR and IGF-1R are capable of triggering their own biological responses by using specific or preferential substrates, molecular adapters, or signaling pathways. In a recent study, we used cDNA microarray analysis to identify genes differentially regulated by insulin and IGF-1. Mouse NIH-3T3 fibroblasts expressing either the wild-type human IGF-1R or IR were stimulated with either IGF-1 or insulin, respectively. We identified 39 genes differentially regulated by insulin and IGF-1. Most of these genes had not been reported previously to be responsive to insulin or IGF-1. The genes induced by IGF-1 generally were involved in mitogenesis or differentiation, while the genes found to be induced by insulin did not conform to any particular category. In a separate study, immortalized breast epithelial cells were stimulated with IGF-1 and a cDNA microarray analysis was used to generate a profile of IGF-1-regulated genes. A number of genes known to be involved in angiogenesis were found to be regulated by IGF-1. These results strongly suggest that this technology may be extremely useful in identifying groups of genes that are specifically regulated by different ligands and their activated receptors.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"58 ","pages":"325-42"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22427756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A functional proteomics approach to signal transduction.","authors":"Paul R Graves,&nbsp;Timothy A J Haystead","doi":"10.1210/rp.58.1.1","DOIUrl":"https://doi.org/10.1210/rp.58.1.1","url":null,"abstract":"<p><p>The purpose of this review is to highlight how proteomics techniques can be used to answer specific questions related to signal transduction in a wide variety of systems. In our laboratory, we utilize proteomic technologies to elucidate signal transduction pathways involved in smooth muscle contraction and relaxation, cell growth and tumorigenesis, and the pathogenesis of malaria. We see the real application of this technology as a tool to enhance the power of existing approaches such as classical yeast and mouse genetics, tissue culture, protein expression systems, and site-directed mutagenesis. Our basic approach is to examine only those proteins that differ by some variable from the control sample. In this way, the number of proteins to be processed by electrophoresis, Edman degradation, or mass spectrometry is greatly reduced. In addition, since only those proteins that change in response to a given biological treatment are analyzed, the experimental outcome provides information about specific signaling pathways. Examples of typical experiments in our laboratory are measurement of changes in protein phosphorylation in response to treatment of cells with growth factors or specific drugs, characterization of proteins associated with a bait protein in a \"pull-down\" experiment, or measurement of changes in protein expression. Frequently, in these experiments, it is necessary to define complex protein mixtures. To achieve this goal, we utilize a variety of techniques to isolate specific types of proteins or \"subproteomes\" for further analysis. In this review, we discuss strategies used in our laboratory for studying signaling pathways, including subproteome isolation, proteome mining, and analysis of the phosphoproteome.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"58 ","pages":"1-24"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22427273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of hematopoietic stem cell self-renewal.","authors":"Tannishtha Reya","doi":"10.1210/rp.58.1.283","DOIUrl":"https://doi.org/10.1210/rp.58.1.283","url":null,"abstract":"<p><p>Every day, billions of new blood cells are produced in the body, each one derived from a hematopoietic stem cell (HSC). Because most mature blood stem cells have a limited life span, the ability of HSCs to perpetuate themselves through self-renewal and generate new blood cells for the lifetime of an organism is critical to sustaining life. A key problem in hematopoietic stem cell biology is how HSC self-renewal is regulated. Recent evidence suggests that signaling pathways classically involved in embryonic development--such as the Wnt signaling pathway--play an important role in regulating stem cell self-renewal. The Wnt signaling pathway has been shown to regulate stem cell fate choice in a variety of organs, including the skin, the nervous system, and the hematopoietic system. In the hematopoietic system, stimulation of hematopoietic progenitors and stem cells with soluble Wnt proteins or downstream activators of the Wnt signaling pathway leads to their expansion. Future studies focusing on the mechanism of action of the Wnt signaling pathway and its interaction with other pathways are needed to gain further insight into the regulation of stem cell self-renewal, not only in the hematopoietic system but also in a variety of other tissues.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"58 ","pages":"283-95"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22427754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a nuclear factor kappa B-dependent gene network.","authors":"Bing Tian,&nbsp;Allan R Brasier","doi":"10.1210/rp.58.1.95","DOIUrl":"https://doi.org/10.1210/rp.58.1.95","url":null,"abstract":"<p><p>Nuclear factor-kappa B (NF-kappaB) is a highly inducible transcription factor that plays an important role in the hepatic acute-phase response, innate/adaptive immunity, and cellular survival through the induction of genetic networks. The major transcriptional-activating species Rel A-NF-kappaB is a cytoplasmic complex whose nuclear translocation is controlled by its association with a family of inhibitory proteins, termed IkappaBs. Activation of NF-kappaB results in the targeted proteolysis of IkappaB, releasing NF-kappaB to enter the nucleus and bind to specific sequences in target promoters. Because the genomic actions of NF-kappaB are influenced by the stimulus applied and the promoter context/chromatin structure in which it binds, the spectrum of NF-kappaB-regulated genes has not been elucidated. We have begun to address this question, exploiting a tightly regulated cellular system expressing a nondegradable IkappaBalpha mutant that completely inhibits NF-kappaB action. High-density oligonucleotide microarrays were used to identify genetic responses in response to complex biological stimuli (viral replication) in the presence and absence of NF-kappaB. Using statistical and informatics tools, we identified two groups of NF-kappaB-dependent genes with distinct expression profiles: 1) a group with high constitutive expression whose expression levels fall in response to viral exposure and constitutive mRNA expression increases from NF-kappaB blockade, and 2) a group where constitutive expression was very low (or undetectable) and, after stimulation, expression levels strongly increased. In this group, NF-kappaB blockade inhibited the viral induction of genes. This latter cluster includes chemokines, transcriptional regulators, intracellular proteins regulating translation and proteolysis, and secreted proteins (e.g., complement components, growth factor regulators). These data reveal complexity in the genetic response to NF-kappaB and serve as a foundation for further informatics analysis to identify genetic features common to up- and downregulated NF-kappaB-dependent promoters.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"58 ","pages":"95-130"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22426612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of defective apoptosis in type 1 diabetes and other autoimmune diseases.","authors":"Takuma Hayashi,&nbsp;Denise L Faustman","doi":"10.1210/rp.58.1.131","DOIUrl":"https://doi.org/10.1210/rp.58.1.131","url":null,"abstract":"<p><p>Lymphocyte development, selection, and education are strictly controlled to prevent autoimmunity, with potentially autoreactive cells being removed by apoptosis. Dysregulation of apoptosis is a central defect in diverse murine autoimmune diseases. In murine models of autoimmune lupus, for example, mutations in the death receptor Fas (CD95) or in its ligand, FasL (CD95L), have been identified and shown to render lymphoid cells resistant to apoptosis. In contrast, select lymphoid subpopulations of mice with autoimmune diabetes manifest an increased susceptibility to apoptosis as a result of impaired activation of the transcription factor nuclear factor-kappa B (NF-kappaB), which normally protects cells against tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis. The genetic basis of this defect in NF-kappaB activation is a mutation in the promoter-enhancer region of a gene that encodes an essential subunit (LMP2) of the proteasome. Although no specific genetic defects have been identified in most common forms of human autoimmune disease, functional assays consistently demonstrate heightened apoptosis attributable to multiple death signaling pathways.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"58 ","pages":"131-53"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22426613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the transcriptional changes underlying functional defects in the mammary glands of prolactin receptor knockout mice.","authors":"Christopher J Ormandy,&nbsp;Matthew Naylor,&nbsp;Jessica Harris,&nbsp;Fiona Robertson,&nbsp;Nelson D Horseman,&nbsp;Geoffrey J Lindeman,&nbsp;Jane Visvader,&nbsp;Paul A Kelly","doi":"10.1210/rp.58.1.297","DOIUrl":"https://doi.org/10.1210/rp.58.1.297","url":null,"abstract":"<p><p>Knockout (KO) mice have been created that carry null mutations of genes encoding molecules essential for prolactin (PRL) release, PRL, the receptor for prolactin (PRLR), and various members of the receptor's signaling pathway. This allowed an in vivo genetic analysis of the role of PRL in target organ function. In PRLKO and PRLRKO mice, mammary ductal side branching was absent, terminal end bud (TEB)-like structures persisted at the ductal termini well into maturity, and no alveolar buds formed along the ductal tree. Transplants of recombined mammary glands formed from stromal and epithelial elements with and without PRLR showed normal development, while supplementation of progesterone levels in PRLKO animals restored ductal side branching. During pregnancy, PRLR heterozygous animals initially showed normal ductal and alveolar development. However, alveolar development stalled during late pregnancy, preventing successful lactation. This defect could be rescued by the loss of a single allele of the suppressor of cytokine signaling (SOCS) 1 gene. Transplants of recombined glands containing PRLRKO epithelium and wild-type (WT) stroma formed alveolar buds during pregnancy but showed no lobuloalveolar development. Recombinations of WT epithelium and PRLRKO stroma showed normal development, demonstrating that a direct action of the lactogenic hormones is confined to the epithelium, to promote lobuloalveolar development. Transcript profiling of epithelial transplants expressing or not expressing PRLR was used during early pregnancy to investigate the transcriptional response to lactogens underlying this defect. Such profiling has identified a number of genes with well-characterized roles in mammary development, in addition to a number of novel transcripts.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"58 ","pages":"297-323"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22427755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic changes in gene expression during human trophoblast differentiation.","authors":"Stuart Handwerger,&nbsp;Bruce Aronow","doi":"10.1210/rp.58.1.263","DOIUrl":"https://doi.org/10.1210/rp.58.1.263","url":null,"abstract":"<p><p>The genetic program that directs human placental differentiation is poorly understood. In a recent study, we used DNA microarray analyses to determine genes that are dynamically regulated during human placental development in an in vitro model system in which highly purified cytotrophoblast cells aggregate spontaneously and fuse to form a multinucleated syncytium that expresses placental lactogen, human chorionic gonadotropin, and other proteins normally expressed by fully differentiated syncytiotrophoblast cells. Of the 6918 genes present on the Incyte Human GEM V microarray that we analyzed over a 9-day period, 141 were induced and 256 were downregulated by more than 2-fold. The dynamically regulated genes fell into nine distinct kinetic patterns of induction or repression, as detected by the K-means algorithm. Classifying the genes according to functional characteristics, the regulated genes could be divided into six overall categories: cell and tissue structural dynamics, cell cycle and apoptosis, intercellular communication, metabolism, regulation of gene expression, and expressed sequence tags and function unknown. Gene expression changes within key functional categories were tightly coupled to the morphological changes that occurred during trophoblast differentiation. Within several key gene categories (e.g., cell and tissue structure), many genes were strongly activated, while others with related function were strongly repressed. These findings suggest that trophoblast differentiation is augmented by \"categorical reprogramming\" in which the ability of induced genes to function is enhanced by diminished synthesis of other genes within the same category. We also observed categorical reprogramming in human decidual fibroblasts decidualized in vitro in response to progesterone, estradiol, and cyclic AMP. While there was little overlap between genes that are dynamically regulated during trophoblast differentiation versus decidualization, many of the categories in which genes were strongly activated also contained genes whose expression was strongly diminished. Taken together, these findings point to a fundamental role for simultaneous induction and repression of mRNAs that encode functionally related proteins during the differentiation process.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"58 ","pages":"263-81"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22426619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The use of DNA microarrays to assess clinical samples: the transition from bedside to bench to bedside.","authors":"John A Copland,&nbsp;Peter J Davies,&nbsp;Gregory L Shipley,&nbsp;Christopher G Wood,&nbsp;Bruce A Luxon,&nbsp;Randall J Urban","doi":"10.1210/rp.58.1.25","DOIUrl":"https://doi.org/10.1210/rp.58.1.25","url":null,"abstract":"<p><p>The advent of gene array technology brings the ability to classify disease states to the molecular level by examining changes in all mRNAs expressed in cells or tissues. Comparing changes in gene expression patterns between normal and diseased cells and/or tissues has elucidated unique subsets of genes identifiable to a specific disease. Already, new subclassifications of specific cancers have been discovered, belying that genomic profiling can uniquely distinguish a specific disease state and tissue of origin. This technology bestows the ability to examine global changes occurring in a cell or tissue(s), thereby allowing the elucidation of alterations in dysregulated biological, biochemical, and molecular events leading to disease states such as diabetes, hypertension, infertility, obesity, osteoporosis, and atherosclerosis. Furthermore, genomic profiling will lead to new molecular targets for the development of drug therapeutics. Futuristically, one could envision personalized patient therapies based upon identification of specific aberrant signaling pathways that can be targeted for drug therapy.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"58 ","pages":"25-53"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22427274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}