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Results for “Genes, Regulator”

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At least 73 records · Page 4Linked to original sources

PubMed2005

Development of a single-cassette system for spatiotemporal gene regulation in mice.

The tetracycline-regulated gene expression system has been widely used in mice to turn a transgene on and off in a target organ, but with only limited success. We developed an advanced system in which a Tet-off regulation unit was integrated into the ROSA26 locus and became active after Cre-mediated excision of the neo(r) gene. We examined the utility of this system through regulable expression of the homeodomain transcription factor pdx-1 and enhanced green fluorescent protein. The resulting mice showed strict tetracycline-regulable gene expression in all the organs where the neo(r) gene had been removed. When combined with organ-specific Cre recombinase transgenic mice, our system allows us to manipulate the gene expression in an organ-specific and temporal manner. This Tet-off system should serve as an efficient tool to analyze the roles of genes in complex biological systems, such as embryogenesis, metabolism, immune system, etc.

Animals↗

PubMed2025

Self-regulating gene therapy ameliorates phenotypes and overcomes gene dosage sensitivity in a mouse model of Rett syndrome.

Conventional methods of gene transfer lead to inconsistent transgene expression within cells. This variability can be problematic, particularly in conditions like Rett syndrome (RTT), a neurological disorder caused by mutations in the MECP2 (methyl-CpG binding protein 2) gene, because overexpression of MECP2 can also cause adverse effects. To address these challenges, we devised a gene regulation system called Expression Attenuation via Construct Tuning (EXACT), which uses a self-contained, microRNA-based feed-forward loop that not only ensures more consistent transgene expression but also protects against excessive expression. Through cell-based screening assays, we demonstrated the ability of the EXACT circuit to modulate the expression of full-length human MeCP2. Compared with a conventional construct, an EXACT-MECP2 construct exhibited a narrower range of cellular protein abundance. Furthermore, the degree of regulation by the EXACT circuit increased with higher transgene doses in vitro and in wild-type mice and mice modeling RTT. On the basis of cellular and in vivo testing, we identified an optimal configuration for the adeno-associated virus serotype 9 (AAV9) construct for self-regulated MECP2 gene therapy, designated NGN-401. Delivery of NGN-401 to neonatal male Mecp2-/y hemizygous mice via intracerebroventricular injection resulted in prolonged survival and amelioration of RTT-like phenotypes compared with vehicle-treated animals. NGN-401 was also well tolerated by female Mecp2+/- mice and healthy juvenile nonhuman primates, in contrast with a conventional construct, which caused toxicity. The results from these studies underpin a first-in-human pediatric trial of NGN-401 in RTT (ClinicalTrials.gov, NCT05898620).

Animals↗

PubMed1974

Nonhistone chromosomal proteins and gene regulation.

Evidence from several model systems suggests that nonhistone chromosomal proteins may regulate gene expression in eukaryotic cells. The data indicate that the synthesis of new species of nonhistone chromosomal proteins as well as modifications of preexisting nonhistone chromosomal proteins are involved in the control of transcription. However, from the vast number of proteins included in this class, it is apparent that, in addition to regulating the transcription of defined genome loci, the nonhistone chromosomal proteins include enzymes that have a general function, proteins that are involved in determining the structure of chromatin, as well as proteins that serve as recognition sites for binding of regulatory macromolecules. The presence of a nucleoplasmic pool of nonhistone chromosomal proteins which may exchange with the chromatin has also been reported (89). While it is clear that the nonhistone chromosomal proteins play a key role in the regulation of gene expression, the exact manner in which they interact with the genome to initiate, modify, or augment the transcription of specific RNA molecules remains to be resolved.

Animals↗

PubMed2003

Identification of reciprocally regulated gene modules in regenerating dorsal root ganglion neurons and activated peripheral or central nervous system glia.

Differential gene expression in the rat after injury of dorsal root ganglion neurons in vivo, and simulation injury of Schwann cells and oligodendrocytes in vitro was analyzed using high-density cDNA microarrays. The analyses were carried out to study the genetic basis of peripheral nerve regeneration, and to compare gene regulation in glia of the central (oligodendrocyte) and peripheral (Schwann cell) nervous systems. The genes showing significant differential regulation in the three study groups represented all aspects of cellular metabolism. However, two unexpected observations were made. Firstly, a number of identical genes were differentially regulated in activated Schwann cells, activated oligodendrocytes and regenerating DRG neurons. Specifically, a group of 113 out of 210 genes that were down-regulated in Schwann cells upon lipopolysaccharide (LPS) treatment, were identical to genes up-regulated in the injured, regenerating DRG. Furthermore, a group of 53 out of 71 genes that were down-regulated in interferon gamma (IFN-gamma)/LPS-activated oligodendrocytes, were identical to genes up-regulated in the DRG neurons. Finally, 22 genes were common to these three groups, i.e., down-regulated in activated oligodendrocytes, down-regulated in activated Schwann cells, and up-regulated in regenerating DRG neurons. Secondly, a group of 16 cell-cycle and proliferation-related genes were up-regulated in the DRG following sciatic nerve crush, despite the absence of cells undergoing mitosis in the DRG, or any significant presence of apoptosis-related gene expression. Therefore, it appears that in these three cell types, large sets of genes are reciprocally regulated upon injury and/or activation. This suggests that the activation of the injury-related gene expression program in cell derivatives of the neuroectoderm involves, in part, highly conserved genetic elements.

Animals↗

PubMed2004

Ternary complex factor-serum response factor complex-regulated gene activity is required for cellular proliferation and inhibition of apoptotic cell death.

Members of the ternary complex factor (TCF) subfamily of the ETS-domain transcription factors are activated through phosphorylation by mitogen-activated protein kinases (MAPKs) in response to a variety of mitogenic and stress stimuli. The TCFs bind and activate serum response elements (SREs) in the promoters of target genes in a ternary complex with a second transcription factor, serum response factor (SRF). The association of TCFs with SREs within immediate-early gene promoters is suggestive of a role for the ternary TCF-SRF complex in promoting cell cycle entry and proliferation in response to mitogenic signaling. Here we have investigated the downstream gene regulatory and phenotypic effects of inhibiting the activity of genes regulated by TCFs by expressing a dominantly acting repressive form of the TCF, Elk-1. Inhibition of ternary complex activity leads to the downregulation of several immediate-early genes. Furthermore, blocking TCF-mediated gene expression leads to growth arrest and triggers apoptosis. By using mutant Elk-1 alleles, we demonstrated that these effects are via an SRF-dependent mechanism. The antiapoptotic gene Mcl-1 is identified as a key target for the TCF-SRF complex in this system. Thus, our data confirm a role for TCF-SRF-regulated gene activity in regulating proliferation and provide further evidence to indicate a role in protecting cells from apoptotic cell death.

Alleles↗

PubMed2004

GATA-6 regulates genes promoting synthetic functions in vascular smooth muscle cells.

OBJECTIVE: Previous studies suggested the zinc-finger transcription factor GATA-6 inhibits vascular smooth muscle cell (VSMC) proliferation and promotes the contractile VSMC phenotype. The objective of this study was to identify bona fide target genes regulated by GATA-6 in VSMCs. METHODS AND RESULTS: Microarray analyses were performed comparing mRNA from rat aortic smooth muscle cells (SMCs) infected with either adenovirus encoding a dominant-negative GATA-6/engrailed fusion protein or with control adenovirus. These studies identified 122 genes differentially expressed by at least 2-fold, including multiple genes involved in cell-cell signaling and cell-matrix interactions. Among these, endothelin-1 and the angiotensin type(1a) (AT(1a)) receptor are known to be induced in VSMCs in response to inflammatory stimuli and to be expressed in a GATA-dependent manner in cardiac myocytes in response to hemodynamic stress. Consistent with these findings, the endothelin-1 and AT(1a) receptor promoters were activated by forced expression of GATA-6 and repressed by forced expression of GATA-6/engrailed. Surprisingly, genes encoding SMC contractile proteins were not altered, and myocardin-induced SMC differentiation was not impaired in GATA-6(-/-) embryonic stem cells. CONCLUSIONS: These data demonstrate that in VSMCs, GATA-6 regulates a set of genes associated with synthetic SMC functions and suggest that this transcriptional pathway may be independent from myocardin-induced SMC differentiation. An unbiased microarray screen of genes regulated by GATA-6 in VSMCs identified multiple genes involved in cell-cell signaling and cell-matrix interactions. The endothelin-1 and the AT1a receptor genes were shown to be direct GATA-6 target genes. These data suggest that GATA-6 plays a role in promoting synthetic functions in VSMCs.

Animals↗

PubMed2004

Gene regulation by Sp1 and Sp3.

The Sp family of transcription factors is united by a particular combination of three conserved Cys2His2 zinc fingers that form the sequence-specific DNA-binding domain. Within the Sp family of transcription factors, Sp1 and Sp3 are ubiquitously expressed in mammalian cells. They can bind and act through GC boxes to regulate gene expression of multiple target genes. Although Sp1 and Sp3 have similar structures and high homology in their DNA binding domains, in vitro and in vivo studies reveal that these transcription factors have strikingly different functions. Sp1 and Sp3 are able to enhance or repress promoter activity. Regulation of the transcriptional activity of Sp1 and Sp3 occurs largely at the post-translational level. In this review, we focus on the roles of Sp1 and Sp3 in the regulation of gene expression.

Animals↗

PubMed2004

Liver-enriched transcription factors in liver function and development. Part II: the C/EBPs and D site-binding protein in cell cycle control, carcinogenesis, circadian gene regulation, liver regeneration, apoptosis, and liver-specific gene regulation.

In the first part of our review (see Pharmacol Rev 2002;54:129-158), we discussed the basic principles of gene transcription and the complex interactions within the network of hepatocyte nuclear factors, coactivators, ligands, and corepressors in targeted liver-specific gene expression. Now we summarize the role of basic region/leucine zipper protein family members and particularly the albumin D site-binding protein (DBP) and the CAAT/enhancer-binding proteins (C/EBPs) for their importance in liver-specific gene expression and their role in liver function and development. Specifically, regulatory networks and molecular interactions were examined in detail, and the experimental findings summarized in this review point to pivotal roles of DBP and C/EBPs in cell cycle control, carcinogenesis, circadian gene regulation, liver regeneration, apoptosis, and liver-specific gene regulation. These regulatory proteins are therefore of great importance in liver physiology, liver disease, and liver development. Furthermore, interpretation of the vast data generated by novel genomic platform technologies requires a thorough understanding of regulatory networks and particularly the hierarchies that govern transcription and translation of proteins as well as intracellular protein modifications. Thus, this review aims to stimulate discussions on directions of future research and particularly the identification of molecular targets for pharmacological intervention of liver disease.

Animals↗

PubMed2006

Phosphorylation of SATB1, a global gene regulator, acts as a molecular switch regulating its transcriptional activity in vivo.

SATB1 regulates gene expression by acting as a "docking site" for several chromatin remodeling enzymes and also by recruiting corepressors (HDACs) or coactivators (HATs) directly to promoters. However, how these contrasting effectors act at the level of SATB1 is not clear. We show here that phosphorylation by PKC acts as a switch to determine whether SATB1 interacts with HDAC1 or PCAF. Phosphorylation and dephosphorylation of SATB1 exerted opposing effects on MAR-linked reporter activity in vivo. SATB1 interacted with both CBP/p300 and PCAF HATs; however, these interactions resulted in the acetylation of the PDZ-like domain of SATB1 by PCAF but not by CBP/p300 and resulted in loss of its DNA binding activity. Using the T cell activation model, we provide mechanistic insights into how IL-2 transcription is reciprocally governed by the phosphorylation status of SATB1 and propose that a similar mechanism may dictate the ability of SATB1 to function as a global regulator.

Acetylation↗

PubMed2004

A cross-talk between hypoxia and TGF-beta orchestrates erythropoietin gene regulation through SP1 and Smads.

Erythropoietin (Epo) is the humoral regulator of red blood-cell production. Low oxygen tension increases the Epo levels by enhancing transcription, through the hypoxia-inducible factor (HIF)-1, a transcriptional modulator in oxygen-regulated gene expression. In the present work, a cooperative interaction between hypoxia, mediated by the HIF-1 complex, and transforming growth factor-beta (TGF-beta), mediated by Smad3/4, was revealed in the Epo gene. This cooperation is due to physical interaction between Smad3/4 and HIF-1alpha. The Smad3/4 binding site is located within the 3' Epo enhancer, downstream from the HRE consensus, and immediately adjacent to the orphan hepatic nuclear factor receptor (HNF-4). HNF-4 is interacting also with Smad3 and the HIF-1 complex, to potentiate further the cooperative effect between both factors. Moreover, Sp1 has been identified as the factor binding the promoter necessary for the full hypoxia inducibility of the EPO gene. However, this full induction is achieved only if the TGF-beta pathway is mediating a cross-talk between promoter (Sp1) and enhancer (HIF-1alpha) regions through Smad3. We show that Sp1 binding to the proximal promoter is relevant for Epo transcription, and contributes to the Epo induction by hypoxia. A functional cooperation among the transcription factors mediating hypoxia (HIF-1, Sp1), the TGF-beta pathway (Smad3/4), and tissue-specific HNF-4 is proposed for the regulation of the Epo gene. In this model, the physical contact between the upstream promoter and the 3' downstream enhancer is mediated by Sp1 and Smad3 factors, and would occur upon bending of the DNA intervening sequences. Thus, Sp1 would reinforce the promoter/enhancer contact, while Smad3 would stabilize the multifactorial complex by interacting with HIF-1/Sp1/HNF-4 and the coactivator CBP/p300. This model may be extended to other genes where collaboration between TGF-beta and hypoxia takes place.

Animals↗

PubMed2000

PART-1: a novel human prostate-specific, androgen-regulated gene that maps to chromosome 5q12.

Genes regulated by androgenic hormones are of critical importance for the normal physiological function of the human prostate gland, and they contribute to the development and progression of prostate carcinoma. We used cDNA microarrays containing 1500 prostate-derived cDNAs to profile transcripts regulated by androgens in prostate cancer cells. This study identified a novel gene that we have designated PART-1 (prostate androgen-regulated transcript 1), which exhibited increased expression upon exposure to androgens in the LNCaP prostate cancer cell line. Northern analysis demonstrated that PART-1 is highly expressed in the prostate gland relative to other normal human tissues and is expressed as different transcripts using at least three different polyadenylation signals. The PART-1 cDNA and putative protein are not significantly homologous to any sequences in the nonredundant public sequence databases. Cloning and analysis of the putative PART-1 promoter region identified a potential binding site for the homeobox gene PBX-la, but no consensus androgen response element or sterol-regulatory element binding sites were identified. We used a radiation hybrid panel and fluorescence in situ hybridization to map the PART-1 gene to chromosome 5q12, a region that has been suggested to harbor a prostate tumor suppressor gene. These results identify a new gene involved in the androgen receptor-regulated gene network of the human prostate that may play a role in the etiology of prostate carcinogenesis.

Amino Acid Sequence↗

PubMed2005

Gene regulation profile reveals consistent anticancer properties of progesterone in hormone-independent breast cancer cells transfected with progesterone receptor.

Absence of estrogen receptor (ER) and progesterone receptor (PR) is the hallmark of most hormone-independent breast cancers. Previous studies demonstrated that reactivation of PR expression in hormone-independent MDA-MB-231 breast cancer cells enabled progesterone to suppress cell growth both in vitro and in vivo. We determined the whole genomic effect of progesterone in PR-transfected MDA-MB-231 cells. We identified 151 progesterone-regulated genes with expression changes > 3-fold after 24 hr treatment. Most are novel progesterone target genes. Real-time RT-PCR analysis of 55 genes showed a 100% confirmation rate. Twenty-six genes were regulated at both 3 and 24 hr. Studies using translation inhibitor suggest that most of the 26 genes are primary progesterone target genes. Progesterone consistently suppressed the expression of genes required for cell proliferation and metastasis and increased the expression of many tumor-suppressor genes. Progesterone also consistently decreased the expression of DNA repair and chromosome maintenance genes, which may be part of the mechanism leading to cell cycle arrest. These data suggest potential usefulness of progestin in combating ER-negative but PR-positive breast cancer and indicate that progesterone can exert a strong anticancer effect in hormone-independent breast cancer following PR reactivation. The identification of many novel progesterone target genes open up new avenues for in-depth elucidation of progesterone-mediated molecular networks.

Breast Neoplasms↗

PubMedDate not supplied

Virulence gene regulation in pathogenic Escherichia coli.

The ability to regulate gene expression throughout the course of an infection is important for the survival of a pathogen in the host. Thus, virulence gene expression responds to environmental signals in many complex ways. Frequently, global regulatory factors associated with specific regulators co-ordinate expression of virulence genes. In this review, we present well-described regulatory mechanisms used to co-ordinate the expression of virulence factors by pathogenic Escherichia coli with a relative emphasis on diseases caused by E. coli in animals. Many of the virulence-associated genes of pathogenic E. coli respond to environmental conditions. The involvement of global regulators, including housekeeping regulons and virulence regulons, specific regulators and then sensor regulatory systems involved in virulence, is described. Specific regulation mechanisms are illustrated using the regulation of genes encoding for fimbriae, curli, haemolysin and capsules as examples.

Animals↗

PubMed1995

Gene regulation by antisense DNA produced in vivo.

Antisense technology has been widely used for regulating gene expression. Single-stranded RNA or DNA complementary to a target mRNA can inhibit the translation of the mRNA. Antisense RNA is produced in vivo, while antisense DNA is chemically synthesized as an oligonucleotide, which is extracellularly added to the cells. To maintain the effect of antisense DNA, a synthetic oligonucleotide has to be constantly added to the system. An advantage of antisense DNA over antisense RNA is that the target mRNA hybridized with the antisense DNA can be specifically digested by ribonuclease H. Here, we attempted to produce in vivo short single-stranded DNAs complementary to a specific mRNA. We demonstrate that such antisense oligodeoxyribonucleotide of a desired sequence can be produced in Escherichia coli using a retron, a bacterial retroelement, as a vector and that the antisense DNA thus produced in vivo can effectively inhibit the expression of a specific E. coli gene, such as the gene for the major outer membrane lipoprotein.

Bacterial Outer Membrane Proteins↗

PubMed2005

Identification and evaluation of NO-regulated genes by differential analysis of primary cDNA library expression (DAzLE).

Nitric oxide (NO) has numerous physiological roles in the cell. One of the actions of NO is gene regulation through protein modification and signal transduction. In neurons, NO can be produced from neuronal NO synthase, which is activated by calcium following N-methyl-D-aspartate (NMDA) receptor activation. Differential analysis of cDNA library expression (DAzLE) was used to identify differentially expressed genes by NO. Fundamentally, this technique combines differential hybridization to isolate genes whose expression is differentially regulated with microarray to analyze the expression of the isolated genes. The expression of genes identified by the DAzLE method is verified further by quantitative real-time polymerase chain reaction (RT-PCR) and/or Northern blot analysis. The high selectivity and sensitivity of this technique for detecting differentially expressed gene transcripts enable the investigation and identification of a panel of genes that are regulated by NO.

Animals↗

PubMed2002

Novel genes regulated by the insulin sensitizer rosiglitazone during adipocyte differentiation.

Thiazolidinediones (TZDs) are a new class of compounds that improve insulin sensitivity in type 2 diabetic patients as well as in rodent models of this disease. These compounds act as ligands for a member of the nuclear hormone receptor superfamily, peroxisome proliferator-activated receptor-gamma (PPAR-gamma), which is highly expressed in adipose tissue and, moreover, has been shown to play an important role in adipocyte differentiation. The strong correlation between the antidiabetic activity of TZDs and their ability to activate PPAR-gamma suggests that PPAR-gamma, through downstream-regulated genes, mediates the effects of TZDs. In this report, we present the isolation and characterization of 81 genes, encoding proteins of known function, differentially expressed during TZD-stimulated differentiation of 3T3-L1 cells. By the use of different reverse- Northern blot techniques, the differential expression of 50 of these genes could be verified, and 21 genes were specifically regulated by a potent TZD during the course of adipocyte differentiation, whereas no effect of a PPAR-gamma antagonist could be observed in mature adipocytes. The differential expression of a large fraction of the isolated genes was also shown to occur in white adipose tissue of ob/ob mice treated with rosiglitazone; combined, our results suggest that an important effect of rosiglitazone in adipose tissue is based on activation of PPAR-gamma in preexisting preadipocytes found among the mature adipocytes, resulting in subsequent adipocyte differentiation.

3T3 Cells↗

PubMed2007

Expression profiling of BEN regulated genes in mouse embryonic fibroblasts.

BEN is a member of the TFII-I family of helix-loop-helix transcription factors. Both TFII-I and BEN are involved in gene regulation through interactions with tissue-specific transcription factors and chromatin remodeling complexes. Identification of the downstream target genes of TFII-I proteins is critical in delineating the regulatory effects of these proteins. In this study, we conducted a microarray analysis to determine gene expression alterations following the overexpression of BEN in primary mouse embryonic fibroblasts (MEFs). We found the BEN-dependent modulation in the expression of large groups of genes representing a wide variety of functional categories including genes important in the immune response, cell cycle, transcriptional regulation and cell signaling. A set of genes identified by the microarray analysis was validated by independent real-time PCR analysis. Among upregulated genes were Shrm, Tgfb2, Ube2l6, G1p2, Ccl7 while downregulated genes were Folr1, Tgfbr2, Csrp2, and Dlk1. These results support a versatile function of TFII-I proteins in vertebrate physiology and lead to an increased understanding of the BEN-dependent molecular events.

Animals↗

PubMed2002

Jak3-regulated genes: DNA array analysis of concanavalin a-interleukin-2-activated chicken T cells treated with a specific jak3 inhibitor.

Janus kinase 3 (Jak3) is important in the activation and proliferation of lymphoid cells and binds to the common gamma subunit of several cytokine receptors, including the interleukin-2 (IL-2) receptor (IL-2R). DNA arrays were used to measure mRNA levels of a large number of genes regulated by signaling through the Jak3 tyrosine kinase pathway by blocking concanavalin A (ConA)-IL-2-activated chicken splenic T cells with a specific Jak3 inhibitor (WHI-P154). Of the 635 genes detected by arrays containing about 1200 cDNAs, 12 were upregulated in control cells compared with inhibitor-treated cells, and 6 were expressed at higher levels in the inhibitor-treated group. By identifying genes that are directly or indirectly regulated by Jak3, we can gain insight into the roles of this key intermediate in avian T cell activation and further our understanding of intracellular signaling networks in the immune response.

Animals↗