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PubMed2000

Characterization of a Drosophila homologue of the human myelodysplasia/myeloid leukemia factor (MLF).

The transcription factor DREF regulates proliferation-related genes in Drosophila. With two-hybrid screening using DREF as a bait, we have obtained a clone encoding a protein homologous to human myelodysplasia/myeloid leukemia factor 1 (hMLF1). We termed the protein Drosophila MLF (dMLF); it consists of a polypeptide of 309 amino acid residues, whose sequence shares 23.1% identity with hMLF1. High conservation of 54.2% identity over 107 amino acids was found in the central region. The dMLF gene was mapped to 52D on the second chromosome by in situ hybridization. Interaction between dMLF and DREF in vitro could be confirmed by glutathione S-transferase pull-down assay, with the conserved central region appearing to play an important role in this. Northern blot hybridization analysis revealed dMLF mRNA levels to be high in unfertilized eggs, early embryos, pupae and adult males, and relatively low in adult females and larvae. This fluctuation of mRNA during Drosophila development is similar to that observed for DREF mRNA, except in the pupa and adult male. Using a specific antibody against the dMLF, we performed immunofluorescent staining of Drosophila Kc cells and showed a primarily cytoplasmic staining, whereas DREF localizes in the nucleus. However, dMLF protein contains a putative 14-3-3 binding motif involved in the subcellular localization of various regulatory molecules, and interaction with DREF could be regulated through this motif. The transgenic fly data suggesting the genetic interaction between DREF and dMLF support this possibility. Characterization of dMLF in the present study provides the molecular basis for analysis of its significance in Drosophila.

Amino Acid Sequence↗
PubMed2001

Characterization of the adenosine deaminase-related growth factor (ADGF) gene family in Drosophila.

A novel family of growth factors, with sequence similarity to adenosine deaminase, has been identified in various organisms including flesh fly, tsetse fly, sand fly, mollusk and human. The human homologue, CECR1, is a candidate gene for the genetic disorder cat eye syndrome. Here, we describe six members of this growth factor family in Drosophila and two in vertebrates. The six Drosophila genes, named adenosine deaminase-related growth factors (ADGF), are found at three different chromosomal locations, with one singleton, two in an inverted orientation, and three in a tandem arrangement. These genes show distinct patterns of expression as measured by RT-PCR and Northern blots, indicating gene-specific function. The presence of six ADGF genes in the Drosophila genome suggests that gene duplication and divergence has been important for these growth factors in insect development. Phylogenetic analysis of the 14 extant ADGF-like gene products shows there are at least three major groups, two of which are found in Drosophila. The third appears specific to the vertebrate line. Seven gene duplications are inferred among the ADGF-like genes, most of which occurred long before the origin of Drosophila. Our analysis predicts the existence of several other unsampled ADGF-like genes, both within the species examined here, and in other related invertebrates.

Amino Acid Sequence↗
PubMed1999

Poly(ADP-ribose) polymerase interacts with novel Drosophila ribosomal proteins, L22 and l23a, with unique histone-like amino-terminal extensions.

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that recognizes and binds to the nicks and ends of DNA, and catalyses successive ADP-ribosylation reactions. To clarify the function of PARP at the molecular level, we searched proteins which interact with PARP. In the auto-modification domain of PARP in Drosophila, there is a putative leucine-zipper motif which can interact with other protein molecules. To find interacting proteins we examined the auto-modification domain of Drosophila PARP, using the Far-Western screening method. From six independent cDNA clones isolated, we characterized two clones, PBP-3 and PBP-12. The predicted amino acid sequences from 109 to 269 of PBP-3 and from 184 to 312 of PBP-12 had more than 62% identities to mammalian L23a (rpl23a) and L22 (rpl22), the ribosomal proteins of the large subunit. This indicated that PBP-3 and PBP-12 are Drosophila homologues of L23a and L22, respectively. These Drosophila ribosomal protein L22 and L23a have additional Ala-, Lys- and Pro-rich sequences at the amino terminus, which have a resemblance to the carboxy-terminal portion of histone H1. Thus, Drosophila L22 and L23a might have two functions, namely the role of DNA-binding similar to histone H1 and the role of organizing the ribosome.

Amino Acid Sequence↗
PubMed1999

Origin of new genes and source for N-terminal domain of the chimerical gene, jingwei, in Drosophila.

This paper deals with a general question posed by the origin of new processed chimerical genes: when a new retrosequence inserts into a new genome position, how does it become activated and acquire novel protein function by recruiting new functional domains and regulatory elements? Jingwei (jgw), a newly evolved functional gene with a chimerical structure in Drosophila, provides an opportunity to examine such questions. The source of its exon encoding C-terminal peptide has been identified as an Adh retrosequence, which extends the concept of exon shuffling from recombination to retroposition as a general molecular mechanism for the origin of a new gene. However, the origin of 5' exons remains unclear. We examined two hypotheses concerning the origin of these non-Adh-derived jgw exons: (i) these exons might originate from a unique genomic sequence that fortuitously evolved a standard intron-exon structure and regulatory sequence for jgw; (ii) these exons might be a duplicate of an unrelated previously existing gene. Genomic Southern analysis, in conjunction with construction and screening of a genomic bookshelf (sub-library), was conducted in a group of Drosophila species. The results demonstrated that there are duplicate genes containing the same structure as the recruited portion of jgw. We name this duplicate gene in Drosophila teissieri and Drosophila yakuba and its orthologous gene in Drosophila melanogaster as yellow-emperor (ymp). Thus, the 5' exons/introns originated from a previously existing gene that provided new modules with specific sub-function to create jgw.

Amino Acid Sequence↗
PubMed2000

Hyperactivation of the Drosophila Hop jak kinase causes the preferential overexpression of eIF1A transcripts in larval blood cells.

Jak kinase-Stat protein pathways play a critical role in the response of blood cells to a range of cytokines and growth factors. We are using the fruit fly, Drosophila melanogaster, as a model system to elucidate additional components of Jak-Stat pathways, and to determine how abnormalities in this pathway lead to hematopoietic leukemia-like defects. To identify downstream targets, we conducted a molecular screen for genes whose transcripts are overexpressed in response to activation of the Drosophila Hop Jak kinase. We identified a Drosophila homolog of eIF1A, a eukaryotic initiation factor found in humans and other eukaryotes. D-eIF1A is highly overexpressed in the hemocytes and lymph glands of third instar larvae carrying the dominant, gain-of-function mutation hop(Tum-l). A quantitative comparison of poly(A)(+) RNA levels between D-eIF1A and other known Drosophila translation initiation factors indicates that D-eIF1A transcripts preferentially overaccumulate in response to the hyperactive Hop pathway. Our results support the model that D-eIF1A is one of the target genes through which the Drosophila Jak kinase pathway regulates hemocyte development.

Amino Acid Sequence↗
PubMed2002

Characterization of Dir: a putative potassium inward rectifying channel in Drosophila.

Potassium channels vary in their function and regulation, yet they maintain a number of important features - they are involved in the control of potassium flow, cell volume, cell membrane resting potential, cell excitability and hormone release. The potassium (K(+)) inward rectifier (Kir) superfamily of channels are potassium selective channels, that are sensitive to the concentration of K(+) ions. They are termed inward rectifiers since they allow a much greater K(+) influx than efflux. There are at least seven subfamilies of Kir channels, grouped according to sequence and functional similarities (Curr. Opin. Neurobiol. 5 (1995) 268; Annu. Rev. Physiol. 59 (1997) 171). While numerous Kir channels have been discovered in a variety of organisms, Drosophila inward rectifier (Dir) is the first putative inward rectifier to be studied in Drosophila. In fact, there are only three genes (including Dir) encoding putative inward rectifiers in the Drosophila genome. Though there are other known potassium channels in Drosophila such as ether-a-go-go and shaker, most are voltage-gated channels. As an important first step in characterizing Kir channels in Drosophila, we initiated studies on Dir.

Amino Acid Sequence↗
PubMed1999

mGCMa is a murine transcription factor that overrides cell fate decisions in Drosophila.

During neural development of Drosophila melanogaster, Glial Cells Missing (GCM), functions as a binary switch that promotes glial cell fate while simultaneously inhibiting the neuronal fate. Sequence similarities between GCM and the recently identified mouse protein mGCMa are strictly limited to the aminoterminal DNA-binding domain. Here we show that mGCMa efficiently activates transcription in Drosophila cells just as Drosophila GCM activates transcription in mammalian cells. Transactivation potential was present in two separate regions of mGCMa outside the DNA-binding domain. One of them mapped to the carboxyterminal 88 amino acids, a location corresponding exactly to the transactivation domain of GCM. Similarities between GCM and mGCMa were also observed in vivo. Overexpression of mGCMa in the developing nervous system of Drosophila embryos led to an increase in glial-like cells at the expense of neurons. Outside the neurogenic region, mGCMa interfered with epidermal development, as evident from changes in cell morphology and marker expression. Thus, mGCMa function is at least partially independent of a cell's predisposition to a neural fate. The potent activity of mGCMa in Drosophila and its extensive functional similarities to GCM make mGCMa a candidate for a regulator of mouse glial development.

Animals↗
PubMed2000

Identification of a mouse germ cell-less homologue with conserved activity in Drosophila.

Drosophila Germ cell-less (Gcl) has previously been shown to be important in early events during the formation of pole cells, which are the germ cell precursors in the fly. We have isolated a 524 amino acid mouse gene with 32% identity and 49% similarity to Drosophila gcl, termed mgcl-1. Like Drosophila Gcl, mGcl-1 localizes to the nuclear envelope. Ectopic expression of mgcl-1 in Drosophila rescues the gcl-null phenotype, indicating that mGcl-1 is a functional homologue of Gcl. mgcl-1 maps to chromosome 6 at 47.3 cM, and is expressed at low levels at all embryonic stages examined from 8.5 to 18.5 d.p.c. as well as in many adult tissues. Different from Drosophila gcl, mgcl-1 is not highly expressed at the time the primordial germ cells appear in the mouse, but high mgcl-1 expression is found in selected mouse adult male germ cells. The differences in these expression patterns in light of conserved activity between the two genes is discussed.

Amino Acid Sequence↗
PubMed2000

A cyclase-associated protein regulates actin and cell polarity during Drosophila oogenesis and in yeast.

BACKGROUND: A polarised cytoskeleton is required to pattern cellular space, and for many aspects of cell behaviour. While the mechanisms ordering the actin cytoskeleton have been extensively studied in yeast, little is known about the analogous processes in other organisms. We have used Drosophila oogenesis as a model genetic system in which to investigate control of cytoskeletal organisation and cell polarity in multicellular eukaryotes. RESULTS: In a screen to identify genes required for Drosophila oocyte polarity, we isolated a Drosophila homologue of the yeast cyclase-associated protein, CAP. Here we show that CAP preferentially accumulates in the oocyte, where it inhibits actin polymerisation. CAP also has a role in oocyte polarity, as cap mutants fail to establish the proper, asymmetric distribution of mRNA determinants within the oocyte. Similarly in yeast, loss of CAP causes analogous polarity defects, altering the distribution of actin filaments and mRNA determinants. CONCLUSIONS: This study identifies CAP as a new effector of actin dynamics in Drosophila. As CAP controls the spatial distribution of actin filaments and mRNA determinants in both yeast and Drosophila, we conclude that CAP has an evolutionarily conserved function in the genesis of eukaryotic cell polarity.

Actins↗
PubMed2001

Drosophila fushi tarazu. a gene on the border of homeotic function.

BACKGROUND: Hox genes specify cell fate and regional identity during animal development. These genes are present in evolutionarily conserved clusters thought to have arisen by gene duplication and divergence. Most members of the Drosophila Hox complex (HOM-C) have homeotic functions. However, a small number of HOM-C genes, such as the segmentation gene fushi tarazu (ftz), have nonhomeotic functions. If these genes arose from a homeotic ancestor, their functional properties must have changed significantly during the evolution of modern Drosophila. RESULTS: Here, we have asked how Drosophila ftz evolved from an ancestral homeotic gene to obtain a novel function in segmentation. We expressed Ftz proteins at various developmental stages to assess their potential to regulate segmentation and to generate homeotic transformations. Drosophila Ftz protein has lost the inherent ability to mediate homeosis and functions exclusively in segmentation pathways. In contrast, Ftz from the primitive insect Tribolium (Tc-Ftz) has retained homeotic potential, generating homeotic transformations in larvae and adults and retaining the ability to repress homothorax, a hallmark of homeotic genes. Similarly, Schistocerca Ftz (Sg-Ftz) caused homeotic transformations of antenna toward leg. Primitive Ftz orthologs have moderate segmentation potential, reflected by weak interactions with the segmentation-specific cofactor Ftz-F1. Thus, Ftz orthologs represent evolutionary intermediates that have weak segmentation potential but retain the ability to act as homeotic genes. CONCLUSIONS: ftz evolved from an ancestral homeotic gene as a result of changes in both regulation of expression and specific alterations in the protein-coding region. Studies of ftz orthologs from primitive insects have provided a "snap-shot" view of the progressive evolution of a Hox protein as it took on segmentation function and lost homeotic potential. We propose that the specialization of Drosophila Ftz for segmentation resulted from loss and gain of specific domains that mediate interactions with distinct cofactors.

Amino Acid Sequence↗
PubMed2002

sickle, a novel Drosophila death gene in the reaper/hid/grim region, encodes an IAP-inhibitory protein.

Inhibitors of apoptosis proteins (IAPs) interact with caspases and inhibit their protease activity, whereas the IAP-inhibitory proteins Smac/DIABLO in mammals and Reaper, Hid, and Grim in flies relieve IAP-mediated inhibition to induce cell death. Here we describe the functional characterization of the novel Drosophila cell death protein Sickle (Skl), which binds to IAPs and neutralizes their apoptotic inhibitory activity. Skl exhibits no sequence homology to Reaper, Hid, Grim, or Smac/DIABLO, except within the 4 residue N-terminal IAP binding motif. Skl interacts with Drosophila and mammalian IAPs and can promote caspase activation in the presence of IAPs. Consistent with these findings, expression of Skl in Drosophila and mammalian cell lines or in Drosophila embryos induces apoptosis. Skl can also synergize with Grim to induce cell death in the Drosophila eye imaginal disc. Based on biochemical and structural data, the N terminus of Skl, like that of the mammalian Smac/DIABLO, is absolutely required for its apoptotic and caspase-promoting activities and its ability to interact with IAPs. These findings point to conservation in the structure and function of the IAP-inhibitory proteins across species and suggest the existence of other family members.

Amino Acid Sequence↗
PubMed1996

The achaete-scute complex proneural genes contribute to neural precursor specification in the Drosophila CNS.

BACKGROUND: The Drosophila central nervous system (CNS) develops from a segmentally reiterated array of 30 neural precursors. Each precursor acquires a unique identity and goes through a stereotyped cell lineage to produce an invariant family of neurons and/or glia. The proneural genes achaete, scute and lethal of scute are required for neural precursor formation in the Drosophila CNS, and are expressed in overlapping subsets of 'proneural cell clusters' from which a single neural precursor later develops. Vertebrate achaete-scute homologues are expressed early during neurogenesis, and promote neurogenesis, neuronal development and/or differentiation. The Drosophila proneural achaete-scute genes govern neural precursor formation, but their role in specifying neural precursor identity has not been tested. RESULTS: Here, we test the role of the Drosophila achaete-scute genes in specifying neural precursor identity, focusing on the well characterized CNS MP2 precursor. MP2 delaminates from a cluster of achaete-scute-expressing ectodermal cells. In an achaete-scute double mutant, MP2 formation was reduced (to 11-14 %) as expected because of the function of proneural genes in promoting neural precursor formation. Surprisingly, we also observed that the developing MP2 precursors were incorrectly specified and acquired traits characteristic of adjacent neural precursors. In rescue experiments, achaete or scute, but not lethal of scute, completely restored the normal MP2 identity. CONCLUSIONS: These results demonstrate that the achaete-scute complex genes specify aspects of neural precursor identity in the Drosophila CNS. Given the phylogenetically conserved function of these genes, our results raise the possibility that achaete-scute homologues may help specify neural precursor identity in other organisms.

Animals↗
PubMed1999

A Drosophila TNF-receptor-associated factor (TRAF) binds the ste20 kinase Misshapen and activates Jun kinase.

Two families of protein kinases that are closely related to Ste20 in their kinase domain have been identified - the p21-activated protein kinase (Pak) and SPS1 families [1-3]. In contrast to Pak family members, SPS1 family members do not bind and are not activated by GTP-bound p21Rac and Cdc42. We recently placed a member of the SPS1 family, called Misshapen (Msn), genetically upstream of the c-Jun amino-terminal (JNK) mitogen-activated protein (MAP) kinase module in Drosophila [4]. The failure to activate JNK in Drosophila leads to embryonic lethality due to the failure of these embryos to stimulate dorsal closure [5-8]. Msn probably functions as a MAP kinase kinase kinase kinase in Drosophila, activating the JNK pathway via an, as yet, undefined MAP kinase kinase kinase. We have identified a Drosophila TNF-receptor-associated factor, DTRAF1, by screening for Msn-interacting proteins using the yeast two-hybrid system. In contrast to the mammalian TRAFs that have been shown to activate JNK, DTRAF1 lacks an amino-terminal 'Ring-finger' domain, and overexpression of a truncated DTRAF1, consisting of only its TRAF domain, activates JNK. We also identified another DTRAF, DTRAF2, that contains an amino-terminal Ring-finger domain. Msn specifically binds the TRAF domain of DTRAF1 but not that of DTRAF2. In Drosophila, DTRAF1 is thus a good candidate for an upstream molecule that regulates the JNK pathway by interacting with, and activating, Msn. Consistent with this idea, expression of a dominant-negative Msn mutant protein blocks the activation of JNK by DTRAF1. Furthermore, coexpression of Msn with DTRAF1 leads to the synergistic activation of JNK. We have extended some of these observations to the mammalian homolog of Msn, Nck-interacting kinase (NIK), suggesting that TRAFs also play a critical role in regulating Ste20 kinases in mammals.

Amino Acid Sequence↗
PubMed2000

Distribution of the transposable element Minos in the genus Drosophila.

We analyzed 28 species of the genus Drosophila for the presence of the Tc1-like transposable element Minos using Southern blot hybridization under high stringency conditions. The Minos transposon was found in members of both the Drosophila and the Sophophora subgenus showing a distribution that is wider if compared to other well-studied Drosophila transposons such as the P element, hobo and mariner. The presence of Minos-hybridizing sequences was discontinuous in the Sophophora subgenus, especially in the melanogaster species group. Using the Polymerase Chain Reaction we amplified a portion corresponding to the putative Minos transposase from different Drosophila species. Cloning and sequence analysis of randomly selected Minos copies from D. mojavensisis, D. saltans and D. willistoni supports the idea that event(s) of horizontal transfer may have contributed to the spreading of this transposon in the Drosophila genus.

Animals↗
PubMed2000

CDK inhibitors suppress apoptosis induced by chemicals and by excessive expression of a cell death gene, reaper, in Drosophila cells.

The present study was aimed to investigate whether or not cyclin-dependent kinases (CDKs) participate in different cascades leading to apoptosis. We examined the effects of two CDK inhibitors, olomoucine (OLM) and butyrolactone-I (BL-I), on apoptosis induced in two kinds of Drosophila cell lines. Increases of caspase activity induced by actinomycin D, cycloheximide, H-7 or A23187 in a Drosophila neuronal cell line, ML-DmBG2-c2, and induced by excessive expression of a Drosophila cell death gene, reaper, in Drosophila S2 cells were suppressed by 24-h pretreatment of each CDK inhibitor. Concomitant with the suppression of the caspase activity, fragmentations of cells and DNA, representatives of apoptosis, were also inhibited. These results suggest that CDK(s) participates in progression of apoptosis. However, these effects of the CDK inhibitors were also observed even at lower doses which did not affect cell proliferation. Therefore, it was shown that apoptosis is not always related to cell cycle in Drosophila cells. It was also suggested that the target(s) of the CDK inhibitors locates upstream of caspase in the cascade(s) of apoptosis.

4-Butyrolactone↗
PubMed2001

A new role for cryptochrome in a Drosophila circadian oscillator.

Cryptochromes are flavin/pterin-containing proteins that are involved in circadian clock function in Drosophila and mice. In mice, the cryptochromes Cry1 and Cry2 are integral components of the circadian oscillator within the brain and contribute to circadian photoreception in the retina. In Drosophila, cryptochrome (CRY) acts as a photoreceptor that mediates light input to circadian oscillators in both brain and peripheral tissue. A Drosophila cry mutant, cryb, leaves circadian oscillator function intact in central circadian pacemaker neurons but renders peripheral circadian oscillators largely arrhythmic. Although this arrhythmicity could be caused by a loss of light entrainment, it is also consistent with a role for CRY in the oscillator. A peripheral oscillator drives circadian olfactory responses in Drosophila antennae. Here we show that CRY contributes to oscillator function and physiological output rhythms in the antenna during and after entrainment to light-dark cycles and after photic input is eliminated by entraining flies to temperature cycles. These results demonstrate a photoreceptor-independent role for CRY in the periphery and imply fundamental differences between central and peripheral oscillator mechanisms in Drosophila.

Animals↗
PubMed1993

Involvement of an orthologue of the Drosophila pair-rule gene hairy in segment formation of the short germ-band embryo of Tribolium (Coleoptera)

The segments in long germ-band insect embryos, like Drosophila, are all determined at syncytial blastoderm stage. This is in contrast to short germ-band embryos which show an early determination of only the anterior head segments, whereas the more posterior thoracic and abdominal segments are sequentially added after formation of a primary germ anlage (reviewed in ref. 1). Segment formation in Drosophila involves the pair-rule genes which define double segmental periodicities and which have been considered to represent a special adaptation to the long germ-band type development hairy belongs to the primary pair-rule genes in Drosophila which are directly regulated by the gap genes, such as Krüppel. We have isolated the orthologues of hairy and Krüppel from the flour beetle Tribolium castaneum which has a short germ type development. We show here that hairy is expressed in several stripes at blastoderm stage and later on in two stripes in the growth zone of the developing embryo. Krüppel expression overlaps hairy stripe three and four expression, very similar to Drosophila. This suggests that the segment patterning mechanism that acts in an open blastoderm in Drosophila works in a similar way in the cellularized Tribolium embryo.

Amino Acid Sequence↗
PubMed1993

A mouse homologue of the Drosophila tumour-suppressor gene l(2)gl controlled by Hox-C8 in vivo.

The homeobox is a 183-base-pair DNA sequence originally found in Drosophila segmentation and homeotic genes. In Drosophila, homeotic genes are clustered in the Antennapedia and Bithorax complexes, collectively called the homeotic gene complex (HOM-C). In the mouse genome, about 40 homeobox genes (Hox) are clustered in four chromosomal regions (Hox A to D). The Hox genes are arranged in the same order and have the same anteroposterior pattern of expression as their structural homologue in the HOM-C, suggesting that they control mouse pattern formation in the same way that HOM-C members do in Drosophila. Homeobox gene products are believed to be transcription factors that regulate expression of target genes. A few candidate target genes have been identified in Drosophila by various approaches but the Hox gene targets are poorly understood, mostly because of limitations in the available approaches. Here we identify several candidate Hox gene targets, including a mouse homologue of the Drosophila tumour-suppressor gene l(2)gl, by immunopurification of DNA sequences bound to a Hox protein in native chromatin.

Amino Acid Sequence↗