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PubMed2006

The brain tumor gene negatively regulates neural progenitor cell proliferation in the larval central brain of Drosophila.

Brain development in Drosophila is characterized by two neurogenic periods, one during embryogenesis and a second during larval life. Although much is known about embryonic neurogenesis, little is known about the genetic control of postembryonic brain development. Here we use mosaic analysis with a repressible cell marker (MARCM) to study the role of the brain tumor (brat) gene in neural proliferation control and tumour suppression in postembryonic brain development of Drosophila. Our findings indicate that overproliferation in brat mutants is due to loss of proliferation control in the larval central brain and not in the optic lobe. Clonal analysis indicates that the brat mutation affects cell proliferation in a cell-autonomous manner and cell cycle marker expression shows that cells of brat mutant clones show uncontrolled proliferation, which persists into adulthood. Analysis of the expression of molecular markers, which characterize cell types in wild-type neural lineages, indicates that brat mutant clones comprise an excessive number of cells, which have molecular features of undifferentiated progenitor cells that lack nuclear Prospero (Pros). pros mutant clones phenocopy brat mutant clones in the larval central brain, and targeted expression of wild-type pros in brat mutant clones promotes cell cycle exit and differentiation of brat mutant cells, thereby abrogating brain tumour formation. Taken together, our results provide evidence that the tumour suppressor brat negatively regulates cell proliferation during larval central brain development of Drosophila, and suggest that Prospero acts as a key downstream effector of brat in cell fate specification and proliferation control.

Animals↗
PubMed1994

Increased susceptibility of mice infected with Schistosoma mansoni to recombinant vaccinia virus: association of viral persistence with egg granuloma formation.

BALB/c mice infected 7 weeks previously with Schistosoma mansoni and challenged with a recombinant vaccinia virus vPE16 expressing the human immunodeficiency virus envelope protein gp160 show a marked delay in hepatic viral clearance as compared to mice infected with vPE16 alone. This increase in viral persistence is accompanied by reduced gp120-specific Th1-associated cytokine responses as well as by impaired cytotoxic T lymphocyte (CTL) activity against targets expressing epitopes of the same antigen. To investigate the contribution of these defects to the observed delay in clearance of recombinant vaccinia virus, animals were challenged with vPE16 at different times following S. mansoni infection, and virus titers in tissues and viral-specific immune responses were measured simultaneously in the same animals. While normal resolution of virus occurred in schistosome-infected mice prior to parasite egg deposition, persistence within the liver was observed in animals challenged during the onset and peak phase of granuloma formation (6 to 8 weeks after S. mansoni infection). At later times, when schistosomiasis is in its chronic phase, normal viral clearance returned. This time course of viral resolution correlated in part with the observed pattern of decreased Th1 cytokine production toward viral antigens but was clearly less temporally related to the defect in virus-specific CTL activity. Immunohistochemical staining of liver sections from vaccinia/S. mansoni co-infected mice with polyclonal anti-vaccinia antibodies revealed that viral epitopes are localized primarily within granulomas. These experiments suggest that egg granulomas, by providing a microenvironment for viral expression, in combination with the cytokine imbalance present during schistosome infection, can promote the expansion of vaccinia virus and possibly other viral agents.

Animals↗
PubMed1996

Altered allogeneic response in neonatally anti-MHC class I-treated mice.

Neonatal treatment of C3H mice (H-2k) with anti-Kk monoclonal antibodies results in altered cytotoxic responses against allogeneic targets. After 2-3 weeks of antibody treatment, no difference in the number of CD4+8- or CD4-8+ T cells was observed between the antibody- and saline-treated mice. However, antibody-treated mice had a significantly reduced cytotoxic response against various allogeneic major histocompatibility complex (MHC) class I-expressing targets. The strongest reduction was observed in very young mice (up to 2 weeks of age). As the mice got older, the allo MHC-specific responses reached control levels. No significant changes in T-cell receptor (TCR)-V-region usage was observed even in young antibody-treated mice. The results suggest that the reduction in the number of positively selecting elements reduces alloreactivity and most likely also the diversity of TCR-repertoire. However, the reduced alloresponsiveness was not restricted to either allogeneic K- or D-encoded molecules, suggesting that self MHC-D-region encoded molecules can mediate positive selection of T cells able to react against both K and D region-encoded allogeneic MHC class I molecules.

Animals↗
PubMed2006

Identification of features regulating OST1 kinase activity and OST1 function in guard cells.

The phytohormone abscisic acid (ABA) mediates drought responses in plants and, in particular, triggers stomatal closure. Snf1-related kinase 2 (SnRK2) proteins from several plant species have been implicated in ABA-signaling pathways. In Arabidopsis (Arabidopsis thaliana) guard cells, OPEN STOMATA 1 (OST1)/SRK2E/SnRK2-6 is a critical positive regulator of ABA signal transduction. A better understanding of the mechanisms responsible for SnRK2 protein kinase activation is thus a major goal toward understanding ABA signal transduction. Here, we report successful purification of OST1 produced in Escherichia coli: The protein is active and autophosphorylates. Using mass spectrometry, we identified five target residues of autophosphorylation in recombinant OST1. Sequence analysis delineates two conserved boxes located in the carboxy-terminal moiety of OST1 after the catalytic domain: the SnRK2-specific box (glutamine-303 to proline-318) and the ABA-specific box (leucine-333 to methionine-362). Site-directed mutagenesis and serial deletions reveal that serine (Ser)-175 in the activation loop and the SnRK2-specific box are critical for the activity of recombinant OST1 kinase. Targeted expression of variants of OST1 kinase in guard cells uncovered additional features that are critical for OST1 function in ABA signaling, although not required for OST1 kinase activity: Ser-7, Ser-18, and Ser-29 and the ABA-specific box. Ser-7, Ser-18, Ser-29, and Ser-43 represent putative targets for regulatory phosphorylation and the ABA-specific box may be a target for the binding of signaling partners in guard cells.

Abscisic Acid↗
PubMed2000

[Experimental study on human pancreatic carcinoma treated by cytosine deaminase gene therapy].

OBJECTIVE: To explore the possibility of Escherichia coli cytosine deaminase (CD) gene on human pancreatic carcinoma gene therapy. METHODS: Recombinant adenoviruses containing a carcinoembryonic antigen (CEA) promoter were transiently introduced into SW1990, Capan-2 and Hela cells, separately. The expression of CD gene mRNA was examined by RT-PCR. CD protein level in the transduced cells was analyzed by Western blotting. The sensitivity of the cells to 5-fluorocytosine (5-FC) was determined by MTT assay. RESULTS: A specific expression of cytosine deaminase gene by adenovirus-mediated transfer exhibited only in SW1990 cells (CEA-producing). Transduction of CD gene resulted in significant sensitivity of SW1990 cells to 5-FC. The anticancer effect was seen in vivo in SW1990 xenografts nude mice with in situ CD gene transduction. CONCLUSION: The targeted expression of CD gene combined prodrug 5-FC may be a potential approach for gene therapy for human pancreatic carcinoma.

Adenocarcinoma↗
PubMed2006

Distinct distal regulatory elements control tyrosinase expression in melanocytes and the retinal pigment epithelium.

Pigment cells of mammals are characterized by two different developmental origins: cells of the retinal pigment epithelium (RPE) originate from the optic cup of the developing forebrain, whereas melanocytes arise from the neural crest. The pigmentation gene tyrosinase is expressed in all pigment cells but differentially regulated in melanocytes and RPE. The tyrosinase promoter does not confer strong expression in pigment cells in vivo, while inclusion of a distal regulatory element at position -15 kb is necessary and sufficient to provide strong expression in melanocytes. Nevertheless, the regulatory elements responsible for correct spatial and temporal tyrosinase expression in the RPE remained unidentified so far. In this report, we show that a 186 kb BAC containing the tyrosinase gene provides transgene expression in both RPE and melanocytes indicating the presence of regulatory sequences required for expression in the RPE. A deletion analysis of the BAC was performed demonstrating that a RPE-regulatory element resides between -17 and -75 kb. Using multi-species comparative genomic analysis we identified three conserved sequences within this region. When tested in transgenic mice one of these sequences located at -47 kb targeted expression to the RPE. In addition, deletion of this regulatory element within a tyrosinase::lacZ BAC provided evidence that this sequence is not only sufficient but also required for correct spatial and temporal expression in the RPE. The identification of this novel element demonstrates that tyrosinase gene expression is controlled by separate distal regulatory sequences in melanocytes and RPE.

Albinism, Oculocutaneous↗
PubMed2001

Elevated blood pressure in transgenic mice with brain-specific expression of human angiotensinogen driven by the glial fibrillary acidic protein promoter.

In addition to the circulatory renin (REN)-angiotensin system (RAS), a tissue RAS having an important role in cardiovascular function also exists in the central nervous system. In the brain, angiotensinogen (AGT) is expressed in astrocytes and in some neurons important to cardiovascular control, but its functional role remains undefined. We generated a transgenic mouse encoding the human AGT (hAGT) gene under the control of the human glial fibrillary acidic protein (GFAP) promoter to experimentally dissect the role of brain versus systemically derived AGT. This promoter targets expression of transgene products to astrocytes, the most abundant cell type expressing AGT in brain. All transgenic lines exhibited hAGT mRNA expression in brain, with variable expression in other tissues. In one line examined in detail, transgene expression was high in brain and low in tissues outside the central nervous system, and the level of plasma hAGT was not elevated over baseline. In the brain, hAGT protein was mainly localized in astrocytes, but was present in neurons in the subfornical organ. Intracerebroventricular (ICV) injection of human REN (hREN) in conscious unrestrained mice elicited a pressor response, which was abolished by ICV preinjection of losartan. Double-transgenic mice expressing the hREN gene and the GFAP-hAGT transgene exhibited a 15-mm Hg increase in blood pressure and an increased preference for salt. Blood pressure in the hREN/GFAP-hAGT mice was lowered after ICV, but not intravenous losartan. These studies suggest that AGT synthesis in the brain has an important role in the regulation of blood pressure and electrolyte balance.

Angiotensinogen↗
PubMed2000

Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-beta(1) transgene in the heart.

Increased transforming growth factor (TGF)-beta(1) activity has been observed during pathologic cardiac remodeling in a variety of animal models. In an effort to establish a causal role of TGF-beta(1) in this process, transgenic mice with elevated levels of active myocardial TGF-beta(1) were generated. The cardiac-restricted alpha-myosin heavy chain promoter was used to target expression of a mutant TGF-beta(1) cDNA harboring a cysteine-to-serine substitution at amino acid residue 33. This alteration blocks covalent tethering of the TGF-beta(1) latent complex to the extracellular matrix, thereby rendering a large proportion (>60%) of the transgene-encoded TGF-beta(1) constitutively active. Although similar levels of active TGF-beta(1) were present in the transgenic atria and ventricles, overt fibrosis was observed only in the atria. Surprisingly, increased active TGF-beta(1) levels inhibited ventricular fibroblast DNA synthesis in uninjured hearts and delayed wound healing after myocardial injury. These data suggest that increased TGF-beta(1) activity by itself is insufficient to promote ventricular fibrosis in the adult mouse ventricle.

Age Factors↗
PubMed1998

Cross-clade-specific cytotoxic T lymphocytes in HIV-1-infected children.

We studied cytotoxic T lymphocyte (CTL) cross-reactivity between human immunodeficiency virus type 1 (HIV-1) subtypes within a group of infants infected with either HIV-1 B or non-B clade. Fifteen children were infected with a clade B virus. Nine were infected with non-B virus, including two clade A, four clade D, two clade F, and one clade G. CTL activities from in vitro activated peripheral blood mononuclear cells were tested against autologous cell line infected with recombinant vaccinia viruses encoding for Env, Gag, Pol, or Nef proteins from a clade A or B isolate. HIV-1-specific CTL elicited from infection with clade B virus could lyse targets expressing clade A proteins, and vice versa. In infants with positive CTL responses, cross-clade recognition was predominant and was detected within 88% of the Pol, 83% of the Nef, 67% of the Gag, and 55% of the Env responders. Longitudinal studies showed that CTL cross-reactivity to both B and A targets was stable for several years. Elicitation of CTL reactivities capable of elimination of virus-infected cells is an important goal for the development of an efficient AIDS vaccine. The significant cross-reactivity of CTL shown in this study supports the concept that vaccines developed using a single-clade immunogen may be applicable to induce broadly reactive T cell responses.

Child↗
PubMed2004

Morning and evening peaks of activity rely on different clock neurons of the Drosophila brain.

In Drosophila, a 'clock' situated in the brain controls circadian rhythms of locomotor activity. This clock relies on several groups of neurons that express the Period (PER) protein, including the ventral lateral neurons (LN(v)s), which express the Pigment-dispersing factor (PDF) neuropeptide, and the PDF-negative dorsal lateral neurons (LN(d)s). In normal cycles of day and night, adult flies exhibit morning and evening peaks of activity; however, the contribution of the different clock neurons to the rest-activity pattern remains unknown. Here, we have used targeted expression of PER to restore the clock function of specific subsets of lateral neurons in arrhythmic per(0) mutant flies. We show that PER expression restricted to the LN(v)s only restores the morning activity, whereas expression of PER in both the LN(v)s and LN(d)s also restores the evening activity. This provides the first neuronal bases for 'morning' and 'evening' oscillators in the Drosophila brain. Furthermore, we show that the LN(v)s alone can generate 24 h activity rhythms in constant darkness, indicating that the morning oscillator is sufficient to drive the circadian system.

Animals↗
PubMed1995

Proteolytic maturation of protein C upon engineering the mouse mammary gland to express furin.

Endoproteolytic processing of the human protein C (HPC) precursor to its mature form involves cleavage of the propeptide after amino acids Lys-2-Arg-1 and removal of a Lys156-Arg157 dipeptide connecting the light and heavy chains. This processing was inefficient in the mammary gland of transgenic mice and pigs. We hypothesized that the protein processing capacity of specific animal organs may be improved by the coexpression of selected processing enzymes. We tested this by targeting expression of the human proprotein processing enzyme, named paired basic amino acid cleaving enzyme (PACE)/furin, or an enzymatically inactive mutant, PACEM, to the mouse mammary gland. In contrast to mice expressing HPC alone, or to HPC/PACEM bigenic mice, coexpression of PACE with HPC resulted in efficient conversion of the precursor to mature protein, with cleavage at the appropriate sites. These results suggest the involvement of PACE in the processing of HPC in vivo and represent an example of the engineering of animal organs into bioreactors with enhanced protein processing capacity.

Amino Acid Sequence↗
PubMed2006

The COP9 signalosome regulates Skp2 levels and proliferation of human cells.

The COP9 signalosome (CSN) is a conserved, multisubunit complex first identified as a developmental regulator in plants. Gene inactivation of single CSN subunits results in early embryonic lethality in mice, indicating that the CSN is essential for mammalian development. The pleiotropic function of the CSN may be related to its ability to remove the ubiquitin-like peptide Nedd8 from cullin-RING ubiquitin ligases, such as the SCF complex, and therefore regulate their activity. However, the mechanism of CSN regulatory action on cullins has been debated, since, paradoxically, the CSN has an inhibitory role in vitro, while genetic evidence supports a positive regulatory role in vivo. We have targeted expression of CSN subunits 4 and 5 in human cells by lentivirus-mediated small hairpin RNA delivery. Down-regulation of either subunit resulted in disruption of the CSN complex and in Cullin1 hyperneddylation. Functional consequences of CSN down-regulation were decreased protein levels of Skp2, the substrate recognition subunit of SCF(Skp2), and stabilization of a Skp2 target, the cyclin-dependent kinase inhibitor p27(Kip1). CSN down-regulation caused an impairment in cell proliferation, which could be partially reversed by suppression of p27(Kip1). Moreover, restoring Skp2 levels in CSN-deficient cells recovered cell cycle progression, indicating that loss of Skp2 in these cells plays an important role in their proliferation defect. Our data indicate that the CSN is necessary to ensure the assembly of a functional SCF(Skp2) complex and therefore contributes to cell cycle regulation of human cells.

COP9 Signalosome Complex↗
PubMed2003

TGF-beta1 induces aberrant laminin chain and collagen type IV isotype expression in the glomerular basement membrane.

Transforming growth factor-beta1 (TGF-beta1) contributes to the thickening of the glomerular basement membrane (GBM), abnormal deposition of extracellular matrix (ECM) therein and expansion of the mesangial matrix (MM) in several glomerular kidney diseases. However, the influence of TGF-beta1 on the expression of collagen IV isotypes and laminin chains in the GBM and the MM in vivo is not known in detail. By using transgenic mice with TGF-beta1 expression targeted to the juxtaglomerular apparatus and a combination of immunohistochemistry, Western blotting, immunoelectron microscopy and in situ hybridization, we investigated the contribution of different laminin chains and collagen type IV isotypes to the basement membrane thickening and mesangial expansion. We report that exposure of the glomerulus to TGF-beta1 in vivo induces aberrant deposition of fetal laminin alpha1, alpha2 and beta1 chains and collagen type IValpha1/alpha2 in the GBM. On the other hand, the TGF-beta1-mediated expansion of the mesangial ECM is dominated by the normal components. We found that the cellular origin of at least laminin alpha1 and alpha2 chains may be the glomerular endothelial cells. We speculate that the endothelial cells could contribute to TGF-beta1-induced glomerulopathy and should be considered as target cells for early intervention in glomerular diseases associated with TGF-beta1 in man.

Animals↗
PubMed1998

Molecular and immunological analysis of genetic prostate specific antigen (PSA) vaccine.

Nucleic acid immunization has been investigated as immunotherapy for infectious diseases as well as for treating specific types of cancers. In this approach, nucleic acid expression cassettes are directly inoculated into the host, whose transfected cells become the production source of novel and possibly immunologically foreign protein. We have developed a DNA vaccine construct which encodes for PSA by cloning a cDNA for PSA into a mammalian expression vector under control of a CMV promoter. We investigated and characterized the immunogenicity of PSA DNA expression cassettes in mice. PSA-specific immune responses induced in vivo by immunization were characterized by enzyme-linked immunosorbent assay (ELISA), T helper proliferation cytotoxic T lymphocyte (CTL), and flow cytometry assays. We observed a strong and persistent antibody response against PSA for at least 180 days following immunization. In addition, a significant T helper cell proliferation was observed against PSA protein. Using synthetic peptides spanning the PSA open frame, we identified four dominant T helper epitopes of PSA. Furthermore, immunization with PSA plasmid induced MHC Class I CD8+ T cell-restricted cytotoxic T lymphocyte response against tumor cell targets expressing PSA. The prostate represents a very specific functional organ critical for reproduction but not for the health and survival of the individual. Understanding the immunogenicity of PSA DNA immunization cassettes offers insight into the possible use of this tumor-associated antigen as a target for immunotherapy. These results demonstrate the ability of the genetic PSA to serve as a specific immune target capable of generating both humoral and cellular immune responses in vivo.

Animals↗
PubMed2001

Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus.

The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity. But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism. These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (gamma-aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.

Action Potentials↗
PubMed2005

T cells gene-engineered with DAP12 mediate effector function in an NKG2D-dependent and major histocompatibility complex-independent manner.

NKG2D is an important activating/co-stimulatory receptor harnessed by NK and T cells in immune surveillance. In contrast to NK cells, T cells fail to express the activation-signaling molecule DAP12 even when activated and, therefore, ligation of NKG2D alone is insufficient to induce T cell cytolytic function. To test whether we could endow T cells with NK cell-like effector function, we have engineered DAP12 into T cells by retroviral transduction (T-DAP12). T-DAP12 cells were demonstrated to specifically secrete interferon-gamma following receptor ligation and to mediate potent and specific lysis of the NKG2D ligand (NKG2D-L) (Rae-1beta) expressing MHC class I-deficient and class I-sufficient tumors. To circumvent the inability of T-DAP12 cells to proliferate following NKG2D ligation by Rae-1beta expressing tumors, DAP12 was engineered into OT-1 cells with an endogenous T cell receptor specific for chicken ovalbumin peptide (amino acids 257-264). Importantly, following a period of proliferation through endogenous T cell receptor ligation, OT-1-DAP12 cells retained specificity against NKG2D-L expressing major histocompatibility complex class I-deficient tumor. In adoptive transfer experiments, T-DAP12 cells enhanced the survival of NK cell-depleted RAG-1-deficient mice inoculated with RMA-S-Rae-1beta but not parental RMA-S tumors. Overall, this study demonstrated the significant potential of suppressing tumors and other cellular targets expressing NKG2D-L by endowing T cells with innate NK cell-like function.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Positive impact of inhibitory Ly49 receptor-MHC class I interaction on NK cell development.

NK cells can kill MHC-different or MHC-deficient but not syngeneic MHC-expressing target cells. This MHC class I-specific tolerance is acquired during NK cell development. MHC recognition by murine NK cells largely depends on clonally distributed Ly49 family receptors, which inhibit NK cell function upon ligand engagement. We investigated whether these receptors play a role for the development of NK cells and provide evidence that the expression of a Ly49 receptor transgene on developing NK cells endowed these cells with a significant developmental advantage over NK cells lacking such a receptor, but only if the relevant MHC ligand was present in the environment. The data suggest that the transgenic Ly49 receptor accelerates and/or rescues the development of NK cells which would otherwise fail to acquire sufficient numbers of self-MHC-specific receptors. Interestingly, the positive effect on NK cell development is most prominent when the MHC ligand is simultaneously present on both hemopoietic and nonhemopoietic cells. These findings correlate with functional data showing that MHC class I ligand on all cells is required to generate functionally mature NK cells capable of reacting to cells lacking the respective MHC ligand. We conclude that the engagement of inhibitory MHC receptors during NK cell development provides signals that are important for further NK cell differentiation and/or maturation.

Animals↗
PubMed1991

Differential effect of lithium on fos protooncogene expression mediated by receptor and postreceptor activators of protein kinase C and cyclic adenosine monophosphate: model for its antimanic action.

Lithium salts are the most effective agents used in treating manic-depressive illness. It has been suggested that lithium's therapeutic efficacy could be due to an inhibitory effect on either inositol phospholipid (IP) and/or cyclic nucleotide metabolism. We have investigated the effect of lithium on these two signal transduction pathways in PC12 pheochromocytoma cells by studying a common effector target, expression of the fos protooncogene. We find that lithium, at therapeutic doses, has an augmenting effect on phosphatidylinositol (PI)-mediated fos expression induced by activating a muscarinic cholinergic pathway, whereas it has no effect, at tenfold the therapeutic dose, on fos expression induced by receptor or postreceptor activators of cyclic adenosine monophosphate (cAMP). The lithium augmenting effect is also observed when the cells are treated with phorbol esters, which directly activate protein kinase C (PKC), suggesting that the level of lithium's interaction with the IP pathway is at the postreceptor level. We also show that phorbol esters induce extensive down regulation of subsequent cholinergic and phorbol ester responsiveness as well as heterologous down regulation of cAMP responses. Treatment of down-regulated cells with lithium leads to an enhanced responsiveness when cells are rechallenged with agonists that activate PKC but not by agonists that stimulate cAMP. We also show that carbamazepine, another antimanic agent, has an inhibitory effect on cAMP-mediated fos but no effect on the IP pathway. The opposite effects of lithium and carbamazepine on two critical transducing systems suggest a model for the antimanic action of these agents.

Adrenal Gland Neoplasms↗