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At least 145 records · Page 8Linked to original sources
PubMed2005

Dynamic regulation of molecular chaperone gene expression in polyglutamine disease.

Expanded polyglutamine disease proteins cause adult-onset progressive neurodegeneration. Constitutive overexpression of the Hsp70 molecular chaperone is capable of suppressing polyglutamine neurodegeneration. We showed that endogenous Hsp70 expression was induced, at both transcriptional and translational levels, in Drosophila models of polyglutamine disease. Soon after the endogenous Hsp70 induction reached a maximum level at larval stage, its expression declined progressively with age. We further showed that cellular heat shock response remained intact in aged flies, indicating the decline of Hsp70 levels observed in polyglutamine-expressing flies is not due to normal ageing. In contrast to the well-documented polyglutamine suppression caused by constitutive Hsp70 overexpression, no suppression of degeneration was observed when inducible copies of hsp70 transgenes were instead coexpressed. This supports a transcriptional dysregulation of endogenous hsp70 gene induction in polyglutamine flies. Altogether, we propose that transcriptional malfunctioning of molecular chaperone gene expression contributes to the late-onset and progressive nature of polyglutamine toxicity.

Animals↗
PubMed2005

When size matters: the dynamic regulation of stereocilia lengths.

Stereocilia, the mechanosensitive protrusions in hair cells, are organized into rows of graded heights forming precisely uniform staircase patterns. The actin turnover process in stereocilia follows a treadmill model in which the rate of treadmilling is scaled to the stereocilium's length. Myosin XVa, which is present at the site of actin polymerization at concentrations proportional to the length of the actin filament bundles, plays a combined role with the treadmill machinery in regulating the steady state length of these actin protrusions, together with other myosins localized alongside the actin bundles.

Actins↗
PubMed2006

Developmental expression of mouse Follistatin-like 1 (Fstl1): Dynamic regulation during organogenesis of the kidney and lung.

Follistatin-like 1 (Fstl1) is a distantly related homolog of the Activin and Bone Morphogenetic Protein antagonist Follistatin. Interestingly, this molecule also has homology with the extracellular matrix modifying protein BM-40/SPARC/osteonectin. Previous studies in chick have identified Fstl1 as a regulator of early mesoderm patterning, somitogenesis, myogenesis and neural development. In this study, we determine the developmental expression pattern of Fstl1 in the mouse. We find that Fstl1 is ubiquitously expressed in the early embryo, and that expression becomes regionalized later during development. In the majority of tissues, Fstl1 is strongly expressed in the mesenchymal component and excluded from the epithelium. Notable exceptions include the central nervous system, in which Fstl1 expression is entirely absent with the exception of the choroid plexi and floor plate, the lung, in which Fstl1 expression can be seen in airway epithelia and the kidney, in which collecting ducts and nascent nephron epithelia express the highest levels of Fstl1.

Amino Acid Sequence↗
PubMed2006

Dynamic regulation of cAMP synthesis through anchored PKA-adenylyl cyclase V/VI complexes.

Spatiotemporal organization of cAMP signaling begins with the tight control of second messenger synthesis. In response to agonist stimulation of G protein-coupled receptors, membrane-associated adenylyl cyclases (ACs) generate cAMP that diffuses throughout the cell. The availability of cAMP activates various intracellular effectors, including protein kinase A (PKA). Specificity in PKA action is achieved by the localization of the enzyme near its substrates through association with A-kinase anchoring proteins (AKAPs). Here, we provide evidence for interactions between AKAP79/150 and ACV and ACVI. PKA anchoring facilitates the preferential phosphorylation of AC to inhibit cAMP synthesis. Real-time cellular imaging experiments show that PKA anchoring with the cAMP synthesis machinery ensures rapid termination of cAMP signaling upon activation of the kinase. This protein configuration permits the formation of a negative feedback loop that temporally regulates cAMP production.

A Kinase Anchor Proteins↗
PubMed2004

Developmental expression of methyl-CpG binding protein 2 is dynamically regulated in the rodent brain.

The gene encoding methyl-CpG binding protein 2 (MeCP2) is mutated in the large majority of girls that have Rett Syndrome (RTT), an X-linked neurodevelopmental disorder. To better understand the developmental role of MeCP2, we studied the ontogeny of MeCP2 expression in rat brain using MeCP2 immunostaining and Western blots. MeCP2 positive neurons were present throughout the brain at all ages examined, although expression varied by region and age. At early postnatal ages, regions having neurons that were generated early and more mature had the strongest MeCP2 expression. Late developing structures including cortex, hippocampus and cerebellum exhibited the most significant changes in MeCP2 expression. Of these regions, the cerebellum showed the most striking cell-specific changes in MeCP2 expression. For example, the early-generated Purkinje cells became MeCP2 positive by P6, while the late-generated granule cells did not express MeCP2 until the fourth postnatal week. The timing of MeCP2 expression in the granule cell layer is coincident with the onset of granule cell synapse formation. Although more subtle, the degree of MeCP2 expression in cortex and hippocampus was most closely correlated with synaptogenesis in both regions. Our finding that MeCP2 expression is correlated with synaptogenesis is consistent with the hypothesis that Rett Syndrome is caused by defects in the formation or maintenance of synapses.

Aging↗
PubMed2006

MAP2 and synaptophysin protein expression following motor learning suggests dynamic regulation and distinct alterations coinciding with synaptogenesis.

Learning a new motor skill can induce neuronal plasticity in rats. Within motor cortex, learning-induced plasticity includes dendritic reorganization, synaptogenesis, and changes in synapse morphology. Behavioral studies have demonstrated that learning requires protein synthesis. It is likely that some of the proteins synthesized during learning are involved in, or the result of, learning-induced structural plasticity. We predicted the expression of proteins involved in neural plasticity would be altered in a learning dependent fashion. Long-Evans rats were trained on a series of motor tasks that varied in complexity, so that the effects of activity could be teased apart from the effects of learning. The motor cortices were examined for MAP2 and synaptophysin protein using Western blotting and immunohistochemistry. Western blotting revealed that expression of MAP2 was not detectably influenced by learning, whereas synaptophysin expression increased on day 1, 3, and 5 of complex motor skill learning. Expression of MAP2 does not seem to indicate difficulty of task or duration of training time, whereas increases in synaptophysin expression, which appear diffusely across the cortex, seem to be correlated with the first 5 days of motor skill learning. Similar findings with GAP-43 suggest the change in synaptophysin may coincide with synapse formation. Immunohistochemistry did not reveal any localized changes in protein expression. These data indicate a difference in learning-induced expression in the mammalian brain compared to reports in the literature, which have often focused on stimulation to induce alterations in protein expression.

Adaptation, Physiological↗
PubMed2004

Vinculin--a dynamic regulator of cell adhesion.

The ability of cells to tightly adhere to one another and to the extracellular matrix is fundamentally important in numerous biological processes, including embryogenesis, wound healing and maintenance of tissue integrity. Vinculin, a protein localized at the cytoplasmic face of cell-matrix and cell-cell adhesions, is required for strong cell adhesion. Two new crystal structures reveal that vinculin exhibits a high degree of structural plasticity upon ligand binding that might promote rapid changes in cell adhesion.

Animals↗
PubMed2004

Dynamic regulation of estrogen receptor-beta expression by DNA methylation during prostate cancer development and metastasis.

Estrogen receptor (ER)-beta is thought to exert anti-proliferative effects in the normal prostate but supports prostate cancer (PCa) cell survival. We previously reported that the receptor's expression declined as PCa developed in the gland but reappeared in lymph node and bone metastases. To investigate whether hypermethylation was the underlying mechanism for these phenomena, we first identified two CpG islands (CGIs) encompassing 41 CpG dinucleotides, located separately in the untranslated exon 0N and the promoter region of ER-beta. Using immunostained, laser capture-microdissected samples from 56 clinical specimens, we demonstrated an inverse relationship exists between the extent of ER-beta CGI methylation and receptor expression in normal, hyperplastic, premalignant, and malignant foci of the prostate and in lymph node and bone metastases. Treatment of PCa cell lines (LNCaP and DU145), that express little ER-beta mRNA, with a demethylating agent increased levels of receptor expression thus corroborating our in vivo findings that methylation is involved in ER-beta silencing. Methylation centers in the promoter region and exon 0N were identified by hierarchical cluster analysis of bisulfite sequencing data obtained from 710 alleles. Methylation at these centers was insignificant in normal epithelium, reached 80 to 90% in grade 4/5 PCa, but declined to less than 20% in bone metastases. In addition, progressive methylation spreading from the exonic CGI to the promoter CGI, which correlated with loss of ER-beta expression, was detected in microdissected samples and in cell cultures. Using a new class of methylated oligonucleotides that mediate sequence-specific methylation in cellulo, we demonstrated that methylation of the promoter CGI, but not the exonic CGIs, led to transcriptional inactivation of ER-beta. Our results present the first evidence that epigenetic regulation of ER-beta is a reversible and tumor stage-specific process and that gene silencing via methylated oligonucleotides may have therapeutic potential in the treatment of advanced PCa.

Base Sequence↗
PubMed2003

Dynamic regulation of alternative ATP-binding cassette transporter A1 transcripts.

The ATP-binding cassette transporter A1 (ABCA1) gene, a major regulator of high-density lipoprotein (HDL) metabolism, utilizes several transcriptional start sites. The pattern of transcripts among tissues and cells differed significantly. The longest (class 1) transcripts were abundant in adult brain and fetal tissues. Class 2 transcripts predominated in most other tissues. The shortest (class 3) transcripts were present mainly in adult liver and lung. To study the biochemical significance of changes in transcript distribution, two cell models were compared. In primary human fibroblasts, upregulation of mRNA levels by oxysterols and retinoic acid increased the relative proportion of class 2 transcript compared to class 1. Phorbol ester stimulated human macrophage-derived THP-1 cells increased the abundance of class 1 transcripts relative to class 2. In both cell lines class 3 transcript levels were minimal and unchanged. It is shown here for the first time that the regulation of ABCA1 mRNA levels exploits the use of alternative transcription start sites.

ATP Binding Cassette Transporter 1↗
PubMed2003

Dynamic regulation of MEK/Erks and Akt/GSK-3beta in human end-stage heart failure after left ventricular mechanical support: myocardial mechanotransduction-sensitivity as a possible molecular mechanism.

OBJECTIVE: Left ventricular assist devices (LVAD) are used to 'bridge' patients with end-stage heart failure to transplantation. After long-term LVAD support, ventricular function may partially recover, a process called 'reverse remodeling'. As several kinase-mediated signal transduction pathways have been implicated in the development of cardiac hypertrophy and failure, we examined the activities of the Erks, MEKs, Akt, GSK-3 beta, p70S6K, JNKs and p38 under LVAD support as well as during single myocyte strain and whole heart stretch. METHODS: Western blotting and immunohistochemistry were performed using phospho-specific antibodies in matched samples from ten patients with end-stage heart failure before and after LVAD. Cyclic strain was performed in rat neonatal cardiac myocytes, and tensile stretch applied to Langendorff-perfused mouse hearts via a left ventricular balloon. RESULTS: The activity of Erks and Akt in failing hearts dramatically decreased after LVAD support, while that of GSK-3 beta increased. There was an endo/epicardial gradient for Erk activity which persisted after LVAD despite the reduction of total Erk activity. TUNEL-positivity and myocyte size decreased after LVAD, but independently of changes in kinase activity. In cardiomyocytes and Langendorff-perfused mouse hearts both strain/stretch and its relief regulated the activities of Erks, Akt, and GSK-3 beta. CONCLUSION: Erks and Akt/GSK-3 beta are highly responsive to myocyte stretch in vitro and in vivo, and may be sensitive molecular parameters of 'reverse remodeling' under LVAD support.

Adolescent↗
PubMed2003

Copper ions dynamically regulate beta3 integrin subunit expression in Ishikawa cells.

Copper intrauterine device (IUD) users have a reduced expression of beta3 integrin subunit during the implantation window. This integrin has been found to be a uterine marker for implantation. In order to verify if copper ions are involved in this reduction, beta3 integrin subunit expression was assessed in an in vitro model. The beta3 integrin subunit expression was determined by flow cytometry in the presence of copper D-gluconate and/or epidermal growth factor (EGF). The mean percentages of positive beta3 integrin subunit cells under different culture conditions were: 4.7 +/- 0.29 (mean +/- SEM) in controls; 8.6 +/- 0.59 in the presence of copper; 13.4 +/- 0.05 in the presence of EGF and 20.8 +/- 0.36 in the presence of EGF+copper (analysis of variance, p < 0.0001). Copper D-gluconate up-regulates beta3 integrin subunit expression in vitro both in the presence and absence of EGF. The differences between in vivo and in vitro results should be investigated and may represent interference by other factors such as the inflammatory process associated with the presence of IUDs.

Cations↗
PubMed2002

Dynamic regulation of Brachyury expression in the amphibian embryo by XSIP1.

Xenopus Brachyury (Xbra) plays a key role in mesoderm formation during early development. One factor thought to be involved in the regulation of Xbra is XSIP1, a zinc finger/homeodomain-like DNA-binding protein that belongs to the deltaEF1 family of transcriptional repressors. We show here that Xbra and XSIP1 are co-expressed at the onset of gastrulation, but that expression subsequently refines such that Xbra is expressed in prospective mesoderm and XSIP1 in anterior neurectoderm. This refinement of the expression patterns of the two genes is due in part to the ability of XSIP1 to repress expression of Xbra. This repression is highly specific, in the sense that XSIP1 does not repress the expression of other regionally expressed genes in the early embryo, and that other members of the family to which XSIP1 belongs, such as deltaEF1 and its Xenopus homologue ZEB, cannot regulate Xbra expression. The function of XSIP1 was studied further by making an interfering construct comprising the open reading frame of XSIP1 fused to the VP16 transactivation domain. Experiments using this chimeric protein suggest that XSIP1 is required for normal gastrulation movements to occur and for the development of the anterior neural plate.

Animals↗
PubMed2002

Dynamic regulation of Smad expression during mesenchyme to epithelium transition in the metanephric kidney.

Genetic studies have revealed a role for the transforming growth factor beta (TGFbeta) superfamily growth factors in development of the mouse kidney. In this study, we have characterized developmental expression of Smad proteins, the downstream effectors of TGFbeta superfamily ligands. Immunohistochemistry detecting Smads 1-5 and 8 was performed on 11.25-15.5 dpc kidney sections. We find that Smad proteins are readily detected in metanephric mesenchyme but are coordinately down-regulated in condensing mesenchyme and derivative structures such as renal vesicles. In order to define the stage at which down-regulation occurs, we used the heterologous inducer lithium chloride to promote condensation in isolated cultured mesenchymal explants and subsequently assayed expression of Smad 4. Down-regulation is complete in lithium chloride induced mesenchymal condensates, indicating that Smad regulation takes place at an early stage, prior to mesenchyme to epithelium transition.

Animals↗
PubMed1996

Dynamic regulation of intestinal immunity by hormones of the hypothalamus-pituitary-thyroid axis.

The role of the thymus in the development of murine small intestinal intraepithelial lymphocytes (IELs) has been a controversial topic for decades. This controversy has been further propagated by observations that differences in IEL repertoires vary according to the particular athymic animal model system used to study IELs. In an attempt to understand the bases for these differences, we have undertaken a series of experiments designed to explore the extent to which extraimmunologic events, in particular neuroendocrine factors, play a role in the development of extrathymic IELs. As discussed here, these studies indicate that hormones of the hypothalamus-pituitary-thyroid (HPT) axis exert either positive or negative regulatory effects on intestinal IELs, depending upon the particular hormone. Although the mechanisms by which HPT hormones influence IEL development and immune regulation have yet to be fully delineated, it appears that thyroid-stimulating hormone is a key mediator in this process, and that this may occur via local autocrine/paracrine responses within the intestine itself. The implications of these findings in the context of immunity and disease at the level of the gastrointestinal tract are discussed.

Animals↗
PubMed2000

Dynamic regulation of prothoracic gland ecdysteroidogenesis: Manduca sexta recombinant prothoracicotropic hormone and brain extracts have identical effects.

Multiple assays were conducted in order to determine if the recently available recombinant prothoracicotropic hormone (rPTTH) from Manduca sexta is identical, or similar, to the natural hormone and if results from its use in a variety of assays confirm, or are inconsistent with, previous studies over the past 20years on PTTH action using brain extract. Brain extracts and rPTTH showed similar, if not identical, effects on the cell biology of Manduca prothoracic gland cells with the following results: increased levels of cAMP (adenosine 3':5' cyclic monophosphate) synthesis; requirement for extracellular Ca(2+) in in vitro studies; ecdysteroidogenesis stimulation in vitro; stimulation of general and specific protein synthesis; immunocytochemical identification of the two lateral cells in each brain hemisphere as the source of PTTH (the prothoracicotropes); the ability of antibodies to rPTTH to inhibit ecdysteroidogenesis stimulation in vitro; and the multiple phosphorylation of the ribosomal protein S6. The data revealed that brain extract and rPTTH show equivalent effects in all of the assays, indicating that this rPTTH is the natural PTTH of Manduca and that the data generated with brain extracts over the past two decades are indeed relevant.

Animals↗
PubMed1994

Dynamic regulation of intact and C-terminal truncated insulin receptor phosphorylation in permeabilized cells.

Using digitonin-permeabilized Chinese hamster ovary (CHO) cells that were transfected with intact human insulin receptors (CHO/HIRc cells), we examined insulin receptor phosphorylation and dephosphorylation using pulse-chase techniques. Insulin activated receptor autophosphorylation on tyrosyl residues to a level severalfold over basal, reaching maximal levels after 2, 5, and 10 min of stimulation at 34, 18, and 6 degrees C, respectively. Phosphopeptide analysis revealed that the triply phosphorylated form of the 1146-kinase domain of the insulin receptor was the major species, which is characteristic of the fully active tyrosine kinase function. The dephosphorylation reaction was time- and temperature-dependent with t1/2 values of 0.67 and 2 min at 18 and 6 degrees C, respectively. Vanadate completely inhibited dephosphorylation. Under similar permeabilization conditions when compared with CHO/HIRc cells, CHO/delta CT cells (CHO cells overexpressing a mutated form of the receptor with a 43 amino acid deletion at the C-terminus) stimulated with insulin exhibited larger increases in receptor autophosphorylation levels and in tyrosine kinase activity toward a synthetic peptide substrate; the rate of CHO/delta CT receptor dephosphorylation was not reduced. There was near-complete absence of insulin receptor substrate 1 (IRS-1) in the cell ghosts after permeabilization. We therefore examined the pattern of tyrosine phosphorylation and dephosphorylation of residual cellular proteins in permeabilized CHO/HIRc cells by Western blot analysis. In addition to the 95-kDa receptor beta-subunit, we detected the phosphorylation of two glycoproteins which included the commonly found 120-kDa protein and a novel 195-kDa protein whose dephosphorylation rate is slower than that of receptor beta-subunit.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗