Biomedical subjects

Lorenz Poellinger

Publications and source records attributed to Lorenz Poellinger.

At least 19 recordsLinked to original sources

PubMed2006

HIF1alpha delays premature senescence through the activation of MIF.

Premature senescence in vitro has been attributed to oxidative stress leading to a DNA damage response. In the absence of oxidative damage that occurs at atmospheric oxygen levels, proliferation of untransformed cells continues for extended periods of time. We have investigated the role of the hypoxia-inducible factor 1alpha (HIF1alpha) transcription factor in preventing senescence in aerobic and hypoxic conditions. Using embryonic fibroblasts from a conditional HIF1alpha knockout mouse, we found that loss of HIF1alpha under aerobic conditions significantly accelerated the onset of cellular senescence, and decreased proliferation under hypoxia. Furthermore, we identify the macrophage migration inhibitory factor (MIF) as a crucial effector of HIF1alpha that delays senescence. Inhibition of MIF phenocopies loss of HIF1alpha. Our findings highlight a novel role for HIF1alpha under aerobic conditions, and identify MIF as a target responsible for this function.

Aerobiosis↗

PubMed2006

Degradation of the hypoxia-inducible factor 1alpha: where does it happen?

Adaptive responses to hypoxia are essential for the survival of all organisms. Under hypoxic conditions, transcription of a large group of genes relevant for oxygen homeostasis is induced by the hypoxia-inducible factor-1 (HIF-1). These genes encode proteins that enable the cells to adapt to limiting oxygen levels by increasing oxygen delivery through induction of angiogenesis or erythropoiesis and producing ATP under anaerobic conditions. The stability of HIF-1alpha protein is also target of O2 regulation. At normoxia HIF-1alpha is hydroxylated at specific proline residues by a recently identified family of prolyl hydroxylases. Hydroxylated HIF-1alpha is recognized by the Von Hippel-Lindau tumor suppressor gene product (pVHL) as an ubiquitylation substrate that leads to proteasomal-dependent degradation of HIF-1alpha. We have recently demonstrated that the major subcellular compartment where degradation of HIF-1alpha occurs is dependent on the levels of proteasomal activity and on the localization of HIF-1alpha. Furthermore we have shown that the localization of HIF-1alpha degradation is a cell type-characteristic parameter. These observations indicate new levels of complexity in the regulation of HIF-1alpha degradation.

Animals↗

PubMed2006

Hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha are expressed in kaposi sarcoma and modulated by insulin-like growth factor-I.

PURPOSE: Neoangiogenesis is essential for tumor development. Hypoxia-inducible factor (HIF), a transcriptional factor composed of two subunits (alpha and beta), plays a key role in this process, activating proangiogenic factors such as vascular endothelial growth factor (VEGF). The HIF alpha subunits are critically regulated by oxygen and are also modulated by growth factors. Kaposi sarcoma (KS) is a highly vascular tumor that releases large amounts of VEGF and for which we have recently described an essential role for the insulin-like growth factor (IGF) system. We therefore investigated the expression of HIF alpha subunits in biopsies from KS tumors and their modulation by IGF-I in KSIMM, a KS cell line. RESULTS: Both HIF-1alpha and HIF-2alpha were expressed in KS biopsies in all tumoral stages. HIF-1alpha immunopositivity increased through the tumor development with highest expression in the late nodular stages. In KSIMM cells, IGF-I induced accumulation of both HIF alpha subunits. The induction suggests a translation mechanism as documented by cycloheximide chase experiment coupled with constant RNA levels as evaluated by quantitative real-time PCR. IGF-I-induced HIF alpha accumulation was followed by an increase in HIF function as assessed both by reporter gene assay and by induction of endogenous target gene expression (VEGF-A). Specific blockade of IGF-I receptor with alphaIR3 antibody or with picropodophyllin, a specific IGF-IR tyrosine kinase inhibitor, diminishes the basal and IGF-I-dependent induction of both HIF alpha congeners. CONCLUSION: These novel findings show the coupling between the IGF and HIF signaling in KS and suggest a coordinated contribution by these pathways to the characteristic vascular phenotype of this tumor.

Basic Helix-Loop-Helix Proteins↗

PubMed2006

The constitutively active Ah receptor (CA-Ahr) mouse as a potential model for dioxin exposure--effects in vital organs.

The dioxin/aryl hydrocarbon receptor (AhR) mediates most, if not all, toxic effects of dioxins and functions as a ligand-activated transcription factor regulating transcription of a battery of genes. In order to study the mechanisms behind the toxicity of ligands of the Ah receptor we have created a transgenic mouse model expressing a constitutively active Ah receptor (CA-AhR). The mutant Ah receptor is expressed and functionally active in all organs studied. The purpose of the present study was to characterize histopathologically, the phenotype of the CA-AhR with regard to the liver, kidney, lung, heart, spleen and thymus of male and female transgenic CA-AhR mice. Moreover, cell-specific activity of the CA-AhR using up-regulation of the AhR target gene CYP1A1 as a marker, was also examined. The relative weight of liver, kidney and heart were increased while relative thymus weight was decreased. Furthermore, slight morphological lesions of the liver, kidney and spleen was seen. Expression of CYP1A1 was found in cells corresponding to endothelial cells in all of the organs studied. In some tissues additional cell types, such as hepatocytes, renal tubuli cell and Clara cells expressed CYP1A1. Both the effects on organ weights and the cellular expression of CYP1A1 in CA-AhR mice correspond well to observations in TCDD-exposed mice. In conclusion, this characterization further support that the CA-AhR mouse is a useful model for life-long continuous low-level activity of the AhR, i.e. the dioxin exposure situation of humans of the general population.

Animals↗

PubMed2006

Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype.

In neuroblastoma specimens, HIF-2alpha but not HIF-1alpha is strongly expressed in well-vascularized areas. In vitro, HIF-2alpha protein was stabilized at 5% O2 (resembling end capillary oxygen conditions) and, in contrast to the low HIF-1alpha activity at this oxygen level, actively transcribed genes like VEGF. Under hypoxia (1% O2), HIF-1alpha was transiently stabilized and primarily mediated acute responses, whereas HIF-2alpha protein gradually accumulated and governed prolonged hypoxic gene activation. Knockdown of HIF-2alpha reduced growth of neuroblastoma tumors in athymic mice. Furthermore, high HIF-2alpha protein levels were correlated with advanced clinical stage and high VEGF expression and predicted poor prognosis in a clinical neuroblastoma material. Our results demonstrate the relevance of HIF-2alpha in neuroblastoma progression and have general tumor biological implications.

Animals↗

PubMed2006

Cell-type-specific regulation of degradation of hypoxia-inducible factor 1 alpha: role of subcellular compartmentalization.

The hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcription factor that mediates adaptive cellular responses to decreased oxygen availability (hypoxia). At normoxia, HIF-1 alpha is targeted by the von Hippel-Lindau tumor suppressor protein (pVHL) for degradation by the ubiquitin-proteasome pathway. In the present study we have observed distinct cell-type-specific differences in the ability of various tested pVHL-interacting subfragments to stabilize HIF-1 alpha and unmask its function at normoxia. These properties correlated with differences in subcellular compartmentalization and degradation of HIF-1 alpha. We observed that the absence or presence of nuclear localization or export signals differently affected the ability of a minimal HIF-1 alpha peptide spanning residues 559 to 573 of mouse HIF-1 alpha to stabilize endogenous HIFalpha and induce HIF-driven reporter gene activity in two different cell types (primary mouse endothelial and HepG2 hepatoma cells). Degradation of HIF-1 alpha occurred mainly in the cytoplasm of HepG2 cells, whereas it occurs with equal efficiency in nuclear and cytoplasmic compartments of primary endothelial cells. Consistent with these observations, green fluorescent protein-HIF-1 alpha is differently distributed during hypoxia and reoxygenation in hepatoma and endothelial cells. Consequently, we propose that differential compartmentalization of degradation of HIF-1 alpha and the subcellular distribution of HIF-1 alpha may account for cell-type-specific differences in stabilizing HIF-1 alpha protein levels under hypoxic conditions.

Amino Acid Sequence↗

PubMed2005

Regulation of transactivation function of the aryl hydrocarbon receptor by the Epstein-Barr virus-encoded EBNA-3 protein.

EBNA-3 is one of the Epstein-Barr virus (EBV)-encoded nuclear antigens that is indispensable for immunoblastic transformation and sustained proliferation of B-lymphocytes. The molecular mechanisms responsible for the function of EBNA-3 are poorly understood. We previously found that EBNA-3 interacts with an immunophilin-like protein XAP2/ARA9/AIP, which in mammalian cells is known to interact with the latent aryl hydrocarbon receptor (AhR). AhR is a ligand-inducible transcription factor that mediates cellular responses to environmental pollutants, such as 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD). In this study, we show that EBNA-3 interacts specifically with AhR. The stability of this interaction is determined by the activation state of AhR and its association with XAP2. We and others have demonstrated that XAP2 retains the nonactivated AhR in the cell cytoplasm. However, in the presence of TCDD, the effect of XAP2 on the intracellular localization of AhR was counter-acted by EBNA-3, resulting in nuclear translocation of the AhR. In addition, EBNA-3 enhanced transactivation function by the ligand-activated AhR in cells, as assessed by reporter gene assays. Our data suggested that EBNA-3 plays a role in facilitating the ligand-dependent AhR activation process. Following activation of the AhR, we also observed that EBNA-3 counteracted the inhibitory effect of TCDD on the growth of EBV-carrying lymphoblasts. Taken together, our studies revealed a novel interaction between EBV- and AhR-dependent cellular pathways that control cell proliferation and survival.

Active Transport, Cell Nucleus↗

PubMed2005

Role of CYP3A4 in the regulation of the aryl hydrocarbon receptor by omeprazole sulphide.

Cross-talk between nuclear receptors involved in the control of drug metabolism is being increasingly recognised as a source of drug side effects. Omeprazole is a well known activator of the aryl hydrocarbon receptor (AhR). We investigated the regulation of AhR by omeprazole-sulphide, a degradation metabolite of omeprazole, using CYP1A mRNA induction, reporter gene assay, receptor DNA binding, ligand binding, nuclear translocation, trypsin digests, and drug metabolism analysis in mouse Hepa-1c1c7, human HepG2 cells and primary human hepatocytes. Omeprazole-sulphide is a pure antagonist of AhR in Hepa-1c1c7 and HepG2 hepatoma cell lines. In Hepa-1c1c7 cells, omeprazole-sulphide is a ligand of AhR, inhibits AhR activation to a DNA-binding form, induces a specific pattern of AhR trypsin digestion and inhibits AhR nuclear translocation and subsequent degradation in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. However, in highly differentiated primary human hepatocytes treated with rifampicin an agonist of the pregnane X receptor (PXR), omeprazole-sulphide behaves as an agonist of AhR. Inhibition of drug metabolizing enzymes by ketoconazole restores the antagonist effect of omeprazole-sulphide. Metabolic LC/MS analysis reveals that omeprazole-sulphide (AhR antagonist) is efficiently converted to omeprazole (AhR activator) by cytochrome P450 CYP3A4, a target gene of PXR, in primary human hepatocytes but not in hepatoma cells in which PXR is not expressed. This report provides the first evidence for a cross-talk between PXR/CYP3A4 and AhR. In addition, it clearly shows that conclusions drawn from experiments carried out in cell lines may lead to erroneous in vivo predictions in man.

Active Transport, Cell Nucleus↗

PubMed2005

Stabilized HIF-1alpha is superior to VEGF for angiogenesis in skeletal muscle via adeno-associated virus gene transfer.

Therapeutic angiogenesis provides a potential alternative for the treatment of cardiovascular ischemic diseases. Vascular endothelial growth factor (VEGF) is an important component of the angiogenic response to ischemia. Here we used adeno-associated virus (AAV) gene delivery to skeletal muscle to examine the effects of VEGF vs. a stabilized form of hypoxia-inducible factor-1alpha (HIF-1alpha). The recombinant AAVs were injected into mouse tibialis anterior muscle, and their effects were analyzed by immunohistochemistry and functional assays. These analyses showed that stabilized HIF-1alpha markedly increase capillary sprouting and proliferation, whereas VEGF164 or VEGF120 induced only proliferation of endothelial cells without formation of proper capillary structures. The Evans Blue permeability assay indicated that, unlike VEGF, HIF-1alpha overexpression did not increase vascular leakiness in the transduced muscle. Doppler ultrasound imaging showed that vascular perfusion in the HIF-1alpha treated muscles was significantly enhanced when compared to the controls and not further improved by co-expression of the arteriogenic growth factors angiopoietin-1 or platelet-derived growth factor-B. Our results show that AAV-mediated transduction of a stabilized form of HIF-1alpha can circumvent the problems associated with overexpression of individual angiogenic growth factors. HIF-1alpha should thus offer a potent alternative for pro-angiogenic gene therapy.

Animals↗

PubMed2005

TCR engagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells.

Peripheral T cells encounter rapid decrease in oxygen tension because they are activated by Ag recognition and migrate into inflammatory sites or tumors. Activated T cells, therefore, are thought to have such machineries that enable them to adapt to hypoxic conditions and execute immune regulation in situ. We have recently shown that survival of CD3-engaged human peripheral blood T cells is prolonged under hypoxic conditions and hypoxia-inducible factor-1 (HIF-1) and its target gene product adrenomedullin play a critical role for the process. It is also shown that hypoxia alone is not sufficient, but TCR-mediated signal is required for accumulation of HIF-1alpha in human peripheral T cells. In the present study, we showed that TCR engagement does not influence hypoxia-dependent stabilization but stimulates protein synthesis of HIF-1alpha, most possibly via PI3K/mammalian target of rapamycin system, and that expression of HIF-1alpha and its target genes is blocked by treatment with rapamycin. Since some of those gene products, e.g., glucose transporters and phosphoglycerokinase, are considered to be essential for glycolysis and energy production under hypoxic conditions and adequate immune reaction in T cells, this TCR-mediated synthesis of HIF-1alpha may play a pivotal role in peripheral immune response. Taken together, our results may highlight a novel aspect of downstream signal from Ag recognition by TCR and a unique pharmacological role of rapamycin as well.

Antibodies, Monoclonal↗

PubMed2005

The dioxin/aryl hydrocarbon receptor mediates downregulation of osteopontin gene expression in a mouse model of gastric tumourigenesis.

The dioxin/aryl hydrocarbon receptor functions as a ligand-activated transcription factor regulating transcription of a battery of genes encoding primarily drug-metabolizing enzymes. Expression of a constitutively active mutant of the aryl hydrocarbon receptor (CA-AhR) in transgenic mice results in development of stomach tumours, correlating with increased mortality. We have used suppression subtractive hybridization techniques followed by macroarray analysis to elucidate which genes are differentially expressed during this process. In the glandular stomach of CA-AhR mice, we observed decreased mRNA expression of osteopontin (OPN), a noncollagenous protein of bone matrix that is also involved in several important functions including regulation of cytokine production, macrophage accumulation, cell motility and adhesion. Downregulated expression of OPN during tumour development was confirmed by RT-PCR and RNA blot analysis. Immunohistochemical analysis showed that this decrease was confined to the corpus region, correlating with the restricted localization of the tumours. Decreased OPN mRNA expression was also observed in other organs of CA-AhR mice. Taken together, these results show that OPN is negatively regulated by the dioxin receptor, and that downregulation of its expression correlates with development of stomach tumours in mice expressing a constitutively active mutant of dioxin receptor.

Animals↗

PubMed2005

Physiological activation of hypoxia inducible factor-1 in human skeletal muscle.

The human hypoxia inducible factor 1 (HIF-1) system is activated under various pathological conditions, yet less is known about its physiological regulation in healthy human tissue. We have studied the effect of exercise on the activation of HIF-1 in human skeletal muscle. Employing a model where oxygen consumption increases and oxygen tension can be manipulated, nine healthy male subjects performed 45 min of one-legged knee-extension exercise. Biopsies were taken before, directly after, and 30, 120, and 360 min after exercise. Exercise led to elevated HIF-1alpha protein levels and a more prevalent nuclear staining of HIF-1alpha. Interestingly, a concurrent decrease in von Hippel-Lindau tumor suppressor protein (VHL) levels was detected in some subjects. Moreover, exercise induced an increase in the DNA binding activity of HIF-1alpha. Characterization of gene expression by real-time PCR demonstrated that the HIF-1 target genes VEGF and EPO were activated. VEGF mRNA was further increased when blood flow to the exercising leg was restricted. In conclusion, these data clearly demonstrate that physical activity induces the HIF-1-mediated signaling pathway in human skeletal muscle, providing the first evidence that human HIF-1alpha can be activated during physiologically relevant conditions.

Adolescent↗

PubMed2005

HIF-2alpha expression in human fetal paraganglia and neuroblastoma: relation to sympathetic differentiation, glucose deficiency, and hypoxia.

Solid tumors are frequently necrotic and hypoxic due to poor vascularization. Tumor cells adapt to hypoxia by modulating their phenotype. Key players in this process are the hypoxia-inducible factors (HIF-1alpha to 3alpha). HIFs are also expressed during normal development; for example, HIF-2alpha is specifically expressed and appears to be involved in the development of the murine sympathetic nervous system (SNS). Here, we demonstrate that HIF-2alpha protein is selectively present in human fetal week 8.5 SNS paraganglia. Neuroblastoma is derived from SNS precursors. In a subset of neuroblastomas, a spontaneous neuronal to neuroendocrine differentiation occurs in areas adjacent to necrotic zones. As HIF-2alpha activity has been associated not only with hypoxic but also with hypoglycemic conditions, we have investigated putative effects of hypoxia, glucose depletion, and HIF-2alpha on the neuroblastoma phenotype. HIF-2alpha was detected in hypoxic and in well-oxygenized neuroblastoma cells and tissue, presumably reflecting their embryonic features. With regard to differentiation, hypoxic cells lost their neuronal/neuroendocrine features and gained marker gene expression associated with an immature, neural crest-like phenotype. Low glucose potentiated the effect of hypoxia. These findings suggest that poorly vascularized neuroblastomas become immature and maintain a more aggressive phenotype, which possibly could involve a sustained stabilization and activation of HIF-2alpha.

Base Sequence↗

PubMed2005

Hypoxia requires notch signaling to maintain the undifferentiated cell state.

In addition to controlling a switch to glycolytic metabolism and induction of erythropoiesis and angiogenesis, hypoxia promotes the undifferentiated cell state in various stem and precursor cell populations. Here, we show that the latter process requires Notch signaling. Hypoxia blocks neuronal and myogenic differentiation in a Notch-dependent manner. Hypoxia activates Notch-responsive promoters and increases expression of Notch direct downstream genes. The Notch intracellular domain interacts with HIF-1alpha, a global regulator of oxygen homeostasis, and HIF-1alpha is recruited to Notch-responsive promoters upon Notch activation under hypoxic conditions. Taken together, these data provide molecular insights into how reduced oxygen levels control the cellular differentiation status and demonstrate a role for Notch in this process.

Animals↗

PubMed2004

Role of CBP in regulating HIF-1-mediated activation of transcription.

The hypoxia-inducible factor-1 (HIF-1) is a key regulator of oxygen homeostasis in the cell. We have previously shown that HIF-1alpha and the transcriptional coactivator CBP colocalize in accumulation foci within the nucleus of hypoxic cells. In our further exploration of the hypoxia-dependent regulation of HIF-1alpha function by transcriptional coactivators we observed that coexpression of SRC-1 (another important coactivator of the hypoxia response) and HIF-1alpha did not change the individual characteristic nuclear distribution patterns. Colocalization of both these proteins proved to be mediated by CBP. Biochemical assays showed that depletion of CBP from cell extracts abrogated interaction between SRC-1 and HIF-1alpha. Thus, in contrast to the current model for the assembly of complexes between nuclear hormone receptors and coactivators, the present data suggest that it is CBP that recruits SRC-1 to HIF-1alpha in hypoxic cells. We also observed that CBP, HIF-1alpha/Arnt and HIF-1alpha/CBP accumulation foci partially overlap with the hyperphosphorylated form of RNA polymerase II, and that CBP had a stabilizing effect on the formation of the complex between HIF-1alpha and its DNA-binding partner, Arnt. In conclusion, CBP plays an important role as a mediator of HIF-1alpha/Arnt/CBP/SRC-1 complex formation, coordinating the temporally and hierarchically regulated intranuclear traffic of HIF-1alpha and associated cofactors in signal transduction in hypoxic cells.

Active Transport, Cell Nucleus↗

PubMed2004

A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice.

The dioxin/aryl hydrocarbon receptor (AhR) functions as a ligand-activated transcription factor regulating transcription of a battery of genes encoding enzymes involved in drug metabolism. Known ligands include polycyclic aromatic hydrocarbons, certain polychlorinated biphenyls, and the polyhalogenated dioxins including 2,3,7,8-tetrachlorodibenzo-p-dioxin. Both polyhalogenated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin are potent promoters of rodent hepatocarcinogenesis in two-stage initiation-promotion experiments. Although several lines of evidence indicate the involvement of the AhR in toxic effects mediated by polyhalogenated biphenyls and dioxins, its involvement in tumor promotion has not been unequivocally proven. In the present study, a transgenic mouse line expressing a constitutively active AhR (CA-AhR) has been used to investigate the role of the AhR in hepatocarcinogenesis. Male AhR wild-type and CA-AhR-transgenic B6C3F1-mice were treated with a single injection of the hepatocarcinogen N-nitrosodiethylamine at 6 weeks of age and were subsequently kept untreated on control diet. Thirty five weeks after carcinogen treatment, mice were sacrificed, and the prevalence and multiplicity of liver tumors were determined. Whereas only 1 small liver tumor was observed in 15 AhR-wild-type mice, 19 tumors (two >1 cm in diameter) were present in 18 CA-AhR-transgenic mice. This result demonstrates the oncogenic potential of the activated AhR and implicates an important role of the receptor in promotion of hepatocarcinogenesis. A microarray-based gene expression-profiling analysis revealed down-regulation in the liver of CA-AhR-transgenic mice of a cluster of genes encoding heat shock proteins, including GRP78/BiP, Herp1, Hsp90, DnaJ (Hsp40) homologue B1, and Hsp105, which are important for protein folding and quality control.

Animals↗

PubMed2004

Induction of ID2 expression by hypoxia-inducible factor-1: a role in dedifferentiation of hypoxic neuroblastoma cells.

ID (inhibitor of differentiation/DNA binding) proteins, frequently deregulated in advanced human malignancies, can participate in multiple fundamental traits of cancer, such as block of differentiation, increased proliferation, tissue invasiveness, and angiogenesis. We have previously demonstrated that hypoxia decreases expression of neuronal marker genes in neuroblastoma, but induces genes expressed in the neural crest, such as ID2. Because of its involvement in normal neural crest development and its ability to inhibit proneuronal bHLH proteins, the hypoxic induction of ID2 was of particular interest. Here we report fast induction kinetics of ID2 expression in hypoxic neuroblastoma cells. The up-regulation of ID2 was abolished by addition of actinomycin D, implicating a hypoxia-driven transcriptional mechanism. Analyzing the ID2 promoter revealed several potential binding sites for hypoxia-inducible factors. Subsequent electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated two functional HIF-1 binding sites within ID2 gene regulatory sequences located at -725 and -1893 relative to the transcriptional initiation point. In transfection assays, DNA constructs of the ID2 promoter, including the functional HIF-1 binding sites, induced luciferase reporter activity in a HIF-1-specific manner. These observations demonstrate that ID2 is actively engaged by hypoxia and represents a novel HIF-1 target. Hypoxia-induced ID2 expression could play a significant role in the previously observed dedifferentiation of hypoxic neuroblastoma cells, which in a clinical setting could lead to less mature and more aggressive tumors.

5' Flanking Region↗

PubMed2004

HIF-1 and hypoxic response: the plot thickens.

Hypoxia, or lowered physiological oxygenation, is a component of many diseases. The response to decreased oxygen tensions is also an essential aspect of normal development and physiology. The hypoxic response is chiefly mediated by a single transcription factor--the hypoxia-inducible transcription factor HIF-1. The central role played by HIF-1 in hypoxia-induced transcription has made the focus of intense investigation by biologists from a wide range of disciplines. Recent developments have produced fundamental advances in our understanding of both the regulation and function of this response pathway in animals, and illustrated the potential for manipulation of the pathway for therapeutic purposes.

DNA-Binding Proteins↗