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PubMed1990

Expression of the cell surface antigens RET-PE2 and N-CAM by rat retinal pigment epithelial cells during development and in tissue culture.

Invagination of the optic vesicle to form the optic cup results in the formation of two apposed layers of neuroepithelium which follow divergent developmental pathways. Changes in the expression of cell surface molecules may be either the cause or result of important inductive signals during this process. We have used immunological reagents to study the expression of two molecules in the rat: the neural cell adhesion molecule N-CAM, and a cell membrane-associated protein which is specific for pigment epithelium in the adult, RET-PE2. Both N-CAM and RET-PE2 are present in both layers of the optic cup at embryonic age E13, but they become restricted to inner retina and pigment epithelium, respectively, by E17 and maintain that pattern of expression in the normal adult. Culture of pigment epithelial cells results in the reexpression of N-CAM and the continued expression of RET-PE2. Western blotting reveals that the size and relative proportions of the 180- and 140-kDa N-CAM molecules synthesized by rat pigment epithelial cells in vitro differ from that made by rat brain, retina and liver. Embryonic RPE N-CAM contains the sulfated carbohydrate recognized by the HNK-1 antibody, but this epitope was not present on N-CAM synthesized by cultured RPE cells. The reexpression of an embryonic antigen when placed in culture suggests that pigment epithelial cells retain some degree of plasticity in the adult state.

Animals↗
PubMed2002

Differential expression and functional analysis of three calmodulin isoforms in germinating pea (Pisum sativum L.) seeds.

Implication of the ubiquitous, highly conserved, Ca2+ sensor calmodulin (CaM) in pea seed germination has been investigated. Mass spectrometry analysis of purified CaM revealed the coexistence in seeds of three protein isoforms, diverging from each other by single amino acid substitution in the N-terminal alpha-helix. CaM was shown to be encoded by a small multigenic family, and full-length cDNAs of the three isoforms (PsCaM1, 2 and 3) were isolated to allow the design of specific primers in more divergent 5' and 3' untranslated regions. Expression studies, performed by semiquantitative RT-PCR, demonstrated differential expression patterns of the three transcripts during germination. PsCaM1 and 2 were detected at different levels in dry axes and cotyledons, and they accumulated during imbibition and prior to radicle protrusion. In contrast, PsCaM3 appeared only upon radicle protrusion, then gradually increased in both tissues. To characterise the biochemical properties of the CaM isoforms, functional analyses were conducted in vitro using recombinant Strep-tagged proteins (CaM1-ST, CaM2-ST and CaM3-ST) expressed in Escherichia coli. Gel mobility shift assays revealed that CaM1-ST exhibited a stoichiometric binding of a synthetic amphiphilic CaM kinase II peptide while CaM2-ST and CaM3-ST affinities for the same peptide were reduced. Affinity differences were also observed for CaM isoform binding to Trp-3, an idealised helical CaM-binding peptide. However, the three proteins activated in the same way the CaM-dependent pea NAD kinase. Finally, the significance of the single substitutions upon CaM interaction with its targets is discussed in a structural context.

Base Sequence↗
PubMed1994

Selective induction of the beta chemokine C10 by IL-4 in mouse macrophages.

The beta chemokines are a family of 8- to 12-kDa leukocyte chemoattractants that are typically produced by activated macrophages or lymphocytes. We examined the expression in primary macrophages of a recently described, and as yet functionally uncharacterized, murine beta chemokine, C10, and contrasted its regulation with that of several other beta chemokines. Although three other beta chemokines, macrophage inflammatory protein-1 alpha (MIP-1 alpha), JE, and RANTES, were all induced by LPS treatment of bone marrow-derived macrophages (BMM) and/or resident peritoneal macrophages (RPM), LPS stimulation of C10 was never observed. Conversely, IL-3 and granulocyte macrophage-CSF (GM-CSF) strongly induced C10 in both macrophage populations, whereas MIP-1 alpha and RANTES showed a weaker induction restricted to BMM. JE was strongly induced but only in BMM. Finally, IL-4 strongly induced C10 in a dose-dependent manner in both BMM and RPM but failed to stimulate any of the other three beta chemokines. The accumulation of C10 protein in culture supernatants paralleled the induction of mRNA, and the combination of IL-4 and GM-CSF led to enhanced protein levels. The expression of the C10 message in response to cytokines was completely blocked by cycloheximide, whereas the other three chemokines were all overexpressed in the presence of this inhibitor. These results demonstrate a sharp divergence between the regulation of C10 expression and that of other chemokines and suggest that this molecule may have distinct functions in host defense.

Amino Acid Sequence↗
PubMed1998

Further analysis of interleukin-2 receptor subunit expression on the different human peripheral blood mononuclear cell subsets.

We have investigated the expression of the three components of the interleukin-2 receptor (IL-2Ralpha, IL-2Rbeta, and IL-2Rgamma) on the surface of the various peripheral blood mononuclear cell (PBMC) subsets by flow cytometry analysis. The PBMC were immediately isolated (ficoll) from blood collected on heparin as anticoagulant. The three IL-2R components are absent or only marginally detectable on CD4 T lymphocytes. No expression of the IL-2R chains is found for the B lymphocytes. In most donors, the three chains are not detectable on CD8 T lymphocytes, but for a few of them, IL-2Rbeta or IL-2Rgamma are clearly expressed. CD56 high (IL-2Ralpha+) and CD56 low (IL-2Ralpha-) natural killer (NK) cells express IL-2Rbeta, but not IL-2Rgamma. IL-2Rgamma is expressed by monocytes of all donors although with variable intensity. When blood is collected on other anticoagulants or when cells are isolated 1 day after collection, IL-2Ralpha, IL-2Rbeta, and IL-2Rgamma are largely expressed on the surface of most PBMC. This observation provides a possible explanation for divergent data previously reported on IL-2R expression. Finally, we show that IL-2Rgamma, which is not detectable on the cell surface of lymphocytes, is nevertheless expressed and stored as an intracellular component. This result is in agreement with the constitutive expression of the IL-2Rgamma gene and suggests a specific regulatory mechanism for IL-2Rgamma membrane translocation.

Anticoagulants↗
PubMed2007

Stretch-activated signaling pathways responsible for early response gene expression in fetal lung epithelial cells.

High-tidal volume ventilation has been shown to increase the expression of several inflammation-associated genes prior to overt physiologic lung injury. Herein, using an in vitro stretch system, we investigated the mechanotransduction pathways involved in ventilation-induced expression of these early response genes (i.e., early growth response gene (Egr)1, heat-shock protein (HSP)70, and the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, and MIP-2). Mechanical stretch of fetal lung epithelial cells activated various signaling pathways, resulting in transient or progressive increases in gene expression of the early response genes. The transient increase in Egr1 and IL-6 expression was mediated via p44/42 mitogen-activated protein kinase (p44/42 MAPK), while nuclear factor-kappaB (NF-kappaB) was responsible for the sustained and progressive increase in expression of HSP70 and MIP-2. Blockage of Egr-1 expression did not affect the upregulation of IL-6, HSP70, MIP-2, and itself by stretch. Inhibition of calcium mobilization abolished stretch-induced p44/42 MAPK activation and NF-kappaB nuclear translocation as well as increased expression of all early response genes. Similar results were obtained with an inhibitor of Ras. These results suggest that mechanical stretch of fetal lung epithelial cells evokes a complex network of signaling molecules, which diverge downstream to regulate the temporal expression of a unique set of early response genes, but upstream converge at calcium. Thus, calcium mobilization may be a point of hierarchical integration of mechanotransduction in lung epithelial cells.

Animals↗
PubMed1994

Mouse homeobox gene Dbx: sequence, gene structure and expression pattern during mid-gestation.

Homeobox genes regulate multiple aspects of mouse development including the axial patterning in the central nervous system. Some of the more divergent members of this gene family are expressed in the anterior region of the central nervous system where the Hox genes are not expressed. We previously reported the isolation of a mouse homeobox gene, Dbx, from the forebrain. Here we describe its genomic structure, complete cDNA sequence, characterization of the basal promoter and the expression pattern at different stages of the developing embryo. During early and mid-gestation, Dbx expression is restricted to the telencephalon, diencephalon, dorsal mesencephalon and spinal cord. At later gestational stages, Dbx expression continues in the dorsal mesencephalon and diencephalon, in which expression is more restricted than at the earlier stages. Dbx transcripts were also detected in the primitive cerebellum. At all stages, the Dbx expressing regions contain a high proportion of proliferating cells, suggesting a role for Dbx in patterning the central nervous system during embryogenesis.

Amino Acid Sequence↗
PubMed1991

Heterogeneity in plasminogen activator (PA) levels in human prostate cancer cell lines: increased PA activity correlates with biologically aggressive behavior.

Plasminogen activators (PA), particularly the lower Mr urokinase (u-PA) type, have been associated with tumor cell invasion and metastasis. We have examined the expression of PA by two human prostate cancer cell lines (PC-3 and DU-145) using functional and immunologic techniques. The culture media and cell extracts of the more aggressive PC-3 cell line contained more than two-fold greater PA activity than the relatively indolent DU-145 cell line. Zymographic studies identified the PA expressed as u-PA. PC-3 cells expressed an additional lower molecular weight form of u-PA not noted in DU-145 cells. Heterogeneity in u-PA expression was shown by the fibrin lysis assay, immunohistochemistry, and dual parameter flow cytometry indicating the presence of phenotypically divergent cell populations. Increased u-PA expression may identify those tumor cells that possess aggressive biological potential.

Flow Cytometry↗
PubMed1989

HLA class I gene expression on human primary tumours and autologous metastases: demonstration of selective losses of HLA antigens on colorectal, gastric and laryngeal carcinomas.

The expression of HLA class I antigens was studied in 99 primary tumour (colorectal, gastric and laryngeal carcinomas) and 57 autologous metastases using immunohistological techniques and monoclonal antibodies against class I monomorphic determinants, HLA-B isotypic determinants and HLA polymorphic determinants. Fourteen per cent of colorectal, 9.6% of gastric and 20% of laryngeal carcinomas completely lacked class I molecules. Selective losses of HLA-B antigens were also detected in 8.8, 3.4 and 5.8% of these tumours respectively. Taking into account complete and selective loss of HLA-B the average alteration in the class I molecules expression totalled 21%. The comparison of class I expression between primary tumours and autologous metastases showed differences in 24% of the patients. These differences consisted mainly in a decrease of class I expression by metastases. Nevertheless, four types of divergence were detected in laryngeal carcinomas, namely: +/-, +/+, -/+, -/-. In addition, a clear correlation between degree of differentiation and class I expression was observed in laryngeal tumours. Finally, when class I gene RFLPs were compared with DNA from 15 tumours and autologous normal mucosa or peripheral lymphocytes, no differences were detected between these samples.

Blotting, Southern↗
PubMedDate not supplied

Immunohistochemical expression of transforming growth factor beta 1 and nm-23 H1 antioncogene in prostate cancer: divergent correlation with clinicopathological parameters.

BACKGROUND: Prostate cancer is one of the main causes of morbidity and mortality among men. Several oncogenes and growth factors have been studied in an attempt to explain the molecular basis of carcinogenesis and progress of this carcinoma. In this study we correlated the immunohistochemical expression of antioncogene nm-23 H1 and transforming growth factor beta 1 (TGF-beta 1) with the clinical stage, PSA values, Gleason score and survival in prostate cancer. MATERIALS AND METHODS: Fifty nine patients with prostate cancer were evaluated. PSA measurement, Gleason score determination and clinical staging were recorded for all the patients by the time of initial diagnosis and prior to any treatment. Follow-up ranged from 12 to 40 months. Tissue sections from representative areas of the tumors were immunohistochemically stained for nm-23 H1 and TGF-beta 1. The expression of these markers was correlated with stage, PSA values, Gleason score and survival. RESULTS: There was a negative correlation between nm-23 H1 staining and tumor stage and grade. High grade (Gleason score 8-10) and stage D tumors showed weaker staining than low stage and grade tumors. There was a positive correlation between TGF-beta 1 staining, tumor stage and serum PSA levels. Additionally, TGF-beta 1 proved to be a negative predicting factor for patient survival. In tumors expressing both markers, TGF-beta 1 was the one to determine the aggressiveness of the carcinoma. CONCLUSIONS: nm-23 H1 appears to be a tumor suppressor gene in prostate cancer, while TGF-beta 1 may act as a stimulating agent provoking aggressive behavior and metastasis. Their immunohistochemical staining may constitute complementary information in the evaluation of prostate cancer patients.

Aged↗
PubMedDate not supplied

The value of p53 protein expression in gallbladder carcinoma: analysis of 60 cases.

BACKGROUND/AIMS: Few studies, with small samples and diverging results, have been performed to evaluate the p53 protein expression in gallbladder carcinoma and its relationship to different clinicopathological parameters. Based on these facts, we performed a study for the purpose of assessing p53 expression in this disease and its association to prognostic factors. METHODOLOGY: Samples of 141 gallbladders, with 60 cases of carcinoma, 62 cholelithiasis and 19 without gallstones were assessed using an immunohistochemical technique for the expression of p53 protein, and analyzed for prognosis, survival and other clinicopathological parameters. RESULTS: p53 expression was positive in 58.3% of carcinomas of the gallbladder, 9.7% of the chronic cholecystitis and 10.5% of the gallbladders not associated to stones. In cases of carcinoma of the gallbladder there was no statistically significant association between the expression of this protein, the prognostic factors, histological type or grade, presence of gallstones and survival. CONCLUSIONS: The mutation of gene p53 is involved in the pathogenesis of carcinoma of the gallbladder, and the intense chronic inflammatory process associated or not with cholelithiasis, appears to be one of the factors involved in the genesis of this process. Our data do not show an association between p53 protein expression and patient's survival prognosis.

Adenocarcinoma↗
PubMed1996

The Drosophila kekkon genes: novel members of both the leucine-rich repeat and immunoglobulin superfamilies expressed in the CNS.

We have identified two members of a novel class of genes in Drosophila that encode putative transmembrane proteins with six leucine-rich repeats and a single immunoglobulin loop. These two molecules, Kek1 and Kek2, show striking conservation in their extracellular domains and have large and more divergent intracellular regions. Both genes are expressed in neurons as they differentiate in the embryonic central nervous system (CNS). kek1 is also expressed in other patterned epithelia, such as the follicle cells of the developing egg chamber, where it is found in a dorsal-ventral gradient around the oocyte. The homology of the kek genes to other known adhesion and signaling molecules, together with their expression patterns, suggests that both genes are involved in interactions at the cell surface. Genetic analysis reveals that deletion of the kek1 gene causes no obvious developmental defects. The coexpression of kek2 in the CNS leads us to suggest that Kek1 is part of a family of cell surface proteins with redundant function.

Amino Acid Sequence↗
PubMed1997

Comparative analysis of AP-2 alpha and AP-2 beta gene expression during murine embryogenesis.

Transcription factor AP-2 has been identified as playing important roles during embryonic development of the neural tube, neural crest derivatives, skin, and urogenital tissues. Recently, we isolated a second AP-2 transcription factor, AP-2 beta, which is 76% homologous to the previously known AP-2 alpha gene, and showed that both genes are coexpressed in murine embryos at day 13.5 and 15.5 post coitum (pc). In the current study, we used specific cRNA probes to study comparatively AP-2 alpha and AP-2 beta expression by in situ hybridization of murine embryonic tissue sections. Our results reveal that expression of both genes starts at day 8 pc in the lateral head mesenchyme and extraembryonic trophoblast. The expression pattern was identical until day 10 pc but diverged significantly during later stages of development. From day 11 forward, specific expression patterns of AP-2 alpha and AP-2 beta mRNA were observed. Specific AP-2 beta signals were detected in the midbrain, sympathetic ganglia, adrenal medulla, and cornea. Specific AP-2 alpha signals were present in the limb buds, dorsal root ganglia, tooth germs, and Moll's and Meibom's glands. In contrast, expression of both genes occurred in skin, facial mesenchyme, spinal cord, cerebellum, and renal tubular epithelia. Our results indicate that both genes are expressed with different temporal and spatial patterns during embryonic development.

Animals↗
PubMed1992

Myosin heavy chain composition of single fibres and their origins and distribution in developing fascicles of sheep tibialis cranialis muscles.

The myosin heavy chain (MHC) composition of single muscle fibres in developing sheep tibialis cranialis muscles was examined immunohistochemically with monoclonal antibodies to MHC isozymes. Data were collected with conventional microscopy and computerized image analysis from embryonic day (E) 76 to postnatal day (PN) 20, and from adult animals. At E76, 23% of the young myofibres stained for slow-twitch MHC. The number of these fibres considerably exceeded the number of primary and secondary myotubes. By E100, smaller fibres, negative for slow-twitch MHC, encircled each fibre from the initial population to form rosettes. A second population of small fibres appeared in the unoccupied spaces between rosettes. Small fibres, whether belonging to rosettes or not, did not initially express slow-twitch MHC, expressing mainly neonatal myosin instead. These small fibres then diverged into three separate groups. In the first group most fibres transiently expressed adult fast myosin (maximal at E110-E120), but in the adult expressed slow myosin. This transformation to the slow MHC phenotype commenced at E110, was nearing completion by 20 postnatal days, and was responsible for approximately 60% of the adult slow twitch fibre population. In the other two groups expression of adult fast MHC was maintained, and in the adult they accounted for 14% (IIa MHC) and 17% (IIb MHC) of the total fibre numbers. We conclude that muscle fibre formation in this large muscle involves at least three generations of myotube. Secondary myotubes are generated on a framework of primary myotubes and both populations differentiate into the young myofibres which we observed at E76 to form rosettes. Tertiary myotubes, in turn, appear in the spaces between rosettes and along the borders of fascicles, using the outer fibres of rosettes as scaffolds.

Animals↗
PubMed2005

Expression of AmHNF6, a sea star orthologue of a transcription factor with multiple distinct roles in sea urchin development.

The sea urchin transcription factor SpHNF6 is an early activator of differentiation genes in skeletogenic lineages and regulatory genes in the oral ectoderm. We report here the cloning and the expression of an orthologue of this gene, AmHNF6, from the sea star Asterina miniata. The vertebrate and the echinoderm hnf6 and onecut genes belong to the novel ONECUT homeo domain class of transcription factors. In blastula stage sea star embryos, AmHNF6 is expressed everywhere except around the vegetal pole. As is observed in sea urchin, by the end of gastrulation, the expression of AmHNF6 is distinctly localized to the ciliary bands. This terminal phase of expression has remained unchanged since the divergence of these two taxa half a billion years ago.

Amino Acid Sequence↗
PubMed1988

Concerted gene duplications in the two keratin gene families.

Evolutionary trees were derived from the keratin protein sequences using the Phylogeny Analysis Using Parsimony (PAUP) set of programs. Three major unexpected conclusions were derived from the analysis: The smallest keratin protein subunit, K#19 (Moll et al. 1982), is not the most primitive one, but has evolved to fulfill a highly specialized function, presumably to redress the unbalanced synthesis of keratin subunits. Second, the ancestors of keratins expressed in the early embryonic stages, K#8 and K#18, were the first to diverge from the ancestors of all the other keratins. The branches leading to these two keratins are relatively short, indicating a comparatively strong selection against changes in the sequences of these two proteins. Third, the two keratin families show extraordinary parallelism in their patterns of gene duplications. In both families the genes expressed in embryos diverged first, later bursts of gene duplications created the subfamilies expressed in various differentiated cells, and relatively recent gene duplications gave rise to the hair keratin genes and separated the basal cell-specific keratin from those expressed under hyperproliferative conditions. The parallelism of gene duplications in the two keratin gene families implies a mechanism in which duplications in one family influence duplication events in the other family.

Animals↗
PubMedDate not supplied

Developmental mechanisms of threshold evolution in a polyphenic beetle.

Polyphenic development is thought to play a pivotal role in the origin of morphological novelties. However, little is known about how polyphenisms evolve in natural populations, the developmental mechanisms that may mediate such evolution, and the consequences of such modification for patterns of morphological variation. Here we examine the developmental mechanisms of polyphenism evolution in highly divergent natural populations of the dung beetle, Onthophagus taurus. Males of this species express two alternative morphologies in response to larval feeding conditions. Favorable conditions cause males to grow larger than a threshold body size and to develop a pair of horns on their heads. Males that encounter relatively poor conditions during larval life do not reach this threshold size and remain hornless. Exotic populations of O. taurus have diverged dramatically in body size thresholds in less than 40 years since introduction to new habitats, resulting in the expression of highly divergent and novel horn length-body size scaling relationships in these populations. Here we show that larvae of populations that have evolved a larger threshold body size (1) have to accumulate greater mass to become competent to express the horned morph, (2) require more time to complete the final instar, (3) are less sensitive to the juvenile hormone (JH) analogue methoprene, and (4) exhibit a delay in the sensitive period for methoprene relative to other developmental events. JH has been shown previously to control horn expression in this species. Our results show that threshold evolution may be mediated via changes in the degree and timing of sensitivity to JH and may result in correlated changes in the dynamics and duration of larval development. Strain-specific differences in JH sensitivity have previously been demonstrated in other insects. However, to the best of our knowledge this is the first demonstration that changes in the timing of the sensitive period for JH may play an equally important role in the evolution of novel thresholds. We discuss our findings in the context of the developmental regulatory mechanisms that underlie polyphenic development and use our results to explore the consequences of, and constraints on, polyphenism evolution in nature.

Animals↗
PubMed2002

Trypanosoma brucei expression-site-associated-gene-8 protein interacts with a Pumilio family protein.

The expression site (ES) loci of Trypanosoma brucei are a valuable model for allelic exclusion and post-transcriptional regulation in a highly divergent eukaryote. ES exist to facilitate the expression and switching of the variant surface glycoproteins (VSG) that are central to trypanosome virulence and persistence. A collection of other potential virulence determinants, known as expression-site-associated-genes (ESAGs), are co-transcribed from the single upstream promoter. ESAGs may be involved in regulating the transcriptional state of the ES, as well as contributing additional surface proteins and receptors. We have previously shown that a putative regulatory protein, ESAG8, accumulates within the nucleolus, although 20% of the protein is cytoplasmic. Here we identify TbPUF1, a cytoplasmic ESAG8-interacting protein that falls into the Puf family of regulators of mRNA stability. Our experiments show that, as in other Puf family proteins, the most C-terminal repeats of TbPUF1 mediate its interaction with ESAG8. TbPUF1 is essential for cell viability, and preliminary results suggest that its overexpression seriously affects parasite virulence. T. brucei is the most evolutionary divergent organism in which a Puf family protein has been identified, and our initial experiments suggest that this protein may also regulate RNA stability in trypanosomes.

Amino Acid Sequence↗
PubMed1988

Characterization of cDNA sequences for LHCI apoproteins in Euglena gracilis: the mRNA encodes a large precursor containing several consecutive divergent polypeptides.

Screening of a lambda gt11 cDNA expression library with antibodies directed against LHCII allowed the detection of several clones which differ markedly from the previously described cDNAs encoding LHCII apoproteins. A Northern analysis revealed a transcript size of 4.2 kb, whereas clones encoding LHCII hybridize with mRNAs in the range of 7.5 kb. Nucleotide sequencing of 2 clones showed open reading frames of 530 and 331 codons, respectively. Within these reading frames, 5 analogous motifs can be delimited corresponding to coding regions for around 180 amino acids (molecular weight, 18-19 kDa). The 5 segments share between 50% and 80% homology. Comparison with a tomato LHCI sequence indicates conserved regions at the two ends, and a central part highly divergent and containing a large deletion. By hybrid-selected translation, followed by immunoprecipitation with a monoclonal antibody directed against LHCI apoprotein, a protein of around 100 kDa is obtained. In vivo, the same antibody recognizes peptides of around 20 kDa. These results, coupled with our previous observations concerning LHCII, confirm that in Euglena at least, some chloroplast proteins encoded in the nucleus are synthesized by large mRNAs containing the information for several consecutive divergent peptides. Implications for processing and chloroplast import are discussed.

Amino Acid Sequence↗