Inhibition of the Notch signal transducer CSL by Pkc53E-mediated phosphorylation to fend off parasitic immune challenge in .

Notch signalling activity regulates hematopoiesis in and vertebrates alike. Parasitoid wasp infestation of larvae, however, requires a timely downregulation of Notch activity to allow the formation of encapsulation-active blood cells. Here, we show that the CSL transcription factor Suppressor of Hairless [Su(H)] is phosphorylated at Serine 269 in response to parasitoid wasp infestation.

Novel Genome-Engineered Alleles Differentially Affect Lateral Inhibition and Cell Dichotomy Processes during Bristle Organ Development.

Hairless (H) encodes the major antagonist in the Notch signaling pathway, which governs cellular differentiation of various tissues in . By binding to the Notch signal transducer Suppressor of Hairless (Su(H)), H assembles repressor complexes onto Notch target genes. Using genome engineering, three new alleles, , and were generated and a phenotypic series was established by several parameters, reflecting the residual H-Su(H) binding capacity.

Numerous Serine/Threonine Kinases Affect Blood Cell Homeostasis in .

Blood cells in serve primarily innate immune responses. Various stressors influence blood cell homeostasis regarding both numbers and the proportion of blood cell types. The principle molecular mechanisms governing hematopoiesis are conserved amongst species and involve major signaling pathways like Notch, Toll, JNK, JAK/Stat or RTK.

The Binding of CSL Proteins to Either Co-Activators or Co-Repressors Protects from Proteasomal Degradation Induced by MAPK-Dependent Phosphorylation.

The primary role of Notch is to specify cellular identities, whereby the cells respond to amazingly small changes in Notch signalling activity. Hence, dosage of Notch components is crucial to regulation. Central to Notch signal transduction are CSL proteins: together with respective cofactors, they mediate the activation or the silencing of Notch target genes.

The Membrane-Bound Notch Regulator Mnr Supports Notch Cleavage and Signaling Activity in .

The Notch signaling pathway is pivotal to cellular differentiation. Activation of this pathway involves proteolysis of the Notch receptor and the release of the biologically active Notch intracellular domain, acting as a transcriptional co-activator of Notch target genes. While the regulation of Notch signaling dynamics at the level of ligand-receptor interaction, endocytosis, and transcriptional regulation has been well studied, little is known about factors influencing Notch cleavage.

Phospho-Site Mutations in Transcription Factor Suppressor of Hairless Impact Notch Signaling Activity During Hematopoiesis in .

The highly conserved Notch signaling pathway controls a multitude of developmental processes including hematopoiesis. Here, we provide evidence for a novel mechanism of tissue-specific Notch regulation involving phosphorylation of CSL transcription factors within the DNA-binding domain. Earlier we found that a phospho-mimetic mutation of the CSL ortholog Suppressor of Hairless [Su(H)] at Ser impedes DNA-binding.

Nucleo-cytoplasmic shuttling of murine RBPJ by Hairless protein matches that of Su(H) protein in the model system Drosophila melanogaster.

CSL transcription factors are central to signal transduction in the highly conserved Notch signaling pathway. CSL acts as a molecular switch: depending on the cofactors recruited, CSL induces either activation or repression of Notch target genes. Unexpectedly, CSL depends on its cofactors for nuclear entry, despite its role as gene regulator.

Limited Availability of General Co-Repressors Uncovered in an Overexpression Context during Wing Venation in .

Cell fate is determined by the coordinated activity of different pathways, including the conserved Notch pathway. Activation of Notch results in the transcription of Notch targets that are otherwise silenced by repressor complexes. In , the repressor complex comprises the transcription factor Suppressor of Hairless (Su(H)) bound to the Notch antagonist Hairless (H) and the general co-repressors Groucho (Gro) and C-terminal binding protein (CtBP).

Drosophila Xrcc2 regulates DNA double-strand repair in somatic cells.

Genomic integrity is challenged by endo- and exogenous assaults that are combated by highly conserved DNA repair mechanisms. Repair of DNA double-strand breaks (DSBs) is of particular importance, as DSBs inflict chromosome breaks that are the basis of genomic instability. High fidelity recombination repair of DSBs relies on the Rad51 recombinase, aided by several Rad51 paralogs.

Genetic interactions between and mutants during eye development of .

Background: In the development of the fly eye involves the activity of several, interconnected pathways that first define the presumptive eye field within the eye anlagen, followed by establishment of the dorso-ventral boundary, and the regulation of growth and apoptosis. In mutant flies, parts of the eye or even the complete eye are absent because the eye field has not been properly defined. Manifold genetic interactions indicate that influences the activity of several signalling pathways, resulting in a conversion of eye tissue into epidermis, and in the induction of apoptosis.

An RBPJ- Model Reveals Dependence of RBPJ Protein Stability on the Formation of Transcription-Regulator Complexes.

Notch signaling activity governs widespread cellular differentiation in higher animals, including humans, and is involved in several congenital diseases and different forms of cancer. Notch signals are mediated by the transcriptional regulator RBPJ in a complex with activated Notch (NICD). Analysis of Notch pathway regulation in humans is hampered by a partial redundancy of the four Notch receptor copies, yet RBPJ is solitary, allowing its study in model systems.

Nucleo-cytoplasmic shuttling of Drosophila Hairless/Su(H) heterodimer as a means of regulating Notch dependent transcription.

Activation and repression of Notch target genes is mediated by transcription factor CSL, known as Suppressor of Hairless (Su(H)) in Drosophila and CBF1 or RBPJ in human. CSL associates either with co-activator Notch or with co-repressors such as Drosophila Hairless. The nuclear translocation of transcription factor CSL relies on co-factor association, both in mammals and in Drosophila.

Loss of putzig in the germline impedes germ cell development by inducing cell death and new niche like microenvironments.

Germline stem cell development and differentiation is tightly controlled by the surrounding somatic cells of the stem cell niche. In Drosophila females, cells of the niche emit various signals including Dpp and Wg to balance stem cell renewal and differentiation. Here, we show that the gene pzg is autonomously required in cells of the germline to sustain the interplay between niche and stem cells.

Protein Kinase D Is Dispensable for Development and Survival of .

Members of the Protein Kinase D (PKD) family are involved in numerous cellular processes in mammals, including cell survival after oxidative stress, polarized transport of Golgi vesicles, as well as cell migration and invasion. PKD proteins belong to the PKC/CAMK class of serine/threonine kinases, and transmit diacylglycerol-regulated signals. Whereas three PKD isoforms are known in mammals, contains a single PKD homolog.

Overexpression of the ATR homologous checkpoint kinase Mei-41 induces a G2/M checkpoint in imaginal tissue.

Background: DNA damage generally results in the activation of ATM/ATR kinases and the downstream checkpoint kinases Chk1/Chk2. In the ATR homologue ( is pivotal to DNA damage repair and cell cycle checkpoint signalling. Although various mutant alleles have been analyzed in the past, no gain-of-function allele is yet available.

Complex genetic interactions of novel Suppressor of Hairless alleles deficient in co-repressor binding.

Throughout the animal kingdom, the Notch signalling pathway allows cells to acquire diversified cell fates. Notch signals are translated into activation of Notch target genes by CSL transcription factors. In the absence of Notch signals, CSL together with co-repressors functions as a transcriptional repressor.

p53 and cyclin G cooperate in mediating genome stability in somatic cells of Drosophila.

One of the key players in genome surveillance is the tumour suppressor p53 mediating the adaptive response to a multitude of stress signals. Here we identify Cyclin G (CycG) as co-factor of p53-mediated genome stability. CycG has been shown before to be involved in double-strand break repair during meiosis.

Phosphorylation of Suppressor of Hairless impedes its DNA-binding activity.

Notch signalling activity governs cellular differentiation in higher metazoa, where Notch signals are transduced by the transcription factor CSL, called Suppressor of Hairless [Su(H)] in Drosophila. Su(H) operates as molecular switch on Notch target genes: within activator complexes, including intracellular Notch, or within repressor complexes, including the antagonist Hairless. Mass spectrometry identified phosphorylation on Serine 269 in Su(H), potentially serving as a point of cross-regulation by other signalling pathways.

Hairless-binding deficient Suppressor of Hairless alleles reveal Su(H) protein levels are dependent on complex formation with Hairless.

Cell fate choices during metazoan development are driven by the highly conserved Notch signalling pathway. Notch receptor activation results in release of the Notch intracellular domain (NICD) that acts as transcriptional co-activator of the DNA-binding protein CSL. In the absence of signal, a repressor complex consisting of CSL bound to co-repressors silences Notch target genes.

A triangular connection between Cyclin G, PP2A and Akt1 in the regulation of growth and metabolism in Drosophila.

Size and weight control is a tightly regulated process, involving the highly conserved Insulin receptor/target of rapamycin (InR/TOR) signaling cascade. We recently identified Cyclin G (CycG) as an important modulator of InR/TOR signaling activity in Drosophila. cycG mutant flies are underweight and show a disturbed fat metabolism resembling TOR mutants.

Drosophila Cyclin G Is a Regulator of the Notch Signalling Pathway during Wing Development.

Notch signalling regulates a multitude of differentiation processes during Drosophila development. For example, Notch activity is required for proper wing vein differentiation which is hampered in mutants of either the receptor Notch, the ligand Delta or the antagonist Hairless. Moreover, the Notch pathway is involved in several aspects of Drosophila oogenesis as well.

Association of Thyroid-Stimulating Hormone with Resting Energy Expenditure in Euthyroid Elderly Subjects: A Cross-Sectional Study.

Background: Several studies have reported positive correlations between thyroid-stimulating hormone (TSH) and body mass index (BMI) in euthyroid subjects. As impaired thyroid function is known to affect the metabolic rate, this study investigated whether TSH is associated with resting energy expenditure (REE) in euthyroid elderly subjects, independent of age, anthropometric data and body composition.

Methods: Cross-sectional data of 77 women (66-96 years, BMI 18-36 kg/m²) and 55 men (66-86 years, BMI 20-39 kg/m²) were analyzed.

Generation of New Hairless Alleles by Genomic Engineering at the Hairless Locus in Drosophila melanogaster.

Hairless (H) is the major antagonist within the Notch signalling pathway of Drosophila melanogaster. By binding to Suppressor of Hairless [Su(H)] and two co-repressors, H induces silencing of Notch target genes in the absence of Notch signals. We have applied genomic engineering to create several new H alleles.