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Biomedical subjects

J N Davis

Publications and source records attributed to J N Davis.

At least 37 records · Page 2Linked to original sources
PubMed1998

Genistein-induced upregulation of p21WAF1, downregulation of cyclin B, and induction of apoptosis in prostate cancer cells.

Increased soy consumption in Asian diets, resulting in increased serum isoflavone levels, has been associated with a decreased risk for prostate adenocarcinoma (PCa). The isoflavone genistein is believed to be the anticancer agent found in soy, and significant levels of genistein have been detected in human prostatic fluid, implicating the role of genistein in PCa prevention. Recent studies have demonstrated genistein's ability to inhibit cell growth and induce apoptosis in several cell lines; however, the molecular mechanisms of genistein's effect are not known. We have evaluated the mechanism by which genistein may inhibit PCa cell growth. Here we report that genistein inhibits PCa cell growth in culture in a dose-dependent manner, which is accompanied by a G2/M cell cycle arrest. Cell growth inhibition was observed with concomitant downregulation of cyclin B, upregulation of the p21WAF1 growth-inhibitory protein, and induction of apoptosis. Collectively, these results provide experimental evidence for a novel effect of genistein on cell cycle gene regulation, resulting in the inhibition of cell growth and ultimate demise of tumor cells.

Adenocarcinoma↗
PubMed1998

Bcl-x(l) Bax interaction after transient global ischemia.

Five minutes of bilateral common carotid artery occlusion in the Mongolian gerbil results in a selective, delayed death of CA1 pyramidal neurons. Although Bcl-2 appears to protect a variety of cells from cell death, the precise role of this apoptosis-regulating protein is complicated. We used immunoblots to estimate levels of Bcl-2, Bcl-x(l), and Bax at various times after carotid occlusion. Rather than Bcl-2, Bcl-x(l) appears to be the predominant neuroprotective form of this family of proto-oncogenes in the gerbil hippocampus. After transient ischemia, Bcl-2 and Bcl-x(l) protein levels remained the same. However, Bax levels were dramatically increased at 6 hours after ischemia, compared with sham-operated animals, and were still elevated at 72 hours after ischemia. To monitor dimerization interactions among theses apoptosis-regulating molecules, immunoprecipitation studies were conducted. These studies demonstrated that Bcl-x(l) association with Bax increases after ischemia. Therefore, Bax may disrupt the more favorable Bcl-x(l) (Bcl-2) interactions necessary for normal neuronal functioning and thus promote transient ischemic death.

Animals↗
PubMed1997

Role of apoptotic proteins in ischemic hippocampal damage.

In this review, we have presented evidence that apoptotic proteins may be involved in ischemic cell death. We tried to keep in mind that focal and global ischemia almost certainly produces different forms of cell death. For example, necrotic cell death is clearly part of a focal cerebral infarct, although it is not seen in brief global insults. We also tried to make the point that not all apoptosis is the same and that various forms of non-necrotic cell death, including ischemic cell death after global ischemia, may share some of the same molecular mechanisms as classic forms of apoptosis. Finally, we wish to leave the reader with the clear impression that all the evidence is not in hand. More work needs to be done in animals to define the role of apoptotic proteins. For example, glial cells probably are important in necrosis and may play a role in ischemic cell death after transient global ischemia. Yet it is likely that glial cells die from injury in a different manner than neurons. A better understanding of these processes should lead to new therapeutic approaches that may make possible the salvaging of neurons well after an ischemic insult.

Animals↗
PubMed1997

Nesting and shredding behavior as an indicator of hippocampal ischemic damage.

Mongolian gerbils were subjected to bilateral carotid artery occlusion, exposed to nesting material and examined daily. Five minutes of ischemia significantly reduced nesting behavior for 3 days; while 10 min attenuated nesting 6 days. Semi-novel re-exposure to nesting material also resulted in deficits. These disruptions in nesting behavior directly correlate to the amount of ischemic morphological damage and thus serve as a behavioral indicator of tissue damage.

Animals↗
PubMed1997

Evolutionary theory and the human family.

Emlen's (1995) paper "An evolutionary theory of the family" reviewed existing ideas about the nature of family systems and the reasons why they have evolved in certain animal species. His theorizing led him to propose 15 predictions about how family systems function, based on favorable evidence from various species, mostly birds. While he suggested that these predictions can be applied to the human case, he himself did not attempt to do so. We consider the applicability of Emlen's 15 predictions to the study of human family systems, and find that several aspects of the life history and ecology of Homo sapiens require that they be modified. These considerations include: (1) the importance of intragroup solidarity in the context of intergroup competition: unlike in many other species where dispersal constraints arise from food or breeding site shortages, the primary pressure driving human sociality seems to be competition from other human groups; (2) the complex nature of exchange and reciprocity in human society: reciprocal altruism in particular is integral to human social interaction and leads to a particularly high degree of non-nepotistic helping behavior; and (3) the implications of menopause and the existence of potentially dominant, postreproductive helpers: helpers of this sort have little incentive to disperse or to encourage offspring to disperse, thus greatly increasing family stability.

Animals↗
PubMed1997

Complementation of growth factor receptor-dependent mitogenic signaling by a truncated type I phosphatidylinositol 4-phosphate 5-kinase.

Substitution of phenylalanine for tyrosine at codon 809 (Y809F) of the human colony-stimulating factor 1 (CSF-1) receptor (CSF-1R) impairs ligand-stimulated tyrosine kinase activity, prevents induction of c-MYC and cyclin D1 genes, and blocks CSF-1-dependent progression through the G1 phase of the cell cycle. We devised an unbiased genetic screen to isolate genes that restore the ability of CSF-1 to stimulate growth in cells that express mutant CSF-1R (Y809F). This screen led us to identify a truncated form of the murine type Ibeta phosphatidylinositol 4-phosphate 5-kinase (mPIP5K-Ibeta). This truncated protein lacks residues 1 to 238 of mPIP5K-Ibeta and is catalytically inactive. When we transfected cells expressing CSF-1R (Y809F) with mPIP5K-Ibeta (delta1-238), CSF-1-dependent induction of c-MYC and cyclin D1 was restored and ligand-dependent cell proliferation was sustained. CSF-1 normally triggers the rapid disappearance of CSF-1R (Y809F) from the cell surface; however, transfection of cells with mPIP5K-Ibeta (delta1-238) stabilized CSF-1R (Y809F) expression on the cell surface, resulting in elevated levels of ligand-activated CSF-1R (Y809F). These results suggest a role for PIP5K-Ibeta in receptor endocytosis and that the truncated enzyme compensated for a mitogenically defective CSF-1R by interfering with this process.

Amino Acid Sequence↗
PubMed1996

Cloning and expression of the murine Elf-1 cDNA.

The Ets family of transcription factors has been implicated in the etiology of several types of cancer. We cloned and characterized the gene encoding the murine homologue of one Ets family member, Elf-1 (mElf-1), in order to gain insight into its cellular physiology. We examined mElf-1 mRNA expression in normal mouse tissues and in several murine and human cell lines. Expression of mElf-1, although highest in lymphocytes, was observed in a number of hematopoietic cell lineages, including the myeloid, macrophages and erythroid lineages, and was lowest in the murine fibroblast cell line, NIH3T3. Analysis of human and fetal tissue mRNAs confirmed that mElf-1 is expressed in a variety of cell lineages, principally in hematopoietic cells. Western blot analysis using antiserum generated to a synthetic C-terminal peptide of mElf-1, and extracts prepared from cell lines that expressed the mElf-1 mRNA identified multiple mElf-1 species that migrated near the 97-kDa molecular weight marker. Site selection analysis indicated that the binding site preferred by mElf-1 is very similar to that of the Drosophila melanogaster homologue, E74, and to that of Fli-1, another Ets family member. We conclude that the expression of mElf-1 is not restricted to the lymphoid lineage, and suggest that Elf-1 may regulate the transcription of a broad spectrum of genes.

Amino Acid Sequence↗
PubMed1996

A potential role for Elf-1 in terminal transferase gene regulation.

The terminal deoxynucleotidyltransferase (TdT) gene represents an attractive model for the analysis of gene regulation during an early phase of lymphocyte development. In previous studies, we identified a DNA element, termed D', which is essential for TdT promoter activity in immature lymphocytes, and two classes of D'-binding factors, Ikaros proteins and Ets proteins. Here, we report a detailed mutant analysis of the D' element which suggests that an Ets protein, rather than an Ikaros protein, activates TdT transcription. Since multiple Ets proteins are expressed in developing lymphocytes and are capable of binding to the D' element, DNA affinity chromatography was used to determine if one of the Ets proteins might bind to the D' element with a uniquely high affinity, thereby implicating that protein as a potential TdT activator. Indeed, one binding activity was greatly enriched in the high-salt eluates from a D' affinity column. Peptide microsequencing revealed that the enriched protein was Elf-1. Immunoblot analyses confirmed that in nuclear extracts, Elf-1 has a significantly higher affinity for the D' sequence than does another Ets protein, Ets-1. Transactivation and expression studies support the hypothesis that Elf-1 activates TdT transcription in immature T and B cells. Finally, a D' mutation which selectively reduces Elf-1 binding, but not the binding of other Ets proteins, was found to greatly reduce TdT promoter activity. Although Elf-1 previously had been implicated in the inducible activation of genes in mature T and B cells, our results suggest that it also plays an important role in regulating genes during an early phase of lymphocyte development.

Amino Acid Sequence↗
PubMed1996

The t(12;21) translocation converts AML-1B from an activator to a repressor of transcription.

The t(12;21) translocation is present in up to 30% of childhood B-cell acute lymphoblastic and fuses a potential dimerization motif from the ets-related factor TEL to the N terminus of AML1. The t(12;21) translocation encodes a 93-kDa fusion protein that localizes to a high-salt- and detergent-resistant nuclear compartment. This protein binds the enhancer core motif, TGTGGT, and interacts with the AML-1-binding protein, core-binding factor beta. Although TEL/AML-1B retains the C-terminal domain of AML-1B that is required for transactivation of the T-cell receptor beta enhancer, it fails to activate transcription but rather inhibits the basal activity of this enhancer. TEL/AML-1B efficiently interferes with AML-1B dependent transactivation of the T-cell receptor beta enhancer, and coexpression of wild-type TEL does not reverse this inhibition. The N-terminal TEL helix-loop-helix domain is essential for TEL/AML-1B-mediated repression. Thus, the t(12;21) fusion protein dominantly interferes with AML-1B-dependent transcription, suggesting that the inhibition of expression of AML-1 genes is critical for B-cell leukemogenesis.

Base Sequence↗
PubMed1995

Signaling by N- and C-terminal sequences of parathyroid hormone-related protein in hippocampal neurons.

Parathyroid hormone-related protein (PTHrP) is synthesized in the brain, and a single type of cloned receptor for the N-terminal portion of PTHrP and PTH is present in the central nervous system. Nothing is known about the physiological actions or signaling pathways used by PTHrP in the brain. Using cultured rat hippocampal neurons, we demonstrate that N-terminal PTHrP[1-34] and PTH[1-34] signal via cAMP and cytosolic calcium transients. The cAMP response showed strong acute (< or = 6 h) homologous and heterologous desensitization after preincubation with PTHrP or PTH. In contrast, the acute calcium response did not desensitize after preincubation with PTHrP; in fact, preincubation dramatically recruited additional responsive neurons. Unexpectedly, C-terminal PTHrP[107-139], which does not bind or activate the cloned PTH/PTHrP receptor, signaled in neurons via cytosolic calcium but not cAMP. Although some neurons responded to both PTHrP[1-34] and PTHrP[107-139], others responded only to PTHrP[1-34]. We conclude that certain hippocampal neurons exhibit dual signaling in response to PTHrP[1-34] and that some neurons have a receptor for C-terminal PTHrP that signals only via cytosolic calcium.

Animals↗
PubMed1995

A variant Ewing's sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1.

Most Ewing's sarcomas or related primitive neuroectodermal tumors have the (11;22)(q24;q12) or less frequently the (21;22)(q22;q12) translocation. These rearrangements fuse the EWS gene on chromosome 22q12 to either the FLI1 or ERG genes, both members of the ETS family of transcription factors. Simple variant chromosomal translocations have been occasionally described in these tumors. We have identified a third Ewing's sarcoma translocation, the t(7;22)(p22;q12), that fuses EWS to the human homologue of the murine ETS gene ER81. This gene, designated ETV1 (for ETS Translocation Variant), is located on chromosome band 7p22. Identical EWS nucleotide sequences found in the majority of EWS-FLI1 and EWS-ERG chimeric transcripts are fused to a portion of ETV1 encoding an ETS domain with sequence specific DNA-binding activity. These findings confirm that the fusion of EWS to different ETS family members can result in a similar tumor phenotype.

Adult↗
PubMed1994

A new glibenclamide-insensitive neuroselective hyperpolarizing agent.

We describe a novel compound, (-)-N-(2-ethoxyphenyl)-N'-(1,2,3-trimethylpropyl)-2-nitroethene-1, 1-diamine), Bay x9227, that demonstrates dose-dependent hyperpolarizing activity of remarkable potency (EC50 3 picomolar) and selectivity for CNS neurons and clonal neurotypic cells compared to smooth muscle cells. Single cell membrane potential measurements were obtained in physiologic buffer using the fluorescent probe, bisoxonol. Unlike K+ATP-channel activators including its (+)-enantiomer (Hoffman et al., 1993, Biochem. Biophys. Res. Commun. 190(2), 551), this activity was insensitive to glibenclamide antagonism. These data suggest a novel pharmacologic site for effecting neuroselective hyperpolarization.

Animals↗
PubMed1994

Dual control of myc expression through a single DNA binding site targeted by ets family proteins and E2F-1.

NIH3T3 cells expressing a mutant colony-stimulating factor-1 receptor (CSF-1R) containing a phenylalanine for tyrosine substitution in the tyrosine kinase domain at codon 809 exhibit defective myc regulation and do not enter S phase when stimulated by CSF-1. Enforced expression of either ets-1 or ets-2 in these cells restores their mitogenic response, albeit less efficiently than myc itself, suggesting that ets proteins may regulate c-myc expression. Ets-1 transactivates reporter genes driven by the human and mouse c-myc promoters through the binding site for the transcription factor E2F, the latter being required for E1A- and serum-induced c-myc expression. Analysis of E2F-1 sequences identified a minimal DNA binding domain that is related to those of ets proteins. Although E2F and ets proteins interact with similar consensus DNA binding sites, in vitro binding assays revealed that E2F can bind DNA as a homodimer, whereas ets proteins bind these sites as monomers. E2F and ets proteins do not form heterodimers in vitro and do not transactivate c-myc synergistically. Thus, E2F-1 and ets family members may independently regulate c-myc transcription through the same binding site at different times following growth factor stimulation.

Amino Acid Sequence↗
PubMed1993

Beta-adrenergic receptors in the hippocampal and retrohippocampal regions of rats and guinea pigs: autoradiographic and immunohistochemical studies.

Species differences in the distribution of beta-adrenergic receptors in the hippocampal and retrohippocampal regions of rats and guinea pigs were examined using in vitro autoradiographic techniques. beta 1-receptors were found in the hippocampal area CA1 of both species, although guinea pigs had significantly lower receptor densities in comparison to rats. In guinea pigs, beta 2-adrenergic receptors were predominant in hippocampal area CA1. Hippocampal area CA3 had very low levels of beta 1- and beta 2-receptors in both species. The retrohippocampal area was also found to have a distinct topographic distribution of beta-receptors. In rats, the subiculum and parasubiculum (layers II-III) were heavily labeled for beta 1-receptors; in contrast, guinea pigs had few receptors in these regions. beta 2-receptors were particularly prominent in the parasubicular region in rats. The entorhinal cortex laminae was found to contain beta-receptors in both rats and guinea pigs. Immunohistochemical techniques were used to compare the pattern of catecholaminergic innervation with the receptor distribution within each hippocampal subregion. Despite the general lack of beta-receptors in area CA3, abundant catecholamine immunoreactive fibers were observed in CA3 of rat and guinea pig hippocampus. Significant species differences were found in the distribution of hippocampal beta-adrenergic receptor subtypes, and moreover, in both species the distribution of beta-adrenergic receptors did not coincide with the pattern of hippocampal adrenergic innervation.

Adrenergic beta-Antagonists↗
PubMed1993

Frequency analysis of catecholamine axonal morphology in human brain. I. Effects of postmortem delay interval.

The diverse morphologies of catecholamine axons in the human brain were examined by using tyrosine hydroxylase immunocytochemistry. Human brain tissue was obtained by either rapid autopsy (mean postmortem delay < 1 h) or routine autopsy (mean postmortem delay 5 h). Tissue blocks from the superior frontal cortex (Brodmann area 9), the hippocampal gyrus and the calcarine cortex (Brodmann area 17) were processed for tyrosine hydroxylase immunoreactivity. First, a quantitative method was developed to reliably identify differing morphologies of catecholamine axons in human brain tissue. A total of 625 tyrosine hydroxylase immunoreactive axons were randomly sampled from coded sections and classified into one of six distinct morphological categories. These categories were based upon axonal morphologies which were readily distinguished by trained observers, and moreover, further investigations demonstrated that entire tissue sections could be reliably re-sampled at intervals of up to six months. Second, regional variations in axonal distribution and the effects of increasing postmortem delay in tissue processing on the categories of tyrosine hydroxylase immunoreactive axon morphologies were examined. Postmortem delays of up to 6.5 hours were found to decrease the frequency of fine axons with varicosities (axon type 2) and increase thick-caliber straight axons (axon type 5) in all regions examined. The frequency of other morphological axon types did not change as a function of postmortem delay. In summary, the use of quantitative neuroanatomical measures of the catecholaminergic system in human brain tissue was found to be reliable and valid. It was furthermore demonstrated that postmortem delays affect selected morphological types of catecholamine axons.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Frequency analysis of catecholamine axonal morphology in human brain. II. Alzheimer's disease and hippocampal sympathetic ingrowth.

We have examined the various diverse morphologies of catecholamine axons in the brains of patients with Alzheimer's disease. Alzheimer's disease and aged control brain tissue were obtained by a rapid autopsy protocol (mean postmortem delay < 1 h). Tissue blocks from the superior frontal cortex (Brodmann area 9), the hippocampal gyrus, and the calcarine cortex (Brodmann area 17) were processed for identification of catecholamine axons using tyrosine hydroxylase immunocytochemistry. A total of 1275 tyrosine hydroxylase immunoreactive axons were randomly sampled from coded sections and classified into one of six distinct axon-type categories. The axon classification from patients with Alzheimer's disease significantly differed from those of an age-matched control population in the hippocampus. The Alzheimer's disease brains were decreased in the frequency of very long, thin, tyrosine hydroxylase immunoreactive axons (type 1) and had an increased frequency of shorter, tortuous, axons (type 3). These selective quantitative shifts in hippocampal catecholaminergic axon morphology are consistent with the hypothesis that sympathetic noradrenergic axons invade the hippocampus of patients with Alzheimer's disease. Multivariate modeling of the frequency sampling data found that the axon type classification scheme successfully predicted the presence of Alzheimer's disease. In particular, the use of quantitative neuroanatomical measures of the catecholaminergic system in human brain tissue was found to have errorless predictive ability with respect to late onset (> 75 years) Alzheimer's disease. In summary, the use of quantitative neuroanatomical measures of catecholamine axonal morphologies in Alzheimer's disease brain tissue identified a specific frequency shift which may represent hippocampal sympathetic ingrowth and this unique measure was found to have predictive utility with respect to Alzheimer's disease.

Aged↗
PubMed1993

Extracellular catecholamine levels in rat hippocampus after a selective alpha-2 adrenoceptor antagonist or a selective dopamine uptake inhibitor: evidence for dopamine release from local dopaminergic nerve terminals.

The effect of 6-chloro-2,3,4,5-tetrahydro-3-methyl-1-H-3-benzazepine (SKF 86466), a selective nonimidazoline alpha-2 adrenoceptor antagonist, on hippocampal release of norepinephrine and dopamine in conscious rats was investigated by in vivo microdialysis and high-pressure liquid chromatography. Additionally, extracellular concentrations of hippocampal dopamine (DA) and norepinephrine (NE), during infusion of selective monoamine uptake inhibitors, were determined in freely moving rats. The basal concentration of NE in the dialysate was 4.9 +/- 0.3 pg/20 microliters. Intravenous administration of 5 or 10 mg/kg of SKF 86466 was associated with a transient increase (30 min) of 2-fold (12 +/- 1 pg/20 microliters; P < .05) and 8-fold (39 +/- 3 pg/20 microliters; P < .05), respectively, in dialysate NE, whereas a 1-mg/kg dose had no effect. DA was not detected in basal dialysates, but after the administration of 5 or 10 mg/kg of SKF 86466, 3.9 +/- 0.4 and 6.4 +/- 0.6 pg/20 microliters, respectively, was present in the dialysates. The maximum increase in dialysate DA was reached 60 to 90 min after SKF 86466. The DA was not derived from plasma because plasma NE was elevated after the 5 mg/kg dose of SKF 86466 whereas no plasma DA was detected. In order to determine whether DA was present in noradrenergic nerve terminals, the dopamine beta-hydroxylase inhibitor SKF 102698 was administered (50 mg/kg i.p.). The inhibitor decreased dialysate NE but DA was still not detected in the dialysate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗