Fibroblast growth factor-8b-stimulated myogenic cell proliferation is suppressed by the promyelocytic leukemia gene.
TL;DR: It is believed that PML functions as a stress-response gene in G8 cells rather than as a gene normally involved in regulating muscle development, as it significantly inhibited FGF-8b-stimulated cell proliferation and inhibited AP-1 and E-box transactivation.
Abstract: Muscle cell growth is regulated by growth-promoting and -inhibiting factors. In this study, the physiological effects of fibroblast growth factor (FGF)-8b and the promyelocytic leukemia (PML)
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TL;DR: The hypothesis that Ankrd2 may be involved in sensing stress signals and linking these to muscle gene regulation is strengthened by showing that it not only binds the tumor suppressor protein p53 both in vitro and in vivo but also enhances the up-regulation of the p21(WAFI/CIPI) promoter by p53.
148 citations
TL;DR: It is demonstrated that FGF8 and FGF18 signal through divergent pathways in ovarian granulosa cells, despite reportedly similar receptor activation patterns.
41 citations
TL;DR: The ability of Pien Tze Huang to protect the liver from damage is attained through its ability to modulate the activity of important signal transduction pathways, including AP1, CRE and NFkappaB responsive elements.
Abstract: Pien Tze Huang, a traditional Chinese medicine, has been extensively used as a therapeutic drug in the treatment of liver diseases. In this study, we have examined its ability to protect the liver from carbon tetrachloride (CCl4)-induced damage in the mouse. Histological observations revealed that CCl4 treatment induced extensive degenerative changes in the hepatocytes surrounding the central veins of the liver. However, these changes were much reduced by more than 28% in mice fed with 0.5 mg of Pien Tze Huang/g body weight/dose (3 doses over 36 hr) prior to CCl4 treatment. The effects of Pien Tze Huang were then further investigated in a hepatoma cell line. Flow analysis showed that it had no significant effects on cell proliferation. When the ability of Pien Tze Huang to influence various response elements of important signal transduction pathways was examined in the hepatoma cell line, it was found that Pien Tze Huang stimulated an increase in the response of AP1, CRE and NFkappaB responsive elements. The transcriptional factors of these responsive elements are known to play important roles in regulating cell death and survival. We thus postulate that the ability of Pien Tze Huang to protect the liver from damage is attained through its ability to modulate the activity of these important signal transduction pathways.
26 citations
TL;DR: It is proposed that HSV-1 triggers FGF activity in the CNS for a modulation of tissue response upon infection and uses the viral protein ICP0 for the induction of FGF-expression in CNS cells.
Abstract: Herpes simplex virus-1 (HSV-1) infections of the central nervous system (CNS) can result in HSV-1 encephalitis (HSE) which is characterized by severe brain damage and long-term disabilities. Different cell types including neurons and astrocytes become infected in the course of an HSE which leads to an activation of glial cells. Activated glial cells change their neurotrophic factor profile and modulate inflammation and repair. The superfamily of fibroblast growth factors (FGFs) is one of the largest family of neurotrophic factors comprising 22 ligands. FGFs induce pro-survival signaling in neurons and an anti-inflammatory answer in glial cells thereby providing a coordinated tissue response which favors repair over inflammation. Here, we hypothesize that FGF expression is altered in HSV-1-infected CNS cells. We employed primary murine cortical cultures comprising a mixed cell population of astrocytes, neurons, microglia, and oligodendrocytes. Astrocyte reactivity was morphometrically monitored by an automated image analysis algorithm as well as by analyses of A1/A2 marker expression. Altered FGF expression was detected by quantitative real-time PCR and its paracrine FGF activity. In addition, HSV-1 mutants were employed to characterize viral factors important for FGF responses of infected host cells. Astrocytes in HSV-1-infected cortical cultures were transiently activated and became hypertrophic and expressed both A1- and A2-markers. Consistently, a number of FGFs were transiently upregulated inducing paracrine neurotrophic signaling in neighboring cells. Most prominently, FGF-4, FGF-8, FGF-9, and FGF-15 became upregulated in a switch-on like mechanism. This effect was specific for CNS cells and for a fully functional HSV-1. Moreover, the viral protein ICP0 critically mediated the FGF switch-on mechanism. HSV-1 uses the viral protein ICP0 for the induction of FGF-expression in CNS cells. Thus, we propose that HSV-1 triggers FGF activity in the CNS for a modulation of tissue response upon infection.
13 citations
Cites background from "Fibroblast growth factor-8b-stimula..."
...Alternatively, FGF expression may be induced via ICP0-mediated degradation of promyelocytic leukemia protein (PML) [67] which also suppresses FGF-8 expression [68]....
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TL;DR: The role of FGF8 and FGF18 in ovarian and uterine function is described, and potential differences between rodents and ruminants have been highlighted especially with respect to FGF 18 signalling within the ovarian follicle.
Abstract: Several growth factor families have been shown to be involved in the function of the female reproductive tract. One subfamily of the fibroblast growth factor (FGF) superfamily, namely the FGF8 subfamily (including FGF17 and FGF18), has become important as Fgf8 has been described as an oocyte-derived factor essential for glycolysis in mouse cumulus cells and aberrant expression of FGF18 has been described in ovarian and endometrial cancers. In this review, we describe the pattern of expression of these factors in normal ovaries and uteri in rodents, ruminants and humans, as well as the expression of their receptors and intracellular negative feedback regulators. Expression of these molecules in gynaecological cancers is also reviewed. The role of FGF8 and FGF18 in ovarian and uterine function is described, and potential differences between rodents and ruminants have been highlighted especially with respect to FGF18 signalling within the ovarian follicle. Finally, we identify major questions about the reproductive biology of FGFs that remain to be answered, including (1) the physiological concentrations within the ovary and uterus, (2) which cell types within the endometrial stroma and theca layer express FGFs and (3) which receptors are activated by FGF8 subfamily members in reproductive tissues.
10 citations
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TL;DR: It appears that Fgf8 is structurally the most complex member of the FGF family described to date, with at least seven transcripts encoding a family of secreted FGF8 proteins with different N termini.
Abstract: Evidence is accumulating that members of the FGF gene family provide signals that act locally to regulate growth and patterning in vertebrate embryos. In this report, we provide a detailed analysis of the mouse Fgf8 gene. We have mapped the Fgf8 locus to the distal region of mouse chromosome 19, and sequenced the 5' coding region of the gene. Our data identify a new coding exon, and locate multiple splice donor and splice acceptor sites that can be used to produce at least seven transcripts encoding a family of secreted FGF8 proteins with different N termini. From these results, it appears that Fgf8 is structurally the most complex member of the FGF family described to date. In the embryo, many of the regions in which Fgf8 RNA is localized are known to direct outgrowth and patterning, including the apical ectodermal ridge of the limb bud, the primitive streak and tail bud, the surface ectoderm overlying the facial primorida and the midbrain-hindbrain junction, suggesting that FGF8 may be a component of the regulatory signals that emanate from these regions.
1,222 citations
TL;DR: Exogenous addition to bulk cell cultures of small antisense oligomers inhibits mitogen-induced c-myc protein expression in human T lymphocytes and prevents S phase entry and Interestingly, c- myc antisense treatment did not inhibit G0 to G1 traversal as assessed by morphologic blast transformation, transcriptional activation of the IL-2R and TfR genes, or induction of 3H-uridine incorporation.
Abstract: Initiation of T-lymphocyte proliferation by mitogen or antigen involves a cascade of gene activation events. Thus, by the time mitogen-activated T cells have reached the G1/S interface, many genes that are transcriptionally silent in GO, like the c-myc, IL-2, IL-2 receptor (IL-2R) and transferrin receptor (TfR) genes, have been transcriptionally activated1–4. To understand the role of the individual genes in the activation process, one must be able to interfere specifically with the expression or function of each particular gene product. In this way, by blocking the IL-2R with an antibody, it has been demonstrated that IL-2/IL-2R interaction is required to induce TfR expression in activated T cells3. When the function or expression of intracellular proteins is to be blocked, however, the need to introduce antibodies into the cytoplasm of viable cells, although possible5–7, is a limiting factor. We have taken another approach, namely the exogenous addition to bulk cell cultures of small antisense oligomers. Sequence-specific anti-sense oligodeoxyribonucleotides have been reported to inhibit intracellular viral replication without interfering with cellular protein synthesis8,9. Similarly, rabbit globin mRNA translation in a cell-free system and in rabbit reticulocytes has been inhibited by oligomers complementary to the globin mRNA initiation codon region10. Recently, a pentadecadeoxyribonucleotide complementary to the initiation codon and four downstream codons of human c-myc mRNA was reported to inhibit the proliferation of the human leukaemic cell line HL-60 specifically11. We report here that the same c-myc complementary oligonuelectide inhibits mitogen-induced c-myc protein expression in human T lymphocytes and prevents S phase entry. Interestingly, c-myc antisense treatment did not inhibit G0 to G1 traversal as assessed by morphologic blast transformation, transcriptional activation of the IL-2R and TfR genes, or induction of 3H-uridine incorporation.
673 citations
TL;DR: It is demonstrated that Pml is a mediator of multiple apoptotic signals, and implicate inhibition of apoptosis in the pathogenesis of APL.
Abstract: The PML
gene of acute promyelocytic leukaemia (APL) encodes a cell growth and tumour suppressor, however, the mechanisms by which PML suppresses tumorigenesis are poorly understood. We show here that Pml is required for Fas- and caspase-dependent DNA-damage–induced apoptosis. We also found that Pml is essential for induction of programmed cell death by Fas, tumour necrosis factor α (TNF), ceramide and type I and II interferons (IFNs). As a result, Pml
–/–
mice and cells are protected from the lethal effects of ionizing radiation and anti-Fas antibody. Pml is required for caspase 1 and caspase 3 activation upon exposure to these stimuli. The PML-RARα fusion protein of APL renders haemopoietic progenitor cells resistant to Fas-, TNF- and IFN-induced apoptosis with a lack of caspase 3 activation, thus acting as a Pml dominant-negative product. These results demonstrate that Pml is a mediator of multiple apoptotic signals, and implicate inhibition of apoptosis in the pathogenesis of APL.
587 citations
TL;DR: Results indicate that PML is a critical component of the RA pathway and that disruption of its activity by the PML-RARalpha fusion protein may be important in APL pathogenesis.
Abstract: The PML gene is fused to the retinoic acid receptor α (RARα) gene in chromosomal translocations associated with acute promyelocytic leukemia (APL). Ablation of murine PML protein by homologous recombination revealed that PML regulates hemopoietic differentiation and controls cell growth and tumorigenesis. PML function was essential for the tumor-growth–suppressive activity of retinoic acid (RA) and for its ability to induce terminal myeloid differentiation of precursor cells. PML was needed for the RA-dependent transactivation of the p21WAF1/CIP1 gene, which regulates cell cycle progression and cellular differentiation. These results indicate that PML is a critical component of the RA pathway and that disruption of its activity by the PML-RARα fusion protein may be important in APL pathogenesis.
519 citations
TL;DR: Conditional alleles of myc are created by fusing the hormone-binding domain of the human oestrogen receptor gene to the 5' or the 3' end of human myc to create two chimaeric genes, designated mycer and ermyc, that encode proteins that bind oestrogens with high affinity.
Abstract: The human proto-oncogene myc encodes a nuclear phosphoprotein whose primary biochemical function is still unknown. To facilitate further study of that function, we have created conditional alleles of myc by fusing the hormone-binding domain of the human oestrogen receptor gene to the 5' or the 3' end of human myc. The two chimaeric genes, designated mycer and ermyc, encode proteins that bind oestrogen with high affinity. Expression of one of the genes, mycer, transforms a rat fibroblast cell line in a tightly oestrogen-dependent manner. Transformation is dependent on the presence of a functional myc gene in the chimaera and is reversible upon removal of the hormone. The chimaeric genes will be useful tools to study the mechanisms by which Myc affects cellular phenotype. Recently, chimaeras between the adenovirus E1A protein and the hormone binding domain of the rat glucocorticoid receptor were shown to activate transcription in a manner characteristic for E1A, but in a hormone regulated manner. We therefore asked whether the same strategy could be applied to the product of myc.
492 citations