Who decides when to cleave an ectodomain?

Many life-essential molecules such as growth factors, cytokines, ectoenzymes, and decoy receptors are produced by ectodomain cleavage of transmembrane precursor molecules. Not surprisingly, misregulation of such essential functions is linked to numerous diseases. Ectodomain cleavage is the function of transmembrane ADAMs (a disintegrin and metalloprotease) and other membrane-bound metalloproteases, which have an extracellular catalytic domain.

GenColors-based comparative genome databases for small eukaryotic genomes.

Many sequence data repositories can give a quick and easily accessible overview on genomes and their annotations. Less widespread is the possibility to compare related genomes with each other in a common database environment. We have previously described the GenColors database system (http://gencolors.

Association studies of the copy-number variable ß-defensin cluster on 8p23.1 in adenocarcinoma and chronic pancreatitis.

Background: Human ß-defensins are a family of antimicrobial peptides located at the mucosal surface. Both sequence multi-site variations (MSV) and copy-number variants (CNV) of the defensin-encoding genes are associated with increased risk for various diseases, including cancer and inflammatory conditions such as psoriasis and acute pancreatitis. In a case-control study, we investigated the association between MSV in DEFB104 as well as defensin gene (DEF) cluster copy number (CN), and pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP).

Kcnh1 voltage-gated potassium channels are essential for early zebrafish development.

The Kcnh1 gene encodes a voltage-gated potassium channel highly expressed in neurons and involved in tumor cell proliferation, yet its physiological roles remain unclear. We have used the zebrafish as a model to analyze Kcnh1 function in vitro and in vivo. We found that the kcnh1 gene is duplicated in teleost fish (i.

DNA damage checkpoints in stem cells, ageing and cancer.

DNA damage induces cell-intrinsic checkpoints, including p53 and retinoblastoma (RB), as well as upstream regulators (exonuclease 1 (EXO1), ataxia telangiectasia mutated (ATM), ATR, p16(INK4a) and p19(ARF)) and downstream targets (p21, PUMA (p53 upregulated modulator of apoptosis) and sestrins). Clearance of damaged cells by cell-intrinsic checkpoints suppresses carcinogenesis but as a downside may impair stem cell and tissue maintenance during ageing. Modulating the activity of DNA damage checkpoints can either accelerate or decelerate tissue ageing and age-related carcinogenesis.

p100 Deficiency is insufficient for full activation of the alternative NF-κB pathway: TNF cooperates with p52-RelB in target gene transcription.

Background: Constitutive activation of the alternative NF-κB pathway leads to marginal zone B cell expansion and disorganized spleen microarchitecture. Furthermore, uncontrolled alternative NF-κB signaling may result in the development and progression of cancer. Here, we focused on the question how does the constitutive alternative NF-κB signaling exert its effects in these malignant processes.

Understanding the hypothalamus-pituitary-thyroid axis in mct8 deficiency.

Thyroid hormone (TH) metabolism and action via binding to nuclear receptors are intracellular events that require the passage of TH across the plasma membrane. This process is mediated by specific TH transporters of which the monocarboxylate transporter 8 (Mct8) has received major attention. Mct8 is highly expressed in different tissues such as liver, kidney, thyroid, pituitary and brain.

The N-terminus of the human RecQL4 helicase is a homeodomain-like DNA interaction motif.

The RecQL4 helicase is involved in the maintenance of genome integrity and DNA replication. Mutations in the human RecQL4 gene cause the Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. Mouse models and experiments in human and Xenopus have proven the N-terminal part of RecQL4 to be vital for cell growth.

Accumulation of annexin A5 at the nuclear envelope is a biomarker of cellular aging.

Cellular senescence is a permanent cell cycle arrest induced by short telomeres or oncogenic stress in vitro and in vivo. Because no single of the established biomarkers can reliably identify senescent cells, the application of new ones may aid the diagnosis of aged cells. Here we show that annexin A5 accumulates at the nuclear envelope during replicative and drug-induced cellular senescence in primary human fibroblasts.

The pathophysiological consequences of thyroid hormone transporter deficiencies: Insights from mouse models.

Background: As a prerequisite for thyroid hormone (TH) metabolism and action TH has to be transported into cells where TH deiodinases and receptors are located. The trans-membrane passage of TH is facilitated by TH transporters of which the monocarboxylate transporter MCT8 has been most intensively studied. Inactivating mutations in the gene encoding MCT8 are associated with a severe form of psychomotor retardation and abnormal serum TH levels (Allan-Herndon-Dudley syndrome).

A microinjection protocol for the generation of transgenic killifish (Species: Nothobranchius furzeri).

Background: A challenge in age research is the absence of short-lived vertebrate model organisms. The turquoise killifish Nothobranchius furzeri has an exceptionally short lifespan of 4-10 months depending on the strain. Thus, it possesses the shortest known maximum lifespan of a vertebrate species that can be bred in captivity.

Estradiol increases hematopoietic stem and progenitor cells independent of its actions on bone.

Hematopoietic stem and progenitor cells reside in vascular and endosteal niches in the bone marrow. Factors affecting bone remodeling were reported to influence numbers and mobilization of hematopoietic stem cells. We therefore analyzed the effects of estradiol acting anabolic on bone integrity.

Impact of Oatp1c1 deficiency on thyroid hormone metabolism and action in the mouse brain.

Organic anion-transporting polypeptide 1c1 (Oatp1c1) (also known as Slco1c1 and Oatp14) belongs to the family of Oatp and has been shown to facilitate the transport of T(4). In the rodent brain, Oatp1c1 is highly enriched in capillary endothelial cells and choroid plexus structures where it may mediate the entry of T(4) into the central nervous system. Here, we describe the generation and first analysis of Oatp1c1-deficient mice.

Metal binding dictates conformation and function of the amyloid precursor protein (APP) E2 domain.

The amyloid precursor protein (APP) and its neurotoxic cleavage product Aβ are key players in the development of Alzheimer's disease and appear essential for neuronal development and cell homeostasis in mammals. Proteolytic processing of APP is influenced by metal ions, protein ligands and its oligomerization state. However, the structural basis and functional mechanism of APP regulation are hitherto largely unknown.

Mapping of quantitative trait loci controlling lifespan in the short-lived fish Nothobranchius furzeri--a new vertebrate model for age research.

The African annual fish Nothobranchius furzeri emerged as a new model for age research over recent years. Nothobranchius furzeri show an exceptionally short lifespan, age-dependent cognitive/behavioral decline, expression of age-related biomarkers, and susceptibility to lifespan manipulation. In addition, laboratory strains differ largely in lifespan.

Activation of Ras requires the ERM-dependent link of actin to the plasma membrane.

Background: Receptor tyrosine kinases (RTKs) participate in a multitude of signaling pathways, some of them via the small G-protein Ras. An important component in the activation of Ras is Son of sevenless (SOS), which catalyzes the nucleotide exchange on Ras.

Principal Findings: We can now demonstrate that the activation of Ras requires, in addition, the essential participation of ezrin, radixin and/or moesin (ERM), a family of actin-binding proteins, and of actin.

Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells.

Despite several side effects, glucocorticoids (GCs) have been widely used for 60 y to treat rheumatoid arthritis on the basis of their antiinflammatory effects. However, the cells targeted by GCs and the transcriptional mechanisms underlying their actions through the glucocorticoid receptor (GR) in steroid therapy remain poorly defined. Using cell type-specific GR-deficient mice subjected to antigen-induced arthritis (AIA) as a model of human rheumatoid arthritis, we show that GC action on T cells but not myeloid cells is critical for therapeutic intervention in AIA.

MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway.

Primary microcephaly 1 is a neurodevelopmental disorder caused by mutations in the MCPH1 gene, whose product MCPH1 (also known as microcephalin and BRIT1) regulates DNA-damage response. Here we show that Mcph1 disruption in mice results in primary microcephaly, mimicking human MCPH1 symptoms, owing to a premature switching of neuroprogenitors from symmetric to asymmetric division. MCPH1-deficiency abrogates the localization of Chk1 to centrosomes, causing premature Cdk1 activation and early mitotic entry, which uncouples mitosis and the centrosome cycle.

Purification of the proprotein convertase furin by affinity chromatography based on PC-specific inhibitors.

In eucaryotes, many secreted proteins and peptides are proteolytically excised from larger precursor proteins by a specific class of serine proteases, the proprotein/prohormone convertases (PCs). This cleavage is essential for substrate activation, making the PCs very interesting pharmacological targets in cancer and infectious disease research. Correspondingly, their structure, function and inhibition are intensely studied - studies that require the respective target proteins in large amounts and at high purity.

Phylogeny-wide analysis of social amoeba genomes highlights ancient origins for complex intercellular communication.

Dictyostelium discoideum (DD), an extensively studied model organism for cell and developmental biology, belongs to the most derived group 4 of social amoebas, a clade of altruistic multicellular organisms. To understand genome evolution over long time periods and the genetic basis of social evolution, we sequenced the genomes of Dictyostelium fasciculatum (DF) and Polysphondylium pallidum (PP), which represent the early diverging groups 1 and 2, respectively. In contrast to DD, PP and DF have conventional telomere organization and strongly reduced numbers of transposable elements.

Phylogeny, genetic variability and colour polymorphism of an emerging animal model: the short-lived annual Nothobranchius fishes from southern Mozambique.

Nothobranchius are a group of small, extremely short-lived killifishes living in temporary savannah pools in Eastern Africa and that survive annual desiccation of their habitat as dormant eggs encased in dry mud. One mitochondrial (COI) and three nuclear (CX32.2, GHITM, PNP) loci were used to investigate the phylogenetic relationship of Nothobranchius species from southern and central Mozambique.

Point mutation at the Nbs1 Threonine 278 site does not affect mouse development, but compromises the Chk2 and Smc1 phosphorylation after DNA damage.

NBS1, mutated in Nijmegen breakage syndrome (NBS), senses the DNA double strand breaks (DSBs) and initiates the DNA damage response (DDR) by activating ATM kinase. Meanwhile, NBS1 is phosphorylated by ATM at Serine 278 and Serine 343 and thereby assists the activation of the ATM downstream targets. To study the physiological function of the Nbs1 phosphorylation, we have knocked in a point mutation in the moue genome that results in the replacement of Threonine 278 (equivalent to the human Serine 278) by Alanine.

Mitochondrial DNA copy number and function decrease with age in the short-lived fish Nothobranchius furzeri.

Among vertebrates that can be kept in captivity, the annual fish Nothobranchius furzeri possesses the shortest known lifespan. It also shows typical signs of aging and is therefore an ideal model to assess the role of different physiological and environmental parameters on aging and lifespan determination. Here, we used Nothobranchius furzeri to study whether aging is associated with mitochondrial DNA (mtDNA) alterations and changes in mitochondrial function.

Comprehensive assessment of sequence variation within the copy number variable defensin cluster on 8p23 by target enriched in-depth 454 sequencing.

Background: In highly copy number variable (CNV) regions such as the human defensin gene locus, comprehensive assessment of sequence variations is challenging. PCR approaches are practically restricted to tiny fractions, and next-generation sequencing (NGS) approaches of whole individual genomes e.g.