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PubMed2002

Assessment of ecologic and biologic factors leading to hantavirus pulmonary syndrome, Colorado, U.S.A.

AIM: To understand the ecologic parameters of Sin Nombre virus (SNV; family Bunyaviridae, genus Hantavirus) infections in the deer mouse (Peromyscus maniculatus), environmental variables impacting the rodent populations, and the conditions under which SNV is amplified. This may help us understand the antecedents of human risk for developing hantavirus pulmonary syndrome (HPS) as a consequence of SNV infection. METHOD: Each 6 weeks, we trapped, measured, tagged, bled, and released rodents at three widely spaced sites in Colorado, USA: Fort Lewis (1994-2001), Molina (1994-2001), and Pinyon Canyon Maneuver Site (1995-2001). The ELISA method was used to test rodent blood samples for IgG antibody to SNV antigen. RESULTS: Where rodent species richness was high, the prevalence of infection of deer mice (as determined by the presence of antibody) with SNV was low, and vice versa. There was a higher prevalence of antibody to SNV in male than in female rodents, and seasonal differences were observed in acquisition of SNV between male and female deer mice. Long-lived infected deer mice served as transseasonal, over-winter reservoirs for the virus, providing the mechanism for its survival. CONCLUSION: Prevalence of rodent infection appears to be associated with fluctuations in deer mouse populations and, indirectly, with timing and amount of precipitation and the resulting biologic events (a trophic cascade). Together with information regarding transseasonal maintenance of SNV, seasonal differences in acquisition of SNV between sexes, group foraging, and various other factors may expand our understanding of the risk factors for acquiring HPS. Taken together and applied, we anticipate developing methods for preventing this disease as well as diseases caused by other rodent-borne viruses.

Adolescent↗

PubMed2001

Control of Ca(2+) influx by cannabinoid and metabotropic glutamate receptors in rat cerebellar cortex requires K(+) channels.

1. In the rodent cerebellum, both presynaptic CB1 cannabinoid receptors and presynaptic mGluR4 metabotropic glutamate receptors acutely depress excitatory synaptic transmission at parallel fibre-Purkinje cell synapses. Using rat cerebellar slices, we have analysed the effects of selective CB1 and mGluR4 agonists on the presynaptic Ca(2+) influx which controls glutamate release at this synapse. 2. Changes in presynaptic Ca(2+) influx were determined with the Ca(2+)-sensitive dyes fluo-4FF AM or fluo-3 AM. Five stimulations delivered at 100 Hz or single stimulations of parallel fibres evoked rapid and reproducible transient increases in presynaptic fluo-4FF or fluo-3 fluorescence, respectively, which decayed to prestimulus levels within a few hundred milliseconds. Bath application of the selective CB1 agonist WIN55,212-2 (1 microM) markedly reduced the peak amplitude of these fluorescence transients. This effect was fully reversed by the selective CB1 antagonist SR141716-A (1 microM). 3. Bath application of the selective mGluR4 agonist L-AP4 (100 microM) also caused a transient decrease in the peak amplitude of the fluorescence transients evoked by parallel fibre stimulation. 4. Bath application of the potassium channel blocker 4-AP (1 mM) totally prevented both the WIN55,212-2- and the L-AP4-induced inhibition of peak fluorescence transients evoked by parallel fibre stimulation. 5. The present study demonstrates that activation of CB1 and mGluR4 receptors inhibits presynaptic Ca(2+) influx evoked by parallel fibre stimulation via the activation of presynaptic K(+) channels, suggesting that the molecular mechanisms underlying this inhibition involve an indirect inhibition of presynaptic voltage-gated Ca(2+) channels rather than their direct inhibition.

4-Aminopyridine↗

PubMed1994

Brain stem localization of rodent esophageal premotor neurons revealed by transneuronal passage of pseudorabies virus.

BACKGROUND/AIMS: Brain stem premotor neurons control swallowing through contacts with both afferent neurons and motoneurons. The location and connectivity of premotor neurons innervating the esophagus was determined using pseudorabies virus. METHODS: In 30 rats, viral injections were made into either the cervical or subdiaphragmatic esophagus, cricothyroid muscle, or stomach. After a 48-62-hour survival, brain sections were processed immunocytochemically for the virus. RESULTS: Neuronal labeling was limited to the compact formation of the nucleus ambiguus for survivals of 48-54 hours. At 57-62-hour survivals, virus-labeled second-order neurons (premotor neurons) were localized to the central subnucleus of nucleus of the solitary tract. Injections in the cricothyroid muscle and stomach resulted in distinct patterns of motoneuronal labeling in the nucleus ambiguus and dorsal motor nucleus and premotor neuronal labeling in the nucleus of the solitary tract. CONCLUSIONS: Virus-labeled premotor neurons in the nucleus of the solitary tract occurred as a result of retrograde transport of the virus from the nucleus ambiguus because no viral antigen was present in the tractus solitarius. The esophagus is controlled by a central circuit whereby esophageal vagal afferents terminate on premotor neurons in the central subnucleus that in turn innervate esophageal motoneurons in the nucleus ambiguus.

Animals↗

PubMed2004

Central nervous system effects of the crude extract of Erythrina velutina on rodents.

The aqueous extract (AE) of Erythrina velutina prolonged the sleep duration induced by sodium pentobarbital (control: 6.4 +/- 1.2 min; extract 10 mg/kg, 47.1 +/- 3.9 min; extract 100 mg/kg, 109.4 +/- 7.2 min; F = 243, P < 0.001). In the open field, the extract at the doses of 10 and 50 mg/kg did not changed the number of crossings, rearings nor groomings. On the other hand, at the dose of 200 mg/kg it reduced the number of crossings (q = 6.25, P < 0.05) and groomings (q = 3.91, P < 0.05). When exposed during three consecutive days to the open field, the control animals showed habituation for crossings (F = 17.56, P < 0.001) and rearings (F = 14.01, P < 0.001). The same was not true for animals treated with 10 mg/kg of the extract (crossings: F = 3.59, P > 0.05; rearings: F = 3.62, P > 0.05). At the same dose, the extract blocked the acquisition of foot shock memory (P = 0.9219) when compared to the control values (P = 0.0078). Our data showed that the crude extract of Erythrina velutina at lower doses interferes with mnemonic process for different tasks, while at higher doses, the sedative and neuromuscular blocking actions are the main effects.

Animals↗

PubMed1993

Gene regulation in rodent hepatocytes during development, differentiation and disease.

The expression of genes in the liver is mostly controlled at the transcriptional level and depends on the regulatory interactions between cis-acting sequences and trans-acting molecules. Proximal promoters and distant enhancers in combination with a number of hepatocyte-enriched DNA-binding proteins and general transcription factors interact specifically with these elements and control the expression of liver-specific genes. Hepatocyte-enriched regulatory proteins have been isolated from liver nuclear extracts, characterized, and their corresponding genes have been cloned. These include the hepatocyte nuclear factors 1, 3, 4 (HNF-1,3,4), some members of the CAAAT/enhancer binding protein (C/EBP) family, and D site binding protein (DBP). These factors belong to larger families and are able to form heterodimers, perhaps with the exception of the HNF-3 family, with other members of the same family. Interestingly, the majority of the genes encoding such proteins are themselves regulated at the transcriptional level, although both transcriptional and post-transcriptional events modulate their expression during development, hepatocyte differentiation and disease, suggesting that a transcriptional cascade may play a critical role in mammalian liver development and differentiation.

Animals↗

PubMed2004

A simple pupil-independent method for recording eye movements in rodents using video.

Previous techniques using video to acquire torsional eye-movement recordings in humans have needed to control confounding effects associated with dilation of the pupil. A new pupil-independent, three-dimensional eye-movement recording method was developed to overcome the reliance on tracking the pupil by interpolating between two artificial landmarks placed on the eye. This technique reliably quantified torsional changes in angular eye position at variable amplitudes of horizontal and vertical excursion over at least a 20 degrees range. Application of this system to rodents naturally lacking a clearly defined pupil allows behavioral researchers to obtain torsion in addition to horizontal and vertical changes in angular eye position.

Algorithms↗

PubMed2003

Methylenedioxymethamphetamine (MDMA, 'ecstasy') serves as a robust positive reinforcer in a rat runway procedure.

Although 'ecstasy' (3,4-methylenedioxymethamphetamine, MDMA) is, after marijuana, the second most prevalent illegal drug of abuse in European adolescents, animal experimental evidence of MDMA's reinforcing effect has remained scarce, particularly in the rodent model, raising questions about the robustness of MDMA's reinforcing effect under controlled laboratory conditions. In the present rat runway study, Sprague-Dawley and Long-Evans rats were given the opportunity to run for intravenous injections of saline or MDMA (1 mg/kg). MDMA significantly decreased runtimes in both rat strains. Thus, MDMA's positive reinforcing effect can be demonstrated not only across rat strains but also across operant conditioning paradigms. These findings should reassure the drug abuse research community that the investigation of MDMA's reinforcing effect in the inexpensive and widely used rodent model is indeed feasible.

Animals↗

PubMed1992

The antibody repertoire in infection and vaccination with Dictyocaulus viviparus: heterogeneity in infected cattle and genetic control in guinea pigs.

The antigen recognition profiles of serum antibody from calves infected or vaccinated with irradiated Dictyocaulus viviparus larvae were analysed by immunoprecipitation of radio-iodinated in vitro-released excretory-secretory materials from live adult parasites. Immunoprecipitates were analysed by SDS-PAGE and considerable heterogeneity in antigen recognition between individual animals was observed, regardless of infection regimen. This heterogeneity was also found to occur amongst outbred guinea pigs infected with the parasite and permitted an examination of the genetics of the effect using inbred guinea pigs (Strains 2 and 13). The antibody repertoires of the two strains were distinct, with only slight variation occurring between individuals within a strain. Previous work on nematode infections in rodents has demonstrated a role for the major histocompatibility complex (MHC) in the control of the immune repertoire. If this, as is probable, holds for the guinea pig, then it can be ascribed to the MHC Class II region because Strain 2 and Strain 13 bear identical Class I alleles but disparate Class II alleles. Whilst there is no evidence to date that the efficiency of vaccination of cattle is influenced by genetic factors, the operation of vaccines based on a single or a few molecularly cloned parasite antigens might be seriously compromised by the kind of genetic restriction to the immune repertoire described here.

Animals↗

PubMed1994

The effects of radiation on the expression of a newly cloned and characterized rat cyclin B mRNA.

PURPOSE: To evaluate the hypothesis that the radiation induced G2 delay in the cell cycle is associated with radiation induced effects on cyclin B expression in a rodent cell system. METHODS AND MATERIALS: Two rodent, rat and Chinese hamster, cyclin B cDNAs were cloned and characterized. The two rodent species were 85% and 86% identical, respectively, when compared to the human cyclin B, indicating that they are the rodent homologous of cyclin B. 3.7 cells (rat embryo cells transformed by H-ras and v-myc) were synchronized and then irradiated. Flow cytometry and Northern blots were performed to evaluate the effects of radiation on cyclin expression in relation to phase of the cell cycle. RESULTS: Examination of the rodent cyclin B sequences revealed only two regions with significant divergence to the human sequence, one in the lysine rich region adjacent to the cyclin destruction box, which is the putative site for ubiquitination, and one at the C terminal end. Although many of the amino acids diverged in the lysine rich region, the positions of the lysines themselves were virtually invariant suggesting their potential importance in ubiquitination. Both rodent species were also noted to have a PEST-like sequence which occurs in the human, but not in non-mammalian cyclins cloned to date and could also potentially contribute to rapid destruction. The rat and Chinese hamster mRNAs contain much longer 3' untranslated regions than the published human sequence with multiple AUUUA and AUUU motifs which are seen in other mRNAs with rapid turnover times. This feature has not been previously found in cyclin mRNAs. In addition we have found that in the 3' region of the rodent cDNAs we find two potential polyadenylation sites suggesting that this gene may have several transcripts. Our studies suggest that multiple mechanisms of control of mammalian cyclin B destruction exist, both at the mRNA and protein level. Evidence is also provided that the levels of rat cyclin B mRNA peaks during G2/M. Irradiation is shown to induce a G2 delay in synchronized 3.7 cells, compared to unirradiated controls, and the delay is temporally related to decreased levels of cyclin B mRNA expression. Since the G2 delay induced by ionizing radiation may contribute to the ability of cells to survive irradiation, cyclin B expression may be a key component in the determination of sensitivity or resistance to radiation therapy. CONCLUSION: The isolation and characterization of two rodent cyclin B's confirm that multiple mechanisms of control of mammalian cyclin B destruction exist. Our studies show that rat cyclin B expression is influenced by radiation and is temporally related to the delay in the G2 phase induced by radiation.

Amino Acid Sequence↗

PubMed2000

Neuronal localization of sterol regulatory element binding protein-1 in the rodent and primate brain: a light and electron microscopic immunocytochemical study.

Sterol regulatory element binding proteins are membrane-bound transcription factors that activate expression of several genes controlling cellular cholesterol and fatty acid homeostasis. The present study aimed to investigate the in vivo expression of sterol regulatory element binding protein-1 in the normal rodent and primate brain, and in the brain in Niemann-Pick type C disease mice. These mutant animals have lysosomal cholesterol accumulation and progressive neurodegeneration caused by an inactivating mutation of the NPC1 gene whose protein product functions in vesicular lipid trafficking. Western blot analysis of rat hippocampal homogenates with an affinity purified rabbit polyclonal antibody directed against an internal epitope of sterol regulatory element binding protein-1 identified a major 68,000 mol. wt protein consistent with the amino-terminal, transcriptionally active fragment of sterol regulatory element binding proteins-1. Immunocytochemically, this antibody revealed dense sterol regulatory element binding protein-1 staining of nuclei and light staining of the cytoplasm of cells in the neocortex and hippocampus in the rat, mouse and monkey brain. By electron microscopy of immunogold-labeled brain sections, these densely labeled cells were found to be neurons. In contrast, normal glial cells had little or no sterol regulatory element binding protein-1 immunoreactivity even at a developmental stage (postnatal day 9) which coincides with active myelination in the rat brain. Also, in contrast to the normal mouse brain, Niemann-Pick type C mice showed reduced staining of cortical and hippocampal neuronal nuclei. Since sterol regulatory element binding protein-1 has been shown to be a transcriptional regulator of fatty acid synthesis in vivo, the current findings of a predominantly neuronal nuclear expression of the 68,000 mol. wt transcriptionally active fragment of sterol regulatory element binding protein-1 highlights the established role of phospholipid metabolites and other fatty-acid containing lipids in neuronal signal transduction and other neuronal functions. Reduced sterol regulatory element binding protein-1 expression in neurons in Niemann-Pick type C may reflect a deficiency in fatty acid synthesis that could contribute to the neuronal dysfunction in this disorder.

Animals↗

PubMed2002

Cardiac troponin T and creatine kinase MB content in skeletal muscle of the uremic rat.

BACKGROUND: The assertion that creatine kinase MB (CK-MB) and the developmental isoforms of cardiac troponin T (cTnT) are expressed by skeletal muscle in some clinical settings is an extrapolation from nonuremic rodent studies. We studied the content of CK-MB and cTnT in skeletal muscle of the renal-insufficient rat. METHODS: Skeletal muscles (gastrocnemius) were collected from both five-sixths nephrectomized rats (n = 11) and sham-operated controls (n = 11). cTnT content was analyzed by Elecsys (Roche), immunoblotting, and immunohistochemistry with antibodies M7 and M11-7 (Roche). CK isoenzymes were analyzed electrophoretically. RESULTS: Trace concentrations of cTnT were detected in some of the skeletal muscle samples [controls (3 of 11) and uremic rats (1 of 11)] at concentrations <0.01% of that detected in heart. By contrast, positive staining appeared in both groups with M11-7 by immunoblotting and immunohistochemistry. No immunoreactivity was detected in skeletal muscle using M7 in the immunoblot format, although immunoreactivity was detected by immunohistochemistry in all samples. The median percentages of CK-MB were 6.0% and 4.1% for the skeletal muscle from control and uremic rats, respectively. CONCLUSION: The detection of cTnT and CK-MB in skeletal muscle does not differ for uremic rats compared with sham-operated controls. cTnT isoforms detected by qualitative methods are not detected with the cTnT immunoassay. Observations with rodents should not necessarily be extrapolated to humans.

Animals↗

PubMed1989

Thermoregulatory patterns of two sympatric rodents: Otomys unisulcatus and Parotomys brantsii.

1. The adaptations to an arid environment in two closely related rodent species were investigated. 2. The rate of oxygen consumption (VO2), body temperature (Tb), evaporative water loss and minimal conductance in Otomys unisulcatus and Parotomys brantsii were determined under controlled conditions at ambient temperatures (Ta), ranging from 11-31 C. 3. Physiological features atypical of desert-adapted rodents include a basal metabolic rate higher than predicted by body mass, the low "lower critical temperature" and symptoms of heat stress at 31 degrees C. 4. The low Tb and wide thermoneutral zone recorded for both species are characteristic of desert rodent species. 5. These species' physiological abilities reflect their mesic phylogeny and we suggest that behaviour must play an important role in their survival in semi-arid areas.

Acclimatization↗

PubMed2002

Circadian control of neurogenesis.

The life-long addition of new neurons has been documented in many regions of the vertebrate and invertebrate brain, including the hippocampus of mammals (Altman and Das, 1965; Eriksson et al., 1998; Jacobs et al., 2000), song control nuclei of birds (Alvarez-Buylla et al., 1990), and olfactory pathway of rodents (Lois and Alvarez-Buylla, 1994), insects (Cayre et al., 1996) and crustaceans (Harzsch and Dawirs, 1996; Sandeman et al., 1998; Harzsch et al., 1999; Schmidt, 2001). The possibility of persistent neurogenesis in the neocortex of primates is also being widely discussed (Gould et al., 1999; Kornack and Rakic, 2001). In these systems, an effort is underway to understand the regulatory mechanisms that control the timing and rate of neurogenesis. Hormonal cycles (Rasika et al., 1994; Harrison et al., 2001), serotonin (Gould, 1999; Brezun and Daszuta, 2000; Beltz et al., 2001), physical activity (Van Praag et al., 1999) and living conditions (Kemperman and Gage, 1999; Sandeman and Sandeman, 2000) influence the rate of neuronal proliferation and survival in a variety of organisms, suggesting that mechanisms controlling life-long neurogenesis are conserved across a range of vertebrate and invertebrate species. The present article extends these findings by demonstrating circadian control of neurogenesis. Data show a diurnal rhythm of neurogenesis among the olfactory projection neurons in the crustacean brain, with peak proliferation during the hours surrounding dusk, the most active period for lobsters. These data raise the possibility that light-controlled rhythms are a primary regulator of neuronal proliferation, and that previously-demonstrated hormonal and activity-driven influences over neurogenesis may be secondary events in a complex circadian control pathway.

Animals↗

PubMed2005

Changes in serum leptin levels in strenuous exercise and its relation to zinc deficiency in rats.

This study aimed to investigate the possible changes in serum leptin concentration caused by acute exercise and the effects of zinc deficiency on these changes. Forty male rats were divided into control-control, control-exercise, zinc-deficient-control, and zinc-deficient-exercise groups (10 rats in each). Control-exercise and zinc-deficient-exercise groups performed exercise at 6 m/min speed on a rodent treadmill for 60 min or until exhaustion. All rats were decapitated 48 h after the exercise, and blood samples were collected to determine serum leptin and zinc levels. Serum leptin levels in the exercise groups were lower than in the control groups. Leptin levels in the zinc-deficient-control group were lower than in the control-control group. The mean exercise time of control-exercise group was significantly longer than the zinc-deficient-exercise group. We conclude that serum leptin levels significantly decrease both 48 h after strenuous exercise and in the zinc-deficient rats, and there is a further decrease in leptin levels when rats fed on a zinc-deficient diet performed exercise.

Animals↗

PubMed2006

Controlled cortical impact in swine: pathophysiology and biomechanics.

Investigations of the basic pathological, cellular, and molecular mechanisms of traumatic brain injury (TBI) over the past two decades have been carried out primarily in rodents. Unfortunately, these studies have not translated into improved outcome in patients with TBI. To better model human TBI, a swine model of controlled cortical impact (CCI) was developed. A CCI device was used to generate a focal lesion in 23 anesthetized male Yorkshire swine. In 10 swine, CCI parameters of velocity and dwell time were varied to achieve a consistent injury (3.5 m/sec, 400 msec, respectively). In 13 swine, depth of depression was varied from 9 to 12 mm. Physiological data, including heart rate (HR), mean arterial blood pressure (MAP), intracranial pressure (ICP), and cerebral perfusion pressure (CPP), were collected for 10 h after injury. Following injury, ICP and HR increased above baseline values in all swine, with a more pronounced elevation in animals impacted to a depth of depression of 12 mm. An 11-mm depth of depression was found to most closely mimic pathological features of human TBI with edema, infiltration of inflammatory cells, pericapillary hemorrhage, and petechial hemorrhages in the white matter. Injury to a depth of depression of 12 mm resulted in cortical laceration obscuring these features. Immunohistological staining with Neu-N, MAP-2, and Fluoro Jade B revealed evidence of degenerating neurons, axonal disruption, and impending cell death. These results indicate that the swine model of CCI results in a defined and reproducible injury with pathological features similar to human TBI. Physiological parameters after injury are readily monitored in a setting mimicking conditions of an intensive care unit, establishing a more clinically relevant experimental model for future investigations.

Animals↗

PubMed1981

[Genetic and epigenetic control of adenosine deaminase expression. Analysis of human and man-mouse hybrid cells (author's transl)].

Analysis of human-rodent hybrids showed the following: the assignment of the ADA1 structural gene to chromosome 20; the identification in hybrids of a new ADA, referred to as ADAx, with a migration more rapidly anodal than ADAd and less rapidly anodal than ADA1 (product of allele 1 or 2); ADAx and d are formed by ADA1 and ADCP (an adenosine deaminase complexing protein). ADCP synthesis is controlled, at least, by a gene (ADCP2) localized on chromosome 2, probably in the IDH1 region; the combined action of another gene (ADCP1), assigned by other authors to chromosome 6, could be neither proved nor disproved, if this gene exists, it must be on 6p or in the 6qter region; the presence of chromosomes 20, 2, and 6 does not constitute a sufficient condition for the formation of ADAx and d, in either the hybrids or the human strains or lines: other factors intervene in its formation, i.e., an interaction between the culture medium, the human parental strain or line, and the rodent parental line.

Adenosine Deaminase↗

PubMedDate not supplied

One whisker whisking: unit recording during conditioned whisking in rats.

Understanding of the functional neurobiology of the rodent whisker system would be advanced by neurobehavioral studies in awake, behaving animals that combine unit recording from structures at various levels of the system with quantitative characterization of the kinematics and temporal organization of whisking. Such studies require the solution of a number of methodological problems. These include: chronic recording procedures ensuring unit isolation, stability and maximum yield, monitoring and display of unit activity and whisker movements within the same (ms) timeframe and behavioral paradigms which bring whisking movement parameters under the control of the experimenter rather than the rat. Here we describe a head-fixed rodent preparation which makes possible chronic recording of unit activity in the awake, whisking rat, combined with real-time, high resolution monitoring of whisker and pad movements in two dimensions and under behavioral control. While the head-fixed "whisking" preparation has some inherent limitations, it may be used to address a number of important neurobehavioral problems. We suggest that it should contribute significantly to understanding the functional neurobiology of the whisker system.

Animals↗

PubMed2004

CCAAT/Enhancer binding protein delta (c/EBPdelta) regulation and expression in human mammary epithelial cells: II. Analysis of activating signal transduction pathways, transcriptional, post-transcriptional, and post-translational control.

CCAAT/enhancer binding protein delta (C/EBPdelta) plays a key role in mammary epithelial cell G0 growth arrest. C/EBPdelta gene expression is down-regulated in rodent mammary tumorigenesis and in human breast cancer, suggesting that "loss of function" alterations in C/EBPdelta gene expression are common in mammary gland malignancies. The goal of this study was to systematically investigate the mechanisms controlling C/EBPdelta gene expression in MCF-10A and MCF-12A human mammary epithelial cell lines. The results demonstrate that G0 growth arrest conditions (i.e., serum and growth factor withdrawal or Oncostatin M (OSM) treatment) result in the activation of JAK1, JAK2, and Tyk 2, members of the Janus kinase family of non-receptor tyrosine kinases, in MCF-10A and MCF-12A cells. Growth arrest or OSM treatment also specifically increases activated (phosphorylated) signal transduction and activators of transcription 3 (STAT3) levels, demonstrating that STAT3, not STAT1 or STAT5, is the downstream target of the activated Janus kinases in MCF-10A and MCF-12A cells. Whole cell lysates from G0 growth arrested (GA) and OSM-treated MCF-12A cells exhibit increased acute phase response element (APRE) binding compared to lysates from growing (GR) MCF-12A cells. Transient transfection using C/EBPdelta promoter-luciferase constructs demonstrated that the APRE (STAT3) consensus binding site is essential for growth arrest or OSM induction of the C/EBPdelta promoter. Mutation of the C/EBPdelta promoter STAT3 site or expression of a dominant negative STAT3 construct (STAT3delta) reduces C/EBPdelta promoter activity in response to growth arrest conditions. The human C/EBPdelta promoter also contains an Sp1 site at -61 bp (relative to the transcriptional start site) which is required for basal transcriptional activation. Mutation or deletion of the Sp1 site decreases promoter activity in response to growth arrest conditions. Treatment with the transcriptional inhibitor actinomycin D demonstrated that the C/EBPdelta mRNA exhibits a relatively short half-life (approximately 40 min). Similarly, treatment with the translational inhibitor anisomysin demonstrated that the C/EBPdelta protein half-life was also relatively short (approximately 160 min). These results indicate that the human C/EBPdelta gene is controlled at multiple levels, consistent with a role for C/EBPdelta in cell cycle control and/or cell fate determination.

Animals↗