Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transient focal ischemia-reperfusion in the cerebral cortex caused regional alteration of DNA-binding activities of transcription factors AP-1, CREB, Sp-1, and NF-kB. The changes were time-dependent. During the first 24 hr of reperfusion after 90 min ischemia, there was an increase in the binding activity of AP-1 only in the region surrounding the ischemic cortex. Five days after ischemia, an increase in the binding activities of CREB, Sp-1, and NF-kB, but not AP-1, was noted in the ischemic cortex, and to a lesser extent, Sp-1 and NF-kB, in the surrounding region. The binding activities of these transcription factors were reduced by hydrogen peroxide but could be restored by dithiothreitol and 2-mercaptoethanol. These results are the first demonstration of ischemia-induced differential regulation of transcription factor binding activities which are time-, region-, and redox state dependent.
 ...
PMID:Alteration of transcription factor binding activities in the ischemic rat brain. 762 34

The transcription factors controlling the complex genetic response to ischemia and their modes of regulation are poorly understood. We found that ATF-2 and c-Jun DNA binding activity is markedly enhanced in post-ischemic kidney or in LLC-PK1 renal tubular epithelial cells exposed to reversible ATP depletion. After 40 min of renal ischemia followed by reperfusion for as little as 5 min, binding of ATF-2 and c-Jun, but not ATF-3 or CREB (cAMP response element binding protein), to oligonucleotides containing either an ATF/cAMP response element (ATF/CRE) or the jun2TRE from the c-jun promoter, was significantly increased. Binding to jun2TRE and ATF/CRE oligonucleotides occurred with an identical time course. In contrast, nuclear protein binding to an oligonucleotide containing a canonical AP-1 element was not detected until 40 min of reperfusion, and although c-Jun was present in the complex, ATF-2 was not. Incubating nuclear extracts from reperfused kidney with protein phosphatase 2A markedly reduced binding to both the ATF/CRE and jun2TRE oligonucleotides, compatible with regulation by an ATF-2 kinase. An ATF-2 kinase, which phosphorylated both the transactivation and DNA binding domains of ATF-2, was activated by reversible ATP depletion. This kinase coeluted on Mono Q column chromatography with a c-Jun amino-terminal kinase and with the peak of stress-activated protein kinase, but not p38, immunoreactivity. In conclusion, DNA binding activity of ATF-2 directed at both ATF/CRE and jun2TRE motifs is modulated in response to the extreme cellular stress of ischemia and reperfusion or reversible ATP depletion. Phosphorylation-dependent activation of the DNA binding activity of ATF-2, which appears to be regulated by the stress-activated protein kinases, may play an important role in the earliest stages of the genetic response to ischemia/reperfusion by targeting ATF-2 and c-Jun to specific promoters, including the c-jun promoter and those containing ATF/CREs.
 ...
PMID:Ischemia and reperfusion enhance ATF-2 and c-Jun binding to cAMP response elements and to an AP-1 binding site from the c-jun promoter. 853 Apr 13

This article reviews findings up to the end of 1997 about the inducible transcription factors (ITFs) c-Jun, JunB, JunD, c-Fos, FosB, Fra-1, Fra-2, Krox-20 (Egr-2) and Krox-24 (NGFI-A, Egr-1, Zif268); and the constitutive transcription factors (CTFs) CREB, CREM, ATF-2 and SRF as they pertain to gene expression in the mammalian nervous system. In the first part we consider basic facts about the expression and activity of these transcription factors: the organization of the encoding genes and their promoters, the second messenger cascades converging on their regulatory promoter sites, the control of their transcription, the binding to dimeric partners and to specific DNA sequences, their trans-activation potential, and their posttranslational modifications. In the second part we describe the expression and possible roles of these transcription factors in neural tissue: in the quiescent brain, during pre- and postnatal development, following sensory stimulation, nerve transection (axotomy), neurodegeneration and apoptosis, hypoxia-ischemia, generalized and limbic seizures, long-term potentiation and learning, drug dependence and withdrawal, and following stimulation by neurotransmitters, hormones and neurotrophins. We also describe their expression and possible roles in glial cells. Finally, we discuss the relevance of their expression for nervous system functioning under normal and patho-physiological conditions.
 ...
PMID:Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins. 985 69

Two unilateral hypoxic-ischemia (HI) models (moderate and severe) in immature rat brain have been used to investigate the role of various transcription factors and related proteins in delayed neuronal death and survival. The moderate HI model results in an apoptotic-like neuronal death in selectively vulnerable regions of the brain while the more severe HI injury consistently produces widespread necrosis resulting in infarction, with some necrosis resistant cell populations showing evidence of an apoptotic type death. In susceptible regions undergoing an apoptotic-like death there was not only a prolonged induction of the immediate early genes, c-jun, c-fos and nur77, but also of possible target genes amyloid precursor protein (APP751) and CPP32. In contrast, increased levels of BDNF, phosphorylated CREB and PGHS-2 were found in cells resistant to the moderate HI insult suggesting that these proteins either alone or in combination may be of importance in the process of neuroprotection. An additional feature of both the moderate and severe brain insults was the rapid activation and/or proliferation of glial cells (microglia and astrocytes) in and around the site of damage. The glial response following HI was associated with an upregulation of both the CCAAT-enhancer binding protein alpha (microglia only) and NFkappaB transcription factors.
 ...
PMID:Neuronal death and survival in two models of hypoxic-ischemic brain damage. 1020 30

Cells respond to external stimuli by changes in gene expression that are largely dependent on transcription factors (TFs). We studied the behavior of some TFs in rat liver during ischemia, postischemic reperfusion, and heat shock. Knowledge of the conditions at the end of ischemia is essential to understand changes occurring at reperfusion. The TFs investigated are known to be typically responsive to heat shock (HSF), hypoxia (HIF-1), pro- and antioxidant conditions (AP-1), or to various environmental changes (HNF-1 and ATF/CREB family). The most relevant new information includes the following: 1) Liver ischemia activates extremely rapidly the DNA binding capacity of HSF, soon followed by analogous activation of HIF-1 and AP-1. 2) After a certain lag time from the activation of HIF-1, mRNAs accumulate for two glycolytic enzymes, in particular Aldolase A and Heme Oxygenase 1, which contain HIF-1 sequences in their promoters. 3) Reperfusion, which is known to further increase the binding of HSF and to induce NFkappaB binding, abrogates or decreases the binding of HIF-1 and AP-1, stimulated by ischemia, and activates the binding of ATF/CREB. Later on, a second peak of AP-1 binding is induced. 4) Heat shock activates both ischemia-responsive and reperfusion-responsive TFs. 5) Preliminary experiments of supergelshift reveal that the activation of AP-1 at reperfusion or upon heat shock may result from the different involvement of the component subunits.
 ...
PMID:Differential activation of some transcription factors during rat liver ischemia, reperfusion, and heat shock. 1039 95

The purpose of this review is to discuss ATF3, a member of the ATF/CREB family of transcription factors, and its roles in stress responses. In the introduction, we briefly describe the ATF/CREB family, which contains more than 10 proteins with the basic region-leucine zipper (bZip) DNA binding domain. We summarize their DNA binding and heterodimer formation with other bZip proteins, and discuss the nomenclature of these proteins. Over the years, identical or homologous cDNA clones have been isolated by different laboratories and given different names. We group these proteins into subgroups according to their amino acid similarity; we also list the alternative names for each member, and clarify some potential confusion in the nomenclature of this family of proteins. We then focus on ATF3 and its potential roles in stress responses. We review the evidence that the mRNA level of ATF3 greatly increases when the cells are exposed to stress signals. In animal experiments, the signals include ischemia, ischemia coupled with reperfusion, wounding, axotomy, toxicity, and seizure; in cultured cells, the signals include serum factors, cytokines, genotoxic agents, cell death-inducing agents, and the adenoviral protein E1A. Despite the overwhelming evidence for its induction by stress signals, not much else is known about ATF3. Preliminary results suggest that the JNK/SAPK pathway is involved in the induction of ATF3 by stress signals; in addition, IL-6 and p53 have been demonstrated to be required for the induction of ATF3 under certain conditions. The consequences of inducing ATF3 during stress responses are not clear. Transient transfection and in vitro transcription assays indicate that ATF3 represses transcription as a homodimer; however, ATF3 can activate transcription when coexpressed with its heterodimeric partners or other proteins. Therefore, it is possible that, when induced during stress responses, ATF3 activates some target genes but represses others, depending on the promoter context and cellular context. Even less is understood about the physiological significance of inducing ATF3. We will discuss our preliminary results and some reports by other investigators in this regard.
 ...
PMID:ATF3 and stress responses. 1044 Feb 33

Cyclic AMP (cAMP) response element binding protein (CREB) is a transcription factor that has been implicated in neuronal responses to ischemia. We examined the effect of global cerebral ischemia in the rat on the expression of CREB, its transcriptionally active phosphorylated form (pCREB), and the nuclear adaptor protein, CREB binding protein (CBP). Global ischemia induced the expression of pCREB and CBP in vulnerable neurons of the hippocampal CA1 sector. In primary cultures of murine cortical neurons subjected to hypoxia, CBP was selectively expressed in cells with morphologically intact cell nuclei, and not in cells with condensed or fragmented nuclei indicative of irreversibly damaged neurons. These results support a role for transcriptional activation by CREB and CBP in neuronal cell-survival programs following cerebral ischemia.
 ...
PMID:Cyclic AMP response element binding protein (CREB) and CREB binding protein (CBP) in global cerebral ischemia. 1134 20

Activating transcription factor 3 (ATF3) is a member of the CREB/ATF family of transcription factors. Previously, we demonstrated that the expression of the ATF3 gene is induced by many stress signals. In this report, we demonstrate that expression of ATF3 is induced by cardiac ischemia coupled with reperfusion (ischemia-reperfusion) in both cultured cells and an animal model. Transgenic mice expressing ATF3 under the control of the alpha-myosin heavy chain promoter have atrial enlargement, and atrial and ventricular hypertrophy. Microscopic examination showed myocyte degeneration and fibrosis. Functionally, the transgenic heart has reduced contractility and aberrant conduction. Interestingly, expression of sorcin, a gene whose product inhibits the release of calcium from sarcoplasmic reticulum, is increased in these transgenic hearts. Taken together, our results indicate that expression of ATF3, a stress-inducible gene, in the heart leads to altered gene expression and impaired cardiac function.
 ...
PMID:Transgenic mice with cardiac-specific expression of activating transcription factor 3, a stress-inducible gene, have conduction abnormalities and contractile dysfunction. 1148 22

Phosphorylation of cyclic adenosine monophosphate (AMP) response element binding protein (CREB) was examined immunohistochemically in the corpus callosum of the rat brain at various time points after 90-minute focal cerebral ischemia. Focal ischemia was induced by occlusion of the middle cerebral artery (MCA) using the intraluminal suture method. Sham animals showed that numerous oligodendrocytes (OLGs) constitutively express unphosphorylated CREB. Local cerebral blood flow (lCBF) measured by the 14C-iodoantipyrine method was reduced from 44.2 +/- 15.4 (mL 100 g(-1) min(-1)) to 18.4 +/- 3.8 and from 53.9 +/- 14.4 to 4.8 +/- 4.5 in the medial and the lateral regions of the corpus callosum, respectively, during MCA occlusion (MCAO). After release of the MCAO, lCBF recovered to the control level in each region. The medial region of the corpus callosum showed a marked increase in phosphorylated CREB-positive OLGs at 3.5 hours of recirculation, and it remained increased until 2 weeks of recirculation as it gradually declined. The activation of CREB phosphorylation in the OLGs was accompanied by expression of antiapoptotic protein bcl-2, normal staining with cresyl violet, and negative TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling) staining. Myelination detected by immunostaining with anti-myelin basic protein (MBP) antibody and anti-myelin associated glycoprotein (MAG) antibody remained normal in the medial region of the corpus callosum. The lateral region of the corpus callosum showed a significant but only transient increase in phosphorylated CREB-positive OLGs at 3.5 hours of recirculation, which was followed by a rapid decrease during the subsequent recirculation period. Expression of bcl-2 was suppressed in this region, and demyelination became apparent. These findings suggest that signal transduction through CREB phosphorylation may be closely associated with survival of OLGs and maintenance of myelination in the corpus callosum after cerebral ischemia.
 ...
PMID:Phosphorylation of cyclic adenosine monophosphate response element binding protein in oligodendrocytes in the corpus callosum after focal cerebral ischemia in the rat. 1159 95

In the acute phase of cerebral infarction, many experimental data suggest that free radicals including superoxide, hydroxy radical and nitric oxide are one of the most important factors to cause brain damage. We have clearly detected nitrotyrosine (a marker of endogenous production of peroxynitrite, which is readily produced from superoxide and nitric oxide) in neurons and intraparenchymal vascular walls during post-ischemic reperfusion. Free radical scavengers thus seem to be very promising tools of treatment, and one of them (edaravone) has recently been approved for clinical use in Japan. CREB (cyclic AMP response element binding protein) is a DNA-binding transcription factor, and its function is activated by phosphorylation of Ser133 residue. CREB plays important roles in neuronal development, synaptic plasticity and regeneration. We have found that phosphorylation of CREB is significantly and persistently increased in surviving neurons and oligodendrocytes in post-ischemic brain, while this phosphorylation is only transiently increased in neurons and oligodendrocytes which eventually die. These data suggest that CREB phosphorylation plays an important role in protection of ischemic brain tissue. Oligodendrocyte progenitor cells (OPC) remain abundant throughout the adult brain, and retain their ability to become not only mature oligodendrocytes, but also neurons. We have recently found that OPC are significantly activated and proliferate in the peri-infarct area at 1-2 weeks after ischemia, suggesting that OPC may be involved in the repair mechanisms of ischemic brain. Future targets of stroke treatment should include enhancement of intrinsic protection mechanisms such as CREB phosphorylation and activation of progenitors cells.
 ...
PMID:[Targets of treatment in the acute phase of cerebral infarction]. 1223 93


1 2 3 4 5 6 7 8 9 10 Next >>