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PubMed1989

Functional serum response elements upstream of the growth factor-inducible gene zif268.

The zif268 gene, which encodes a protein with three typical zinc finger sequences, is induced in mouse 3T3 cells by serum, phorbol 12-myristate 13-acetate platelet-derived growth factor, and fibroblast growth factor. The induction is coordinate with that of c-fos. The 5'-flanking region of zif268 contains sequences that resemble known regulatory elements, including four CC(A or T)6GG sequences similar to the core serum response elements (SREs) found upstream of c-fos and actin genes. To determine whether the zif268 SRE-like elements mediate induction, CAT (chloramphenicol acetyltransferase) plasmids with different lengths of zif268 upstream sequences were tested for inducibility in 3T3 cells by serum, platelet-derived growth factor, or phorbol 12-myristate 13-acetate. In addition, double-stranded oligonucleotides corresponding to each of the four zif268 putative SREs were tested individually for responsiveness when placed upstream of a thymidine kinase gene promoter. Each of the four SREs conferred inducibility by the agents tested, and multiple SREs resulted in greater inducibility than did a single element. Each of the zif268 SREs also competed with the c-fos SRE for binding by serum response factor present in HeLa cell nuclear extract. We conclude that the zif268 SRE-like sequences are functional and probably account for the coordinate induction of zif268 and c-fos.

Animals↗
PubMed2000

Alteration of cyclic adenosine monophosphate response element binding protein in rat brain after hypoglycemic coma.

In the current study, the temporal and regional changes of the transcription factor cyclic adenosine monophosphate response element binding protein (CREB) were investigated in rat brains subjected to 30 minutes of hypoglycemic coma followed by varied periods of recovery using Western blot and confocal microscopy. The total amount of CREB was not altered in any area examined after coma. The level of the phosphorylated form of CREB decreased during coma but rebounded after recovery. In the relatively resistant areas, such as the inner layers of the neocortex and the inner and outer blades of the dentate gyms (DG), phospho-CREB increased greater than the control level after 30 minutes of recovery and continued to increase up to 3 hours of recovery. In contrast, little or no increase of phospho-CREB was observed during the recovery period in the outer layers of the neocortex and at the tip of the DG, that is, regions that are selectively vulnerable to hypoglycemic insults. The current findings suggest that a neuroprotective signaling pathway may be more activated in the resistant regions than in the vulnerable ones after hypoglycemic coma.

Animals↗
PubMed2003

Changes of phosphorylation of cAMP response element binding protein in rat nucleus accumbens after chronic ethanol intake: naloxone reversal.

AIM: To study the changes in the expression and phosphorylation of cAMP response element binding protein (CREB) in the rat nucleus accumbens after chronic ethanol intake and its withdrawal. METHODS: Ethanol was given in drinking water at the concentration of 6 % (v/v), for one month. Changes in the levels of CREB and phospho-CREB (p-CREB) protein in the nucleus accumbens were measured by immunohistochemistry methods. RESULTS: Ethanol given to rats in drinking water decreased the level of p-CREB protein in the nucleus accumbens (-75 %) at the time of exposure to ethanol. The decrement of p-CREB protein in the nucleus accumbens remained at 24 h (-35 %) and 72 h (-28 %) of ethanol withdrawal, which recovered toward control level after 7 d of ethanol withdrawal. However, chronic ethanol, as well as ethanol withdrawal failed to produce any significant alteration in the level of CREB protein in the nucleus accumbens. Naloxone (alone) treatment of rats had no effect on the levels of CREB and p-CREB protein in the nucleus accumbens. However, when naloxone was administered concurrently with ethanol treatment, it antagonized the down-regulation of p-CREB protein in the nucleus accumbens (142 %) of rats exposed to ethanol. CONCLUSION: A long-term intake of ethanol solution down-regulates the phosphorylation of CREB in the nucleus accumbens, and those changes can be reversed by naloxone, which may be one kind of the molecular mechanisms associated with ethanol dependence.

Alcoholism↗
PubMed2004

Negative glucocorticoid receptor response elements and their role in glucocorticoid action.

The glucocorticoid receptor (GR) belongs to the steroid hormone receptor subclass of nuclear receptors and controls physiological processes through activation and repression of specific target genes. The ligand-activated receptor dimer activates gene expression by binding to specific DNA sequences (glucocorticoid response element, GRE) in the promoter regions of glucocorticoid-regulated genes. In contrast to the regulation of these classical GREs, the repression of negatively regulated target genes is mediated by negative GREs (nGRE), composite GREs or by transrepression. Due to their broad therapeutic spectrum and superior therapeutic effects glucocorticoids (GCs) are the most effective drugs used for the treatment of acute and chronic inflammatory diseases. Unfortunately, long term systemic therapy with GCs is restricted due to their metabolic side effects. It is assumed that transrepression of transcription factors such as AP-1 and NF-kappa B is the main mechanism by which glucocorticoids mediate their anti-inflammatory activity, whereas the side effects of GCs are mainly mediated by GR-DNA-interaction either by activation or by negative regulation of gene expression. While trans-repression has been characterized in detail, the molecular mechanisms of DNA-dependent cis-repression remain unclear. In this review, we focus on current knowledge about nGRE-mediated target gene repression and the relevance and function of these genes for glucocorticoid action. Negative GREs contribute to the regulation of the hypothalamic-pituitary-adrenal (HPA) axis (POMC and CRH), bone (osteocalcin) and skin (keratins) function, inflammation (IL-1beta), angiogenesis (proliferin) and lactation (prolactin). The discovery of the underlying mechanisms, especially the comparison to positive GREs and trans-repression may help in the future to discover and analyze novel selective GR agonists.

Animals↗
PubMed1997

Action potential-dependent regulation of gene expression: temporal specificity in ca2+, cAMP-responsive element binding proteins, and mitogen-activated protein kinase signaling.

Specific patterns of neural impulses regulate genes controlling nervous system development and plasticity, but it is not known how intracellular signaling cascades and transcriptional activation mechanisms can regulate specific genes in response to specific patterns of action potentials. Studies using electrical stimulation of mouse dorsal root ganglion neurons in culture show that the temporal dynamics of intracellular signaling pathways are an important factor. Expression of c-fos varied inversely with the interval between repeated bursts of action potentials. Transcription was not dependent on a large or sustained increase in intracellular Ca2+, and high Ca2+ levels separated by long interburst intervals (5 min) produced minimal increases in c-fos expression. Levels of the transcription factor cAMP-responsive element binding protein (CREB), phosphorylated at Ser-133, increased rapidly in response to brief action potential stimulation but remained at high levels several minutes after an action potential burst. These kinetics limited the fidelity with which P-CREB could follow different patterns of action potentials, and P-CREB levels were not well correlated with c-fos expression. The extracellular-regulated kinase (ERK) mitogen-activated protein kinases (MAPK) also were stimulated by action potentials of appropriate temporal patterns. Bursts of action potentials separated by long intervals (5 min) did not activate MAPK effectively, but they did increase CREB phosphorylation. This was a consequence of the more rapid dephosphorylation of MAPK in comparison to CREB. High expression of c-fos was dependent on the combined activation of the MAPK pathway and phosphorylation of CREB. These observations show that temporal features of action potentials (and associated Ca2+ transients) regulate expression of neuronal genes by activating specific intracellular signaling pathways with appropriate temporal dynamics.

Action Potentials↗
PubMed2006

Identification of peroxisome-proliferator responsive element in the mouse HSL gene.

Hormone-sensitive lipase (HSL) catalyzes the rate-limiting step of lipolysis in adipose tissue. Several studies suggest that protein phosphorylation regulates the HSL enzymatic activity. On the other hand, the precise mechanism of the transcriptional regulation of the HSL gene remains to be elucidated. Here, we identified a functional peroxisome-proliferator responsive element (PPRE) in the mouse HSL promoter by reporter assay in CV-1 cells using serial deletion and point mutants of the 5'-flanking region. Chromatin immunoprecipitation (ChIP) analysis revealed that both peroxisome-proliferator activated receptor (PPARgamma) and retinoid X receptor (RXRalpha) interacted with the region. Binding of the PPARgamma/RXRalpha heterodimer to the PPRE sequence was also confirmed by electrophoretic mobility shift assay. These results indicate that the HSL gene is transcriptionally regulated by PPARgamma/RXRalpha heterodimer, and suggest that a cis-acting element regulates the HSL gene expression.

3T3-L1 Cells↗
PubMed2001

Androgen receptor signalling: comparative analysis of androgen response elements and implication of heat-shock protein 90 and 14-3-3eta.

Androgen receptor (AR) signalling was analysed using as models the cysteine-rich secretory protein-1 (CRISP-1) and CRISP-3 gene promoters, which are differentially regulated by androgen in vivo and contain multiple potential androgen response elements. Using electrophoretic mobility shift assay, we identified several elements with differing affinities for the AR at positions -3706, -1270, -1253 and -350 of the CRISP-1 promoter and at positions -369 and -349 of the CRISP-3 promoter. The strongest binding was observed for the -1253 element of CRISP-1. In transactivation assays using a PC-3 cell line stably transfected with the AR (PC-3/AR), the -1253 element placed as two or four copies upstream of the TK minimal promoter yielded a strong induction of luciferase reporter gene activity in the presence of the androgen methyltrienolone (R1881). In the context of the CRISP promoters a 2-fold induction by R1881 was measured for the CRISP-3 upstream region whereas only limited effects were noted for the CRISP-1 upstream region. The androgenic stimulation of the p(-1253 ARE)(4x)-TK-luciferase reporter construct was dose-dependently inhibited by geldanamycin and radicicol, two compounds that selectively interact with the chaperone protein, heat-shock protein 90. Cotransfection with an expression vector for the 14-3-3eta protein markedly enhanced the androgen-dependent stimulation. These results emphasize the influence of promoter context on androgen regulation and the importance of AR-associated proteins.

14-3-3 Proteins↗
PubMed2004

A HOXA10 estrogen response element (ERE) is differentially regulated by 17 beta-estradiol and diethylstilbestrol (DES).

The molecular mechanisms by which estrogens regulate developmental gene expression are poorly understood. While 17 beta-estradiol is normally present at high concentrations in pregnancy, exposure to the estrogen diethylstilbestrol (DES) in utero induces developmental anomalies of the female reproductive tract. HOX gene expression is altered by DES, leading to abnormal Müllerian duct differentiation. The mechanism of ligand-specific regulation of HOX gene expression by estrogens has not been characterized. To elucidate the molecular mechanism underlying ligand-specific estrogen regulation of HOXA10 expression, we characterized regulatory regions of the human HOXA10 gene. We identified an estrogen response element (ERE) in the human HOXA10 gene that mediated differential ligand-specific estrogen-responsive transcriptional activation. Deletional analysis and reporter expression assays identified two EREs, ERE1 and ERE2, each of which drove estrogen-responsive reporter expression in the Ishikawa human uterine endometrial adenocarcinoma cell line. ERE1 drove reporter expression maximally. This ERE bound ERalpha and ERbeta, and formed a complex that included SRC-1, but not CBP, N-CoR or SMRT. HOXA10 ERE1 drove luciferase reporter activity to eightfold the level driven by the consensus ERE in response to estradiol in Ishikawa cells. While most EREs demonstrate similar transcriptional activity in response to DES or estradiol, here estradiol induced four- to sevenfold greater reporter activity than did DES from HOXA10 ERE1. DES did not alter ER or SRC-1 binding to HOXA10 ERE1. HOXA10 ERE1 therefore demonstrated ligand specificity distinct from the consensus ERE, and unrelated to changes in ER or coactivator/corepressor binding. The ligand specificity of the HOXA10 ERE may explain the molecular mechanism by which DES leads to reproductive anomalies; differential ligand-specific activation of HOX genes may be a molecular mechanism by which DES signaling leads to inappropriate HOX expression and to developmental patterning distinct from that induced by estradiol.

Base Sequence↗
PubMed2002

Identification of an additional hypoxia responsive element in the glyceraldehyde-3-phosphate dehydrogenase gene promoter.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional enzyme overexpressed in many tumors and induced by hypoxia in normal and malignant cells. The degree to which hypoxia transcriptionally activates GAPDH is cell type specific. The GAPDH promoter region contains a hypoxia responsive element (HRE) consisting of a hypoxia inducible factor-1 (HIF-1) consensus binding site plus adjacent sequence [Graven et al. (1999) Biochim. Biophys. Acta 1447, 208-218]. Using transient transfection experiments with the GAPDH promoter region linked to a luciferase reporter gene, we found that GAPDH was transcriptionally activated by hypoxia in each of three human prostate cancer cell lines tested, with the greatest level of induction in the most differentiated cell line. Using sequence analysis of the GAPDH promoter region, we identified a novel HRE distinct from the previously characterized one that consists of two consensus HIF-1 sites arranged as inverted repeats separated by 5 bp. Hypoxia transcriptionally activated a promoter construct in which the previously characterized HRE was mutated and the novel HRE remained intact. Heterologous promoter constructs containing only one or two copies of the novel HRE plus a minimal promoter consisting of a TATA box drove hypoxia inducible expression of the luciferase reporter gene in transient transfection assays. Mutation of HIF-1 sites within the novel HRE resulted in complete loss of function.

Base Sequence↗
PubMed1995

Activation of the interferon-inducible enzymes, 2',5'-oligoadenylate synthetase and PKR by human T-cell leukemia virus type I Rex-response element.

In vitro-synthesized human T-cell leukemia virus type 1 (HTLV-I) Rex response element (Rex-RE) activates the interferon-induced 2',5'-oligoadenylate synthetase (2-50AS) in a dose-dependent manner. In addition, Rex-RE at 1 microgram/ml activates a second interferon-induced enzyme, p68 kinase (PKR); however, at 50 micrograms/ml, Rex-RE inhibits PKR activity. Poly(rl)-poly(rC) (10 micrograms/ml) dissociates the ribonucleoprotein complexes, Rex-RE/2-5OAS, or Rex-RE/PKR, whereas poly(rC) (100 micrograms/ml) does not, indicating the presence of high affinity interactions between Rex-RE and these two enzymes. To further characterize the interaction of Rex-RE with 2-5OAS and PKR, [32P]Rex-RE was uv-cross-linked to 2-5OAS and PKR present in interferon-treated HeLa cell extracts. The affinity of Rex-RE to highly purified 40-kDa human recombinant 2-5OAS was determined to be Kd = 4.7 nM. The relevance of these results to the pathogenesis of HTLV-I-associated adult T-cell leukemia/lymphoma is discussed.

2',5'-Oligoadenylate Synthetase↗
PubMed1994

Differential effects of c-jun and CREB on c-AMP response element activation by Ha-ras.

We have previously shown that a Long Terminal Repeat (LTR) of the Intracisternal A-type Particle (IAP) element was activated by ras oncogenes. Here we show that, like the somatostatin CRE (som CRE) and the collagenase TPA Response Element (coll TRE), the IAP CRE is activated by c-jun and that Val 12 Ha-ras cooperates with c-jun to activate these motifs. Neither jun-B nor jun-D activated the IAP CRE, although they were able to act on the som CRE and the coll TRE and to synergize with ras. The CREB factor activated both CREs and modestly inhibited the coll TRE, but diminished the effect of ras on the coll TRE. Finally, forskolin was shown to cooperate with Ha-ras to activate the CRE and the coll TRE. Taken together, these results show that CREB is not involved in ras activation of the CRE and suggest that c-jun is at least one of the elements implicated in this phenomenon.

3T3 Cells↗
PubMed2007

Cyclic nucleotide response element binding (CREB) protein activation is involved in K562 erythroleukemia cells differentiation.

K562 are human erythroleukemia cells inducible to differentiate into megakaryocytic or erythroid lineage by different agents. Cyclic nucleotide Response Element Binding (CREB) protein, a nuclear transcription factor which mediates c-AMP signaling, is a potential candidate involved in the occurrence of erythroid differentiation and adaptive response. Here we investigated signaling events in K562 cells induced with 30 microM hemin to undergo erythroid differentiation. CREB activation was detected early 1 h after hemin treatment and up to 4 and 6 days of treatment, when K562 terminal differentiation occurs together with caspase-3 maximal activation and PARP degradation. It was interesting to note that after hemin treatment in the presence of SB203580, p38 MAP kinase specific inhibitor, a reduced rate of CREB phosphorylation as well as a lower percentage of CD71/Gly+ (Glycophorin A) cells were detectable, demonstrating the p38 MAP kinase dependency of these phenomena. All in all these results document a novel relationship between CREB activation and differentiation-related apoptotic cell death and assign a role to p38 MAP kinase pathway in determining these events in K562 erythroleukemia cells.

Apoptosis↗
PubMed2001

[The study on the shear stress responsive element in endothelial cells].

Vascular endothelial cells, by virtue of their unique anatomical position, are constantly exposed to the fluid mechanical forces generated by flowing blood. The fluid forces could influence endothelial cell's gene expression. At a molecular level, fluid shear stress is known to increase or decrease the expression of a wide variety of genes. The shear stress responsive element (SSRE) was proposed after the identification of the first SSRE, the GAGACC sequence identified in the platelet-derived growth factor (PDGF) B chain promoter and subsequently identified in other genes whose promoters respond to shear stress. In addition, there are the existence of other positive shear responsive regulatory elements. There is a report on the activation of these promoters in vitro and in vivo and propose an application of these mechanically inducible promoters in the treatment of vascular diseases.

Animals↗
PubMed2002

Mechanism of secalonic acid D-induced inhibition of transcription factor binding to cyclic AMP response element in the developing murine palate.

Regulation of gene expression via the protein kinase A (PKA) pathway is mediated through Ser133 phosphorylation of the transcription factor (TF), cAMP response element (CRE) binding protein (CREB). Secalonic acid D (SAD), a mycotoxin causing cleft palate (CP), induces phosphorylation of palatal CREB in vivo. SAD-induced increase in phosphoCREB (pCREB), however, is associated with decreased binding of TF to CRE in vivo. Mechanism(s) involved in these two effects of SAD were studied using palatal nuclear extracts (PNE). Stimulation of CREB phosphorylation by SAD was confirmed in vitro in both cell culture and cell-free systems, and this phosphorylation was not altered by currently known CREB kinase (PKA, CaMK, MEK, p38MAPK, PKC) or phosphatase inhibitors. SAD-induced increase in pCREB, however, was associated with decreased TF binding to CRE in vitro. Two-dimensional gel analysis ruled out additional inhibitory phosphorylations. Addition of SAD to PNE following an increase in PKA-phosphorylated CREB resulted in reduced TF binding to CRE. Further, SAD was shown to bind directly to phosphorylated nuclear proteins (pCREB) with greater affinity. In addition, the inhibitory effect of SAD occurred with CRE of proliferating cell nuclear antigen (PCNA) gene. These studies confirm that stimulation of CREB phosphorylation by SAD does not involve sites other than Ser133 and is mediated by a novel kinase. They also indicate that SAD directly binds to CREB to inhibit its binding to CRE of genes such as PCNA. This effect could lead to reduced palatal mesenchymal cell number, smaller palatal shelf, and thus CP.

Animals↗
PubMed1996

Prolactin induction of the alpha 2-Macroglobulin gene in rat ovarian granulosa cells: stat 5 activation and binding to the interleukin-6 response element.

alpha 2-Macroglobulin (alpha 2M) is expressed at high levels in the corpus luteum of pregnant rats in response to PRL and rat placental lactogens. These studies document that PRL induction of alpha 2M mRNA occurs rapidly in granulosa cells differentiated to the preovulatory phenotype in the presence of FSH and steroid, is hormone specific [induced by PRL but not by LH or interleukin-6 (IL-6)], and involves tyrosine kinase activity. To analyze the cellular signaling events stimulated by PRL, transient transfections of granulosa cells and electrophoretic mobility shift assays were done using the IL-6 response element (IL-6RE) of the alpha 2M promoter. The IL-6RE consists of two gamma-activating like sequences (GAS) that bind the acute phase response factor (APRF/Stat 3) in rat liver and the mammary gland factor (MGF/Stat 5) from mammary tissue. By transfecting various alpha 2M promoter-luciferase reporter transgenes into the granulosa cell cultures, we show that the GAS-like sites together with the minimal -48 base pairs of the alpha 2M promoter can confer PRL inducibility to the luciferase reporter gene. These same GAS-like sequences of the alpha 2M promoter were used to analyze the DNA-binding activity of proteins in whole cell extracts prepared from differentiated granulosa cells exposed to PRL for 0.25, 0.5, 4, and 20 h. PRL rapidly stimulated the binding of a specific protein to labeled alpha 2M GAS-like oligonucleotide, and this PRL-induced binding activity was shown to contain Stat 5 but not Stat 1 or Stat 3, using specific antibodies in the electrophoretic mobility shift assays. Because both Stat 5 and Stat 3 proteins are present in the whole cell extracts of differentiated granulosa cells, PRL appears to activate detectable amounts of Stat 5 (and not Stat 3). Thus, the initial induction of the alpha 2M gene by PRL in differentiated rat granulosa cells involves, at least in part, the activation (tyrosine phosphorylation?) of Stat 5.

Animals↗
PubMed1999

Xenobiotic-responsive element for the transcriptional activation of the rat Cu/Zn superoxide dismutase gene.

Cu/Zn superoxide dismutase (SOD1) catalyzes the dismutation of superoxide radicals produced from biological oxidation and environmental stresses. A number of xenobiotics are toxic because they generate free radicals, such as superoxide and hydroxyl radicals, through a redox cycle. The xenobiotic responsive element (XRE) was located between the nt -268 and -262 region of the 5'-flanking sequence of the SOD1 gene. Functional analyses of this element by deletion, mutations, and heterologous promoter systems confirmed that the expression of the SOD1 gene was induced by a xenobiotic through the XRE. Gel mobility shift assays showed the xenobiotic inducible binding of the receptor-ligand complex to XRE. The cytoplasmic fraction from nontreated HepG2 cells also contains the factor as a cryptic form and prominently reveals its DNA-binding activity by incubation with betaNF in vitro. These results suggest that the XRE participates in the induction of the rat SOD1 gene by xenobiotics.

Animals↗
PubMed2005

Decoy androgen-responsive element DNA can inhibit androgen receptor transactivation of the PSA promoter gene.

Chemotherapy, hormonal therapy, or surgery may cause devastating toxic or other side effects. Androgen receptors (ARs) in the cytoplasm are activated by binding with androgen. Androgen-activated ARs bind to a specific genomic DNA sequence, the androgen-responsive element (ARE), and initiate gene expression at the transcriptional level. Even without androgen activation, ARs may have a role in androgen-refractory prostate cancer. Thus, inhibition of AR activity may have therapeutic value. We applied a genetic reporter of the Dual-Luciferase Assay System to test whether a short double-stranded genomic DNA containing prostate-specific antigen (PSA) ARE sequence as decoy DNA would inhibit the function of activated AR. A 21-mer phosphorothioated PSA ARE decoy DNA was synthesized, with a plasmid vector containing the PSA promoter upstream from a luciferase gene, the reporter gene. The promoter and reporter were co-transfected into a human prostate cancer cell line PC3-M with the aid of Lipofectamin 2000. After 24 hr exposure to androgens, the cells were lysed and luciferase activity measured to determine the ARE decoy inhibitory effect on the function of ARs. Luciferase activity was reduced significantly in the ARE decoy transfected cells but not with inactive control decoy. The results demonstrate that ARE decoy DNA can effectively suppress androgen-activated ARs in prostate cancer cells and indicate the potential utility of decoy DNA for developing a novel therapy for prostate cancer.

Androgen Receptor Antagonists↗
PubMed2001

Impact of CpG methylation on structure, dynamics and solvation of cAMP DNA responsive element.

Methylation of CpG motifs in DNA is involved in the control of gene expression and in several other epigenic effects. It suppresses also the immuno-stimulation properties of bacterial or viral DNAs that contain CPGS: However, effects of methylation on the DNA structure and dynamics are not clear. Here we carried out a 10 ns MD simulation, confronted to an NMR analysis, of a hexadecanucleotide with the cAMP responsive element (CRE) DNA methylated at its center: d(GAGATGAmCGTCATCTC)(2) (CREmet). Methylation does not introduce significant structure modification but reduces the dynamics. Molecular mechanics and generalized Born solvation energy calculations showed that the stiffness of CREmet arises from both a restriction of the conformational space by the bulky methyl groups and a folding of DNA around the hydrophobic methyls. The latter effect is favored when the GpA steps belonging to the TGA binding half-sites adopt the BII conformation. The inability of the methylated DNAs to interact with their protein partners-either transcription factors for gene regulation or a Toll-like receptor for immunostimulation-could result from both the obstacle created by methyls, preventing crucial interactions, and the loss of DNA flexibility, reducing its adaptability. Results are discussed in the light of NMR and crystallographic data.

Base Sequence↗