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A Philips

Publications and source records attributed to A Philips.

29 records · Page 2Linked to original sources
PubMed1997

Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells.

Within the nuclear receptor family, Nur77 (also known as NGFI-B) distinguishes itself by its ability to bind a target sequence (the NBRE) as a monomer and by its role in T-cell receptor (TCR)-induced apoptosis in T cells. We now report on a novel mechanism of Nur77 action that is mediated by homodimers. These dimers bind a Nur77 response element (NurRE), which has been identified as a target of CRH-induced Nur77 in the pro-opiomelanocortin (POMC) gene promoter. Both halves of the palindromic NurRE are required for responsiveness to physiological signals, like CRH in pituitary-derived AtT-20 cells. Similarly, in T-cell hybridomas, TCR activation induced NurRE but not NBRE reporters. The in vivo signaling function of Nur77 thus appears to be mediated by dimers acting on a palindromic response element of unusual spacing between its half-sites. This mechanism may represent the biologically relevant paradigm of action for this subfamily of orphan nuclear receptors.

Animals↗
PubMed1997

Antagonism between Nur77 and glucocorticoid receptor for control of transcription.

Two important functions of glucocorticoids (Gc), namely, suppression of immune system function and feedback repression of the hypothalamo-pituitary-adrenal (HPA) axis, are mediated through repression of gene transcription. Previous studies have indicated that this repression is exerted in part through antagonism between the glucocorticoid receptors (GR) and the AP-1 family of transcription factors. However, this mechanism could not account for repression of the pro-opiomelanocortin (POMC) gene, an important regulator of the HPA axis. Our recent identification of the orphan nuclear receptor Nur77 as a mediator of CRH induction of POMC transcription led us, in the present work, to show that Gc antagonize this positive signal at two levels. First, Gc partly blunt the CRH induction of Nur77 mRNA, and second, they antagonize Nur77-dependent transcription. GR repression is exerted by antagonism of Nur77 action on the NurRE element of the POMC gene. Gc antagonism of NurRE activity was observed in response to physiological stimuli in both endocrine (CRH induction of POMC) and lymphoid (T-cell receptor activation) cells. In transfection experiments, transcriptional activation by Nur77 and the repressor activity of liganded GR titrated each other on their cognate DNA target. In vitro binding experiments as well as mutation analysis of GR suggest that the mechanism of GR antagonism of Nur77 is very similar to that of the antagonism between GR and AP-1. The convergence of positive signals mediated by Nur77 (and also probably by related family members) and negative signals exerted by GR appears to be a general mechanism for control of transcription, since it is active in both endocrine and lymphoid cells.

Animals↗
PubMed1996

Extra low frequency electric and magnetic fields in the bedplace of children diagnosed with leukaemia: a case-control study.

This retrospective case-control study of 56 cases and 56 controls measured extra low frequency (ELF) electric and magnetic fields between 2000 h and 0800 h in the bedplaces of children with leukaemia. Mean ELF electric field (E-field) levels found in case homes of 13.9 Vm-1 (SD: 13.6) were significantly higher (P < 0.01) compared with only 7.3 Vm-1 (SD: 12.9) in controls matched for age and sex. Moreover, applying conditional logistic regression, a dose-response relationship emerged between E-field exposure and incidence: above 20 Vm-1 the relative risk was 4.69 (95% CI: 1.17-27.78; P = 0.025), whereas at levels of 10-19 Vm-1 it was 2.40 (95% CI: 0.79-8.09) and at levels of 5-9 Vm-1 it was only 1.46 (95% CI: 0.47-5.10). By contrast, similar readings of the rms ELF magnetic field found no significant case-control differences: mean levels in cases' homes of 0.070 microT (SD: 0.070) compared with 0.057 microT (SD: 0.038) in controls. Although there were imperfections in the study design, it is concluded that the importance of the E-field may have been overlooked in epidemiological studies to date.

Adolescent↗
PubMed1994

Genomic cross-talk between the estrogen receptor and growth factor regulatory pathways in estrogen target tissues.

Cell proliferation and differentiation are modulated by both estrogens and growth factors. Even though these two kinds of effectors interact with receptors localized in different compartments of the cell, their nuclear end points are often on the same genes. We review here the first evidence for transcriptional interference between these two regulatory pathways which might be essential in understanding the control of cell proliferation and invasion in human estrogen-responsive cancers.

Animals↗
PubMed1993

Estradiol increases and anti-estrogens antagonize the growth factor-induced activator protein-1 activity in MCF7 breast cancer cells without affecting c-fos and c-jun synthesis.

In estrogen receptor positive human breast cancer cells, anti-estrogens inhibit the mitogenic effect of growth factors in the absence of estrogens. As activator protein-1 (AP-1) activity is one of the first nuclear events following growth factor receptor activation, we studied the effects of estrogens and anti-estrogens on growth factor-induced AP-1 activity using transient transfection of the AP-1-responsive gene (AP-1)4-TK-CAT into MCF7 cells. The growth factor-induced AP-1 response was increased by estradiol and inhibited by anti-estrogens in conditions where growth factor-induced c-fos and c-jun mRNA levels were unchanged by hormone and anti-hormone treatments. The same regulations were obtained when the AP-1 response was directly induced by co-transfection of c-fos and c-jun expression vectors. Co-transfection of the wild-type estrogen receptor HEGO amplified both effects. Inhibition of AP-1 activity by anti-estrogens was unlikely to be explained by the presence of residual estrogens in MCF7 cells. (i) anti-estrogens inhibited AP-1 activity in conditions where they had no effect on basal ERE-mediated activity levels, whereas estradiol was as efficient in stimulating both activities. (ii) The relative efficacy of the two anti-estrogens, OH-tamoxifen and ICI 164,384 in inhibiting these two activities was different; OH-tamoxifen was more efficient in inhibiting ERE-mediated activity, whereas ICI 164,384 was more efficient in trans-repressing AP-1-mediated activity. We conclude that in conditions where c-fos and c-jun syntheses were not affected, the estrogen receptor cooperated with growth factors to stimulate the AP-1 response when activated by estrogens but inhibited AP-1-mediated transcription when occupied by anti-estrogens.

Breast Neoplasms↗
PubMed1993

Synthetic antiestrogens modulate induction of pS2 and cathepsin-D messenger ribonucleic acid by growth factors and adenosine 3',5'-monophosphate in MCF7 cells.

In MCF7 human breast cancer cells, the antiestrogens 4-hydroxy-tamoxifen and ICI 164,384 inhibit the mitogenic activity of epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). These growth factors also stimulate the expression of cathepsin-D and pS2 genes. Therefore, we studied the effects of antiestrogens on growth factor induction of pS2 and cathepsin-D mRNA. The two antiestrogens strongly inhibited the transcriptional induction of pS2 by growth factors. On the contrary, estradiol and IGF-I or EGF had an additive effect on pS2 mRNA accumulation. Growth factor induction of cathepsin-D was also inhibited by ICI 164,384. By contrast, 4-hydroxytamoxifen had an agonist effect on cathepsin-D and an additive effect on IGF-I-induced mRNA. When 12-O-tetradecanoylphorbol-13-acetate or 8-bromo-cAMP (8-Br-cAMP) was used instead of growth factors, similar effects of 4-hydroxytamoxifen and ICI 164,384 were obtained on pS2 (12-O-tetradecanoylphorbol-13-acetate and 8-Br-cAMP) and cathepsin-D (8-Br-cAMP) induction. A mechanism based on the classical competitive inhibition by antiestrogens of estrogen binding and action on the estrogen receptor was very unlikely, as 1) no antigrowth factor activity was obtained with R5020, which was a potent inhibitor of estrogen induction of pS2 and cathepsin-D mRNA; 2) in the Ishikawa endometrial cancer cell line, the cathepsin-D gene is unresponsive to estrogen, but was inhibited by antiestrogen after its induction by EGF or 8-Br-cAMP; and 3) the residual estrogen concentration in cells was too low to induce the expression of estrogen-specific genes. However, antiestrogens did not inhibit the expression of all genes induced by growth factors, as they were without effect on IGF-I induction of glyceraldehyde-3-phosphate dehydrogenase mRNA. These results demonstrate that antiestrogens can modulate the transcription of some growth factor-induced genes and strongly suggest that this effect is not due to interference with residual estrogens.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1985

Affinity purification and refined structural characterization of terminal deoxynucleotidyltransferase.

A total of 56 stable murine hybridoma monoclones that produce homogeneous antibodies against human or calf terminal deoxynucleotidyltransferase have been established. All of the antibodies exhibited specific binding to various Mr forms of terminal transferase and eight possessed neutralizing activity. Results are presented that permitted characterization of ten of these antibodies with respect to their immunoglobulin class, their recognition of calf or human terminal-transferase Mr species by immunoblotting techniques and their recognition of distinct antigenic sites. Terminal transferase was purified in a single step by using an immunoaffinity column constructed with a monoclonal antibody exhibiting a high binding affinity for the enzyme. Single monoclonal antibodies were also used to bind selectively to terminal-transferase antigen in tissue slices and individual cells.

Animals↗