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PubMed1989

Transmembrane topography and evolutionary conservation of synaptophysin.

Synaptophysin is the major integral membrane protein of small synaptic vesicles. Its primary structure deduced from rat and human complementary DNA sequences predicts that synaptophysin contains four transmembrane regions and a carboxyl-terminal domain having a novel repetitive structure. To elucidate the transmembrane organization of this protein in the synaptic vesicle, five antipeptide antibodies were raised. The site-specific antibodies were used to map the cognate sequences to the cytoplasmic or intravesicular side of the synaptic vesicle membrane by determining the susceptibility of the epitopes to proteolysis. The results confirm a topographic model for synaptophysin in which the protein spans the vesicle membrane four times, with both the amino and carboxyl terminus being cytoplasmic. In addition, the evolutionary conservation of the synaptophysin domains was addressed as a function of their membrane localization. To this end the primary structure of bovine synaptophysin was determined. Sequence comparisons between bovine, rat, and human synaptophysin revealed that only the intravesicular loops showed a significant number of amino acid substitutions (22%), while the transmembrane regions and cytoplasmic sequences were highly conserved (3% substitutions). These results depict synaptophysin as a protein with multiple membrane spanning regions whose functional site is likely to reside in highly conserved intramembranous and cytoplasmic sequences.

Amino Acid Sequence↗
PubMed2003

Human synaptobrevin-like 1 gene basal transcription is regulated through the interaction of selenocysteine tRNA gene transcription activating factor-zinc finger 143 factors with evolutionary conserved cis-elements.

The synaptobrevin-like 1 (SYBL1) gene is ubiquitously expressed and codes for an unusual member of the v-SNAREs molecules implicated in cellular exocytosis. This X-linked gene has the peculiarity of also being present on the Y chromosome in a transcriptional inactive status. Moreover, although ubiquitous, the function of SYBL1 is prominent in specific tissues, such as brain. As a first insight into the molecular mechanisms controlling SYBL1 expression, in this report we describe the extent and role of SYBL1 upstream regions and characterize the binding of trans-acting factors. In vivo foot-printing experiments identify three protected regions. Band shift and transient reporter gene assays indicate a strong role of two of these evolutionary conserved regions in regulating SYBL1 transcription. Because one site is the classical CAAT box, we characterized the binding to the other site of the mammalian homologues of the selenocysteine tRNA gene transcription activating factor (Staf) family, zinc-finger transcription factors, and their role in regulating SYBL1 expression. The results reported here clarify that a Staf-zinc finger family factor, together with the CAAT factor, is the major nuclear protein bound to the SYBL1 promoter region and is responsible for its regulation in HeLa cells, thus identifying the basic control of SYBL1 transcription. In vivo binding of Staf proteins to the SYBL1 promoter is confirmed by chromatin immunoprecipitation assays. Our results identify a fourth mRNA promoter stimulated by a member of the Staf-zinc finger family, the function of which on mRNA polymerase II promoters is still very poorly understood.

Animals↗
PubMed1993

[Molecular-genetic analysis of expression features of the evolutionary-conservative neurogene Nc73EF of Drosophila melanogaster].

Molecular-genetic analysis of the Nc (neural conserved) genome sequence of Drosophila melanogaster located at the position 73EF of Drosophila melanogaster was performed. The Nc73EF sequence was shown to be expressed in the nervous system of Drosophila. We constructed the restriction map of this sequence and revealed the main RNA-coding fragment in the 5'-3' orientation. The RNA-dot analysis data demonstrated that expression of the Nc73EF transcripts took place mainly in the nervous system. Hybridization with the human brain poly(A)+RNA confirmed the basic RNA-coding fragment to be evolutionary conservative. Southern blot analysis showed this fragment to be unique in the Drosophila genome. Northern blots detected three transcripts of this DNA fragment.

Animals↗
PubMed2005

Brummer lipase is an evolutionary conserved fat storage regulator in Drosophila.

Energy homeostasis, a fundamental property of all organisms, depends on the ability to control the storage and mobilization of fat, mainly triacylglycerols (TAG), in special organs such as mammalian adipose tissue or the fat body of flies. Malregulation of energy homeostasis underlies the pathogenesis of obesity in mammals including human. We performed a screen to identify nutritionally regulated genes that control energy storage in the model organism Drosophila. The brummer (bmm) gene encodes the lipid storage droplet-associated TAG lipase Brummer, a homolog of human adipocyte triglyceride lipase (ATGL). Food deprivation or chronic bmm overexpression depletes organismal fat stores in vivo, whereas loss of bmm activity causes obesity in flies. Our study identifies a key factor of insect energy homeostasis control. Their evolutionary conservation suggests Brummer/ATGL family members to be implicated in human obesity and establishes a basis for modeling mechanistic and therapeutic aspects of this disease in the fly.

Adipocytes↗
PubMed2003

Evolutionary conservation of the U7 small nuclear ribonucleoprotein in Drosophila melanogaster.

The U7 snRNP involved in histone RNA 3' end processing is related to but biochemically distinct from spliceosomal snRNPs. In vertebrates, the Sm core structure assembling around the noncanonical Sm-binding sequence of U7 snRNA contains only five of the seven standard Sm proteins. The missing Sm D1 and D2 subunits are replaced by U7-specific Sm-like proteins Lsm10 and Lsm11, at least the latter of which is important for histone RNA processing. So far, it was unknown if this special U7 snRNP composition is conserved in invertebrates. Here we describe several putative invertebrate Lsm10 and Lsm11 orthologs that display low but clear sequence similarity to their vertebrate counterparts. Immunoprecipitation studies in Drosophila S2 cells indicate that the Drosophila Lsm10 and Lsm11 orthologs (dLsm10 and dLsm11) associate with each other and with Sm B, but not with Sm D1 and D2. Moreover, dLsm11 associates with the recently characterized Drosophila U7 snRNA and, indirectly, with histone H3 pre-mRNA. Furthermore, dLsm10 and dLsm11 can assemble into U7 snRNPs in mammalian cells. These experiments demonstrate a strong evolutionary conservation of the unique U7 snRNP composition, despite a high degree of primary sequence divergence of its constituents. Therefore, Drosophila appears to be a suitable system for further genetic studies of the cell biology of U7 snRNPs.

Amino Acid Sequence↗
PubMed2000

Drosophila pro-apoptotic Bcl-2/Bax homologue reveals evolutionary conservation of cell death mechanisms.

Genetic analysis of programmed cell death in Drosophila reveals many similarities with mammals. Heretofore, a missing link in the fly has been the absence of any Bcl-2/Bax family members, proteins that function in mammals as regulators of mitochondrial cytochrome c release. A Drosophila homologue of the human killer protein Bok (DBok) was identified. The predicted structure of DBok is similar to pore-forming Bcl-2/Bax family members. DBok induces apoptosis in insect and human cells, which is suppressible by anti-apoptotic human Bcl-2 family proteins. A caspase inhibitor suppressed DBok-induced apoptosis but did not prevent DBok-induced cell death. Moreover, DBok targets mitochondria and triggers cytochrome c release through a caspase-independent mechanism. These characteristics of DBok reveal evolutionary conservation of cell death mechanisms in flies and humans.

Amino Acid Sequence↗
PubMed2004

Evolutionary conservation of a novel splice variant of the Cds1/CHK2 checkpoint kinase restricted to its regulatory domain.

The Cds1/CHK2 kinase plays a key role in the activation of the G(2) checkpoint after DNA damage. Here we report the existence in fission yeast of a short variant (Sv) of Cds1 that is produced through an alternative splicing mechanism leading to a frame shift and premature termination. This SvCds1 protein consists solely of the regulatory region and lacks the catalytic domain. Expression of SvCds1 increases sensitivity to ionizing radiation and, to a lesser extent, to hydroxyurea, but not to UV radiation. We also report that in the human orthologue of Cds1, CHK2, differential splicing of a cryptic exon leads to a frame shift and premature termination producing a short variant (SvCHK2). Thus, we have discovered the existence of an evolutionary conserved mechanism ensuring the production of a catalytically inactive variant Cds1/CHK2 that is restricted to SQTQ and FHA domains and that can act as a dominant negative. The role that this short variant of Cds1/CHK2 might play in the response to DNA damage and the physiopathological consequences are discussed.

Alternative Splicing↗
PubMed2005

Functional analysis of evolutionary conserved clustering of bZIP binding sites in the baculovirus homologous regions (hrs) suggests a cooperativity between host and viral transcription factors.

The genome of the Autographa californica Multinucleocapsid Polyhedrosis Virus (AcMNPV) contains nine interspersed homologous regions (hrs) that function as potent enhancer sequences when linked in cis to either viral or heterologous RNA polymerase II-dependent promoters. Their activity is strongly increased by the binding of the major immediate early viral transregulator IE1 on 28-mer palindromic sites present in hrs. We show that hrs of AcMNPV additionally carry, in the interpalindromic sequences, a large number of cAMP response elements (CRE) and TPA response elements (TRE), known to bind ubiquitous cellular transcription factors of the bZIP family. Moreover, these clusters of CRE and TRE motifs are concentrated in hrs. Analysis of the 25 baculovirus genomes sequenced so far reveals that these motifs are evolutionary conserved in Lepidoptera NPVs, suggesting a functional role in the hr enhancer function. Consistently, EMSA experiments indicate that CRE and on a lesser extent TRE sites specifically bind insect host factors. Moreover, reporter assays reveal that these CRE sites have an additive stimulatory effect on RNAPol II-dependent transcription in Sf9 cells and are potentially able to synergize with the IE1-binding palindrome.

Allosteric Regulation↗
PubMed2002

Genomic structure and evolutionary conservation of the tyrosinase gene family from Fugu.

The tyrosinase gene family encompasses three members, tyrosinase, tyrosinase-related protein 1 (Tyrp1) and dopachrome tautomerase (Dct), which encode for proteins implicated in melanin synthesis. In human and mouse, genomic organization is known for all three genes, revealing common features of regulatory elements and of exon/intron structure. We have set out to identify the complete family from a more primitive vertebrate, the pufferfish Fugu (Takifugu rubripes), which is characterized by a compact genome. We had recently isolated and characterized the Fugu tyrosinase gene (Genesis 28 (2000) 99-105). We now report the isolation and characterization of the two other members of the family, Tyrp1 and Dct. Regulatory sequences from these genes function in mouse pigment cells and are able to mediate reporter gene expression. Our results demonstrate the existence of all three tyrosinase family members in teleosts and underline the evolutionary conservation of the pigmentary system.

5' Flanking Region↗
PubMed1996

Evolutionary conservation and expression patterns of maize starch branching enzyme I and IIb genes suggests isoform specialization.

Expression of the maize (Zea mays L.) starch branching enzyme (SBE) genes Sbe1 and Sbe2 were characterized during kernel development and in vegetative tissues. The onset of Sbe1 and Sbe2 expression during endosperm development was similar to that of other genes involved in starch biosynthesis (Wx, Sh2 and Bt2). However, the expression of Sbe2 peaked earlier than that of Sbe1 in developing endosperm and embryos resulting in a shift in the ratio of Sbe1 to Sbe2 relative message levels during kernel and embryo development. Transcripts hybridizing to the Sbe2 probe were not detectable in leaves or roots which nonetheless have SBEII enzymatic activity, suggesting that there may be another divergent SBEII-like gene(s) in maize. A similar expression pattern is shared between the maize genes and related genes in pea, which together with their evolutionary conservation, suggests that the SBE isoforms may play unique roles in starch biosynthesis during plant development.

1,4-alpha-Glucan Branching Enzyme↗
PubMed1985

Evolutionary conservation of fragile sites induced by 5-azacytidine and 5-azadeoxycytidine in man, gorilla, and chimpanzee.

Lymphocyte cultures from man, gorilla, and chimpanzee were treated with 5-azacytidine and 5-azadeoxycytidine. These cytidine analogues induce common fragile sites in the chromosome bands 1q42 and 19q13 of man. A rare fragile site is induced by 5-azadeoxycytidine in the band 1q24. The optimum conditions required for inducing these new fragile sites were determined by a series of experiments. The common fragile site in human chromosome 1q42 also exists in the gorilla and chimpanzee in the homologous band 1p32. The fragile site in human chromosome 19q13 was demonstrated in the gorilla in the homologous chromosome band 20q13. These are the first examples found of evolutionary highly conserved fragile sites in homologous chromosome bands in related primate species. The interaction between 5-azacytidine, 5-azadeoxycytidine, and chromosomal DNA; the evolutionary conservation of genes located within or closely adjacent to the fragile sites in the chromosome 1 of Hominoidea; and the phylogenetic origin of the two new common fragile sites are discussed.

Animals↗
PubMed1997

Chlamydomonas U2, U4 and U6 snRNAs. An evolutionary conserved putative third interaction between U4 and U6 snRNAs which has a counterpart in the U4atac-U6atac snRNA duplex.

The spliceosomal UsnRNAs U2, U4 and U6 from the green alga Chlamydomonas reinhardtii (Cre) were sequenced using a combination of RNA and cDNA sequencing methods and were compared to other sequenced UsnRNAs. The lengths of Cre U6 and Cre U2 RNAs are similar to those of their higher plant equivalents. Cre U4 RNA is shorter (139 nt) than its counterpart from higher plants (150-154 nt), and contains stem IV and loop D which are absent, with the exception of the Tetrahymena U4 RNA, from the U4 RNAs of other unicellular organisms studied to date. Base-pairing interactions between U6 and U4 RNAs and between U6 and U2 RNAs, identical to those described for mammalian and yeast systems, are structurally feasible in the Cre system. In addition, based on comparative analyses of the predicted U4/U6 RNA duplex from various species, an evolutionary conserved third putative U6-U4 interaction was found. Interestingly, it can also be formed with the recently discovered U6atac and U4atac RNAs. This is a strong support in favor of the possible biological significance of this third putative interaction. Based on comparative analysis, an extension of the earlier described U6-U2 interaction patterns is also proposed.

Alternative Splicing↗
PubMed1984

Monoclonal antibodies directed against human Ia antigens detect an evolutionary conserved epitope on guinea pig Ia antigens with unique functional properties.

Three murine monoclonal antihuman Ia antibodies were found to cross react with guinea pig Ia antigens. Sequential immunoprecipitation studies demonstrated that these antibodies recognized a subset of guinea pig Ia antigens. In competition binding studies, the antihuman Ia antibodies competed with each other, but not with a number of murine monoclonals raised directly to guinea pig Ia antigens. When the antihuman Ia monoclonals were tested for their ability to inhibit the proliferative response of primed guinea pig T cells to antigen-pulsed macrophages, they completely inhibited the response of strain 2 T cells to the complex antigen ovalbumin while having no effect on the response to the copolymer L-glutamic acid, L-lysine. In contrast, the monoclonals raised against guinea pig Ia had much less dramatic effects on the response of uncloned T cells to these antigens. These results suggest that the cross-reactive monoclonals may recognize an evolutionary conserved epitope on Ia that has a regulatory function in T-cell activation.

Animals↗
PubMed1996

Evolutionary conservation of sequence and expression of the bHLH protein Atonal suggests a conserved role in neurogenesis.

atonal is a Drosophila proneural gene that belongs to the family of basic helix-loop-helix (bHLH)- containing proteins. It is expressed in the chordotonal organs and photoreceptor cells, and flies that lack Atonal protein are ataxic and blind. Here we report the cloning of atonal homologs from red flour beetle, puffer fish, chicken, mouse, and human. The bHLH domain is conserved throughout evolution, while the entire coding region is highly similar in mammals. Both the chicken and the mouse homologs are expressed early in embryogenesis in the hind brain, and specifically in cells predicted to give rise to the external granular layer of the cerebellum. In addition, these genes are expressed throughout the dorsal part of the spinal cord, in patterns different from those found for other genes, like LH-2 and wnt-1. The mouse homolog (Math1) maps to mouse chromosome 6, and the human homolog (HATH1) to human chromosome 4q22. Two neurological mouse mutants, Lc and chp, were found to map to the vicinity of Math1, but are not caused by mutations in Math1. The evolutionary conservation of this gene and its mRNA expression patterns during embryogenesis suggests that it plays a key role in the development of the vertebrate central nervous system.

Amino Acid Sequence↗
PubMed1994

The mouse hepatocyte growth factor-encoding gene: structural organization and evolutionary conservation.

A mouse genomic phage library was screened by using a cDNA probe coding for mouse hepatocyte growth factor (HGF). Five overlapping genomic clones which contained the entire mouse HGF gene were isolated and characterized by restriction mapping, Southern hybridization and DNA sequencing. HGF spans about 65 kb and consists of 18 exons separated by 17 introns, similar to its human counterpart. The nucleotide (nt) sequences of the introns at the exon-intron junctions are GT-AG, analogous to those found in other eukaryotic genes. The exon-intron gene organization of HGF is highly homologous to that of several other genes encoding kringle-containing proteins, especially HGF-like protein and plasminogen. This result suggests that HGF probably evolved through gene duplication and/or exon shuffling events from an ancestral gene. Southern hybridization of genomic DNA from different species revealed that a high degree of homology exists among a variety of vertebrates, including chicken, when a mouse HGF cDNA was used as a probe. This evolutionary conservation of HGF strongly suggests that the protein may play an important role in normal cell physiology. Our current results on mouse HGF structure provide basic and detailed information to carry out further manipulation, such as gene targeting.

Animals↗
PubMed1988

Evolutionary conservation of laminin-binding proteins.

1. The virulence of pathogens and metastatic capacity of cancer cells seems to correlate with the ability to adhere to cells and/or to basement membrane components. A key feature of this mechanism is the expression of specific receptors for the basement membrane protein laminin. Three different receptors have been already described in cells phylogenetically very distant, such as human white blood cells, Trichomonas vaginalis and Staphylococcus aureus, all recognizing laminin with the same range of affinity. 2. We have shown that laminin, which is also found in the circulation, enhances phagocytosis of S. aureus by macrophages in a species-specific fashion. Also, monoclonal antibodies (MAb) raised against the bacterial receptor inhibit the phagocytic enhancement mediated by laminin and recognize laminin-binding proteins in unicellular parasites and mammalian cells. The same Mab 1.H12 elutes a 52-kDa protein from bacterial extracts and a 67-kDa band from cancer cell extracts. Since the MAb is a monospecific reagent, results with 1.H12 strongly suggest an evolutionary conservation of the binding site of phylogenetically different laminin receptors.

Animals↗
PubMed2000

Evolutionary conservation of apoptosis mechanisms: lepidopteran and baculoviral inhibitor of apoptosis proteins are inhibitors of mammalian caspase-9.

We cloned a new inhibitor of apoptosis protein (IAP) homolog, SfIAP, from Spodoptera frugiperda Sf-21 cells, a host of insect baculoviruses. SfIAP contains two baculovirus IAP repeat domains followed by a RING domain. SfIAP has striking amino acid sequence similarity with baculoviral IAPs, CpIAP and OpIAP, suggesting that baculoviral IAPs may be host-derived genes. SfIAP and baculoviral CpIAP inhibit Bax but not Fas-induced apoptosis in human cells. Their apoptosis-suppressing activity in mammalian cells requires both baculovirus IAP repeat and RING domains. Further biochemical data suggest that SfIAP and CpIAP are specific inhibitors of mammalian caspase-9, the pinnacle caspase in the mitochondria/cytochrome c pathway for apoptosis, but are not inhibitors of downstream caspase-3 and caspase-7. Thus the mechanisms by which insect and baculoviral IAPs suppress apoptosis may involve inhibition of an insect caspase-9 homologue. Peptides representing the IAP-binding domain of the Drosophila cell death protein Grim abrogated human caspase suppression by SfIAP and CpIAP, implying evolutionary conservation of the functions of IAPs and their inhibitors.

Amino Acid Sequence↗
PubMed1982

Evolutionary conservation of a common pattern of activity of nucleolus organizers during spermatogenesis in vertebrates.

The patterns of activity of the nucleolus organizer regions (NORs) in the spermatogeneses of ten species of all non-mammalian classes of vertebrates and one species of the cephalochordates were investigated with the silver (Ag)-staining technique. The Ag-stainability of the NORs is a measure of the transcriptional activity of the ribosomal RNA genes. In all species, there is a very similar pattern of NOR-activity in the various stages of spermatogenesis. The qualitative analysis of the Ag-stainability of the NORs was in very good agreement with the results obtained for mammals: Ag-stained NORs are detectable during the entire meiotic prophase up to the pachytene stage, completely absent in the meiotic metaphases I and II, and again demonstrable in early spermatid nuclei. The results confirm the occurrence of postmeiotic reactivation of the RNA genes. The preferential inhibition of rRNA synthesis by low doses of actinomycin D induced a rapid decline of the Ag-stainability of the postmeiotically reactivated NORs. The significance of the evolutionary conservation of the postmeiotic NOR-reactivation is discussed.

Animals↗