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Results for “Genes, Regulator”

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At least 145 records · Page 8Linked to original sources
PubMed2006

The neuroprotective WldS gene regulates expression of PTTG1 and erythroid differentiation regulator 1-like gene in mice and human cells.

Wallerian degeneration of injured neuronal axons and synapses is blocked in Wld(S) mutant mice by expression of an nicotinamide mononucleotide adenylyl transferase 1 (Nmnat-1)/truncated-Ube4b chimeric gene. The protein product of the Wld(S) gene localizes to neuronal nuclei. Here we show that Wld(S) protein expression selectively alters mRNA levels of other genes in Wld(S) mouse cerebellum in vivo and following transfection of human embryonic kidney (HEK293) cells in vitro. The largest changes, identified by microarray analysis and quantitative real-time polymerase chain reaction of cerebellar mRNA, were an approximate 10-fold down-regulation of pituitary tumour-transforming gene-1 (pttg1) and an approximate 5-fold up-regulation of a structural homologue of erythroid differentiation regulator-1 (edr1l-EST). Transfection of HEK293 cells with a Wld(S)-eGFP construct produced similar changes in mRNA levels for these and seven other genes, suggesting that regulation of gene expression by Wld(S) is conserved across different species, including humans. Similar modifications in mRNA levels were mimicked for some of the genes (including pttg1) by 1 mm nicotinamide adenine dinucleotide (NAD). However, expression levels of most other genes (including edr1l-EST) were insensitive to NAD. Pttg1(-/-) mutant mice showed no neuroprotective phenotype. Transfection of HEK293 cells with constructs comprising either full-length Nmnat-1 or the truncated Ube4b fragment (N70-Ube4b) demonstrated selective effects of Nmnat-1 (down-regulated pttg1) and N70-Ube4b (up-regulated edr1l-EST) on mRNA levels. Similar changes in pttg1 and edr1l-EST were observed in the mouse NSC34 motor neuron-like cell line following stable transfection with Wld(S). Together, the data suggest that the Wld(S) protein co-regulates expression of a consistent subset of genes in both mouse neurons and human cells. Targeting Wld(S)-induced gene expression may lead to novel therapies for neurodegeneration induced by trauma or by disease in humans.

Animals↗
PubMed2004

Endogenous GATA factors bind the core sequence of the tetO and influence gene regulation with the tetracycline system.

The tetracycline-regulated eukaryotic gene expression systems have been applied in numerous areas of bioscience. The systems utilize a tetracycline-responsive promoter (P(tet)) and synthetic transactivators (tTA or rtTA) that bind to the promoter in the presence or absence of doxycycline, regulating gene expression. Both the basal activity of the P(tet) and the magnitude of regulation by the system vary between cell types. In this investigation we have mapped the positions of endogenous transcription factor binding sites within the P(tet) and through deletion studies determined the portion of the promoter that contributes to basal activity. The tetracycline operator (tetO) repeats appear to be the source of basal activity and they were shown to harbor motifs for GATA transcription factors. The GATA motif is located within the central core of the tetO and so has the potential to compete with tTA and rtTA binding. The molecular interactions of endogenous and overexpressed GATA factors with the GATA motif in the tetO were demonstrated and effects on function of the tetracycline-regulated gene expression system investigated. GATA factors are widespread in embryonic tissues, are expressed within several adult cell types, and display altered expression in disease states. We suggest that endogenous GATA factor expression may influence the degree of gene regulation by the tetracycline system between different cell types. The findings of this study may have implications for the application of the tetracycline system in gene therapy.

Animals↗
PubMed2006

Effects of phosphates on the expression of tissue-nonspecific alkaline phosphatase gene and phosphate-regulating genes in short-term cultures of human osteosarcoma cell lines.

We studied the effects of phosphates on the expression of the human tissue-nonspecific alkaline phosphatase (TNSALP) gene and phosphate-regulating genes in short-term cultures of human osteoblastic osteosarcoma cell lines. When human osteosarcoma cell lines, SaOS-2, MG-63, and U(2)OS were cultured with 10 mM inorganic sodium dihydrogenphosphate, 10 mM beta-glycerophosphate, 250 microM pyridoxal phosphate, or 100 microM inorganic pyrophosphate, enzymatic activity of alkaline phosphatase began to increase at 72 h after addition of sodium dihydrogenphosphate and beta-glycerophosphate in SaOS-2 cells. Pyridoxal phosphate and pyrophosphate did not induce alkaline phosphatase activity. U(2)OS cells slightly reacted to beta-glycerophosphate, but MG-63 cells did not react on exposure to phosphates. In SaOS-2 cells, TNSALP mRNA measured by real-time RT-PCR reached a peak level at 72 h after the addition of beta-glycerophosphate. PHEX and MEPE mRNAs were also induced by beta-glycerophosphate. These results suggest that TNSALP, PHEX and MEPE were concordantly induced by beta-glycerophosphate on mineralisation.

Alkaline Phosphatase↗
PubMed2001

Identification of two estrogen regulated genes associated with growth regulation of human breast cancer.

We have identified two estrogen regulated gene products in the E(2) growth inhibited human breast cancer xenograft, T61; one showing 100% homology to the human BAC clone RP11-112E16, the other 100% homology to the human CPR3/DNJ3 gene. Verification by Northern blot analyses showed an up-regulation of the BAC clone RP11-112E16 and the CPR3/DNJ3 mRNAs upon E(2) treatment. Treatment of T61 tumors with tamoxifen, leading to static tumor growth, also increased the expression of the BAC clone RP11-112E16 and the CPR3/DNJ3 mRNAs. A similar association between growth inhibition and BAC clone RP11-112E16 and CPR3/DNJ3 mRNA induction was observed in MCF-7 cells treated with ICI 182.780. In MCF-7 cells, treatment with E(2) resulted in growth stimulation concomitant with a decrease in the BAC clone RP11-112E16 and CPR3/DNJ3 mRNA expression. Treatment with a combination of E(2) and ICI 182.780 abolished the anti-estrogen induced increase in BAC clone RP11-112E16 and CPR3/DNJ3 mRNA expression, indicating that regulation of the gene products is mediated through the ER. The association between growth inhibition and BAC clone RP11-112E16 or CPR3/DNJ3 mRNA expression was supported by high expression of both gene products in brain tissue. Further investigations are ongoing to clarify the biological function of these two gene products.

Animals↗
PubMed1990

Transvection and long-distance gene regulation.

Numerous genes contain regulatory elements located many tens of kilobases away from the promoter they control. Specific mechanisms must be required to ensure that such distant elements can find and interact with their proper targets but not with extraneous genes. This review explores the connections between transvection phenomena, the activation of domains of homeotic gene expression, position effect variegation and silencers. These various examples of long-distance effects suggest that, in all cases, related forms of chromatin packaging may be involved.

Animals↗
PubMed2001

Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells.

The PR-A and PR-B isoforms of progesterone receptors (PR) have different physiological functions, and their ratio varies widely in breast cancers. To determine whether the two PR regulate different genes, we used human breast cancer cell lines engineered to express one or the other isoform. Cells were treated with progesterone in triplicate, time-separated experiments, allowing statistical analyses of microarray gene expression data. Of 94 progesterone-regulated genes, 65 are uniquely regulated by PR-B, 4 uniquely by PR-A, and only 25 by both. Almost half the genes encode proteins that are membrane-bound or involved in membrane-initiated signaling. We also find an important set of progesterone-regulated genes involved in mammary gland development and/or implicated in breast cancer. This first, large scale study of PR gene regulation has important implications for the measurement of PR in breast cancers and for the many clinical uses of synthetic progestins. It suggests that it is important to distinguish between the two isoforms in breast cancers and that isoform-specific genes can be used to screen for ligands that selectively modulate the activity of PR-A or PR-B. Additionally, use of natural target genes, rather than "consensus" response elements, for transcription studies should improve our understanding of steroid hormone action.

Breast Neoplasms↗
PubMed2001

Cycle-regulated genes and cell cycle regulation.

The transcriptional profile of the entire Caulobacter crescentus genome over a synchronous cell cycle was recently described. The analysis reveals a stunning 553 cell-cycle-regulated genes or orfs, nearly 19% of the genome, including putative functions in virtually all biological activities. Over a quarter of these genes/orfs respond to the Caulobacter master regulator, CtrA, most of them apparently indirectly. The analysis confirms and extends earlier observations showing that many proteins involved in cell cycle functions are expressed at the cell age when they are needed. Conversely, the data suggest that proteins specifically expressed at a particular age may be involved in a process taking place then.

Bacterial Proteins↗
PubMed2005

Role of cyclic GMP in gene regulation.

Cyclic GMP is produced in response to nitric oxide and natriuretic peptides; cGMP is a key regulator of cell proliferation, differentiation, and apoptosis, and plays an important role in many (patho)physiological processes such as synaptic plasticity, angiogenesis, inflammation, and cardiac hypertrophy. The regulation of gene expression by cGMP has been recognized relatively recently, but cGMP-mediated increases or decreases in the mRNA expression of >60 different genes have been described, and gene expression profiling is just beginning to contribute to the growing list of cGMP-regulated genes. Deletion or over-expression experiments in mice involving components of the cGMP signaling pathway have contributed to our understanding of long-term effects of altered cGMP signaling, including the regulation of gene expression. We will discuss transcriptional and post-transcriptional mechanisms of gene regulation by cGMP, and review specific transcription factors and RNA binding proteins targeted by cGMP. Some of the effects of cGMP on gene expression are indirect, through cGMP modulation of other signaling pathways, e. g. mitogen-activated protein kinase pathways. However, some effects of cGMP can be directly attributed to cGMP regulation of specific transcription factors such as CREB, TFII-I or c-Fos, and are mediated by cGMP-dependent protein kinases. We will discuss specific genes regulated by cGMP in the context of their contribution to particular (patho)physiologic processes regulated by cGMP.

Animals↗
PubMed2001

The ASK1 gene regulates B function gene expression in cooperation with UFO and LEAFY in Arabidopsis.

The Arabidopsis floral regulatory genes APETALA3 (AP3) and PISTILLATA (PI) are required for the B function according to the ABC model for floral organ identity. AP3 and PI expression are positively regulated by the LEAFY (LFY) and UNUSUAL FLORAL ORGANS (UFO) genes. UFO encodes an F-box protein, and we have shown previously that UFO genetically interacts with the ASK1 gene encoding a SKP1 homologue; both the F-box containing protein and SKP1 are subunits of ubiquitin ligases. We show here that the ask1-1 mutation can enhance the floral phenotypes of weak lfy and ap3 mutants; therefore, like UFO, ASK1 also interacts with LFY and AP3 genetically. Furthermore, our results from RNA in situ hybridizations indicate that ASK1 regulates early AP3 and PI expression. These results support the idea that UFO and ASK1 together positively regulate AP3 and PI expression. We propose that the UFO and ASK1 proteins are components of a ubiquitin ligase that mediates the proteolysis of a repressor of AP3 and PI expression. Our genetic studies also indicate that ASK1 and UFO play a role in regulating the number of floral organ primordia, and we discuss possible mechanisms for such a regulation.

Arabidopsis↗
PubMed2000

Hypoxia regulates gene expression of alveolar epithelial transport proteins.

Alveolar hypoxia occurs during ascent to high altitude but is also commonly observed in many acute and chronic pulmonary disorders. The alveolar epithelium is directly exposed to decreases in O(2) tension, but a few studies have evaluated the effects of hypoxia on alveolar cell function. The alveolar epithelium consists of two cell types: large, flat, squamous alveolar type I and cuboidal type II (ATII). ATII cells are more numerous and have a number of critical functions, including transporting ions and substrates required for many physiological processes. ATII cells express 1) membrane proteins used for supplying substrates required for cell metabolism and 2) ion transport proteins such as Na(+) channels and Na(+)-K(+)-ATPase, which are involved in the vectorial transport of Na(+) from the alveolar to interstitial spaces and therefore drive the resorption of alveolar fluid. This brief review focuses on gene expression regulation of glucose transporters and Na(+) transport proteins by hypoxia in alveolar epithelial cells. Cells exposed to severe hypoxia (0% or 3% O(2)) for 24 h upregulate the activity and expression of the glucose transporter GLUT-1, resulting in preservation of ATP content. Hypoxia-induced increases in GLUT-1 mRNA levels are due to O(2) deprivation and inhibition of oxidative phosphorylation. This regulation occurs at the transcriptional level through activation of a hypoxia-inducible factor. In contrast, hypoxia downregulates expression and activity of Na(+) channels and Na(+)-K(+)-ATPase in cultured alveolar epithelial cells. Hypoxia induces time- and concentration-dependent decreases of alpha-, beta-, and gamma-subunits of epithelial Na(+) channel mRNA and beta(1)- and alpha(1)-subunits of Na(+)-K(+)-ATPase, effects that are completely reversed after reoxygenation. The mechanisms by which O(2) deprivation regulates gene expression of Na(+) transport proteins are not fully elucidated but likely involve the redox status of the cell. Thus hypoxia regulates gene expression of transport proteins in cultured alveolar epithelial type II cells differently, preserving ATP content.

Animals↗
PubMedDate not supplied

Mitogen-activated protein kinase/extracellular signal-regulated kinase induced gene regulation in brain: a molecular substrate for learning and memory?

The mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) pathway is an evolutionarily conserved signaling cascade involved in a plethora of physiological responses, including cell proliferation, survival, differentiation, and, in neuronal cells, synaptic plasticity. Increasing evidence now implicates this pathway in cognitive functions, such as learning and memory formation, and also in behavioral responses to addictive drugs. Although multiple intracellular substrates can be activated by ERKs, nuclear targeting of transcription factors, and thereby control of gene expression, seems to be a major event in ERK-induced neuronal adaptation. By controlling a prime burst of gene expression, ERK signaling could be critically involved in molecular adaptations that are necessary for long-term behavioral changes. Reviewed here are data providing evidence for a role of ERKs in long-term behavioral alterations, and the authors discuss molecular mechanisms that could underlie this role.

Animals↗
PubMed2003

MLL-mediated transcriptional gene regulation investigated by gene expression profiling.

The human mixed lineage leukemia (MLL) gene is involved in about 50 different chromosomal translocations, associated with the disease phenotype of acute leukemia. However, the normal function of MLL is less understood. Homozygous knockouts of murine Mll were embryonal lethal, while heterozygous disruption led to aberrant hox gene expression associated with skeletal malformations, growth retardation, and impaired hematopoiesis. To understand MLL functions on the molecular level, gene expression profiling experiments were performed with a pair of murine cell lines (MLL(+/+) and MLL(-/-)). Microarray hybridization experiments revealed 197 potential target genes that are differentially expressed, providing new and important clues about MLL functions.

Animals↗
PubMed2000

The genetic background modifies the effects of the obesity mutation, 'fatty', on apolipoprotein gene regulation in rat liver.

BACKGROUND: Obesity is associated with disorders of plasma lipid transport in many, but not in all obese subjects. The effects of obesity on the regulation of genes involved in plasma lipid transport may depend on specific mutations causing or contributing to obesity and/or on interactions of a specific obesity mutation with the genetic background. The 'fatty' (Glu269Pro) leptin receptor mutation causes severe obesity associated with hypertriglyceridaemia and altered hepatic apolipoprotein gene regulation in Zucker fatty rats. OBJECTIVE: To determine whether the effects of the obesity mutation 'fatty' on apolipoprotein gene regulation in rat liver depend on the genetic background. METHODS: We studied hepatic apolipoprotein (apo) A-IV, A-I, and C-III gene expression in obese rats carrying the 'fatty' mutation on the background of the Zucker or Wistar strain. RESULTS: Basal apoA-IV gene expression was increased in fatty rats of both strains, whereas apoA-I and apoC-III gene expression differed between Wistar and Zucker fatty rats: apoA-I gene transcription was reduced to half and apoC-III mRNA was increased two-fold in Wistar fatty, but not in Zucker fatty rats vs lean controls. A fish oil diet suppressed apoA-IV, but not apoA-I gene transcription in Wistar fatty rats, whereas in Zucker fatty rats apoA-IV transcription was unaffected, but apoA-I transcription was suppressed. CONCLUSIONS: Interactions of the 'fatty' leptin receptor mutation with the genetic background significantly affect the basal and diet-induced regulation of the apoA-IV, C-III and A-I genes in rat liver. The genetic background may therefore be a major determinant of the consequences of a specific obesity mutation for plasma lipid transport.

Animals↗
PubMed1991

The search for a grammatical theory of gene regulation is formally justified by showing the inadequacy of context-free grammars.

No one questions the important practical contributions of computer sciences to molecular biology. It may well be that one day theoretical contributions also will become useful. One example of this type of interdisciplinary research is the attempt to construct a grammatical theory of the regulation of gene expression. In this paper, I demonstrate that context-free grammars are inadequate for the description of regulatory properties coded in the DNA. This result is supported by data available in the literature that show changes in the specificity of the recognition between regulatory proteins and their DNA targets. This result is an important limitation for the use of statistical approaches such as information theory as a source of inspiration for a theory of gene regulation. Additionally, such a demonstration gives formal justification to the search for more elaborate grammatical models in the study of gene regulation. Some basic proposals for such grammatical approach have been presented previously.

DNA↗
PubMed1989

Gene regulation from sites near and far.

Although regulation of gene expression from distant sites would seem to have many advantages, this strategy is utilized far more frequently in eukaryotic cells than in prokaryotic cells. The inherent flexibility of DNA allows factors bound to distant regulatory sites to interact with transcription initiation factors or RNA polymerase components at the promoter of the regulated gene. Regulatory domains that are closely linked to the promoter lose this spatial flexibility, and must lie within a defined region in the vicinity of the promoter. The major drawback to regulation of gene expression from distant sites is that any gene with a promoter located within the effective radius of the regulatory factor will respond to its control. Thus, promoters of independently regulated genes must be separated by ample amounts of nonspecific DNA. Prokaryotic cells may have evolved to favor regulation of transcription from closely linked sites because this mechanism allows them to eliminate excess DNA, which may in turn enable them to achieve rapid growth in an energy-limited environment.

DNA↗