MUC1: A multifunctional cell surface component of reproductive tissue epithelia

MUC1 is a large, transmembrane mucin glycoprotein expressed at the apical surface of a variety of reproductive tract epithelia. Functions attributed to MUC1 include those generally associated with mucins such as lubrication and hydration of cell surfaces as well as protection from microorganisms and degradative enzymes. In addition, MUC1 is an effective inhibitor of both cell-cell and cell-extracellular matrix interactions in both normal and malignant contexts. Moreover, a series of recent studies has shown that the highly conserved cytoplasmic tail of MUC1 interacts specifically with a series of important signal transducing molecules including β-catenin, Grb2 and erbB family members. MUC1 expression in normal epithelia can be quite dynamic, varying in response to steroid hormone or cytokine influences. Following malignant transformation, MUC1 often becomes highly overexpressed, loses its apical restriction, and displays aberrant glycosylation and altered mRNA splice variants. Regulation of MUC1 expression can occur at the transcriptional level. In addition, post-translational regulation of cell surface expression occurs via the activity of cell surface proteases or "sheddases" that release soluble forms of the large ectodomains. This review will briefly summarize studies of MUC1 expression and function in reproductive tissues with particular emphasis on the uterus. In addition, current knowledge of the mechanisms of MUC1 gene regulation, metabolic processing and potential signal transducing functions will be presented

Deletion of SERF2 in mice delays embryonic development and alters amyloid deposit structure in the brain

In age-related neurodegenerative diseases, like Alzheimer's and Parkinson's, disease-specific proteins become aggregation-prone and form amyloid-like deposits. Depletion of SERF proteins ameliorates this toxic process in worm and human cell models for diseases. Whether SERF modifies amyloid pathology in mammalian brain, however, has remained unknown. Here, we generated conditional Serf2 knockout mice and found that full-body deletion of Serf2 delayed embryonic development, causing premature birth and perinatal lethality. Brain-specific Serf2 knockout mice, on the other hand, were viable, and showed no major behavioral or cognitive abnormalities. In a mouse model for amyloid-β aggregation, brain depletion of Serf2 altered the binding of structure-specific amyloid dyes, previously used to distinguish amyloid polymorphisms in the human brain. These results suggest that Serf2 depletion changed the structure of amyloid deposits, which was further supported by scanning transmission electron microscopy, but further study will be required to confirm this observation. Altogether, our data reveal the pleiotropic functions of SERF2 in embryonic development and in the brain and support the existence of modifying factors of amyloid deposition in mammalian brain, which offer possibilities for polymorphism-based interventions. </p

Deletion of SERF2 in mice delays embryonic development and alters amyloid deposit structure in the brain

In age-related neurodegenerative diseases, like Alzheimer's and Parkinson's, disease-specific proteins become aggregation-prone and form amyloid-like deposits. Depletion of SERF proteins ameliorates this toxic process in worm and human cell models for diseases. Whether SERF modifies amyloid pathology in mammalian brain, however, has remained unknown. Here, we generated conditional Serf2 knockout mice and found that full-body deletion of Serf2 delayed embryonic development, causing premature birth and perinatal lethality. Brain-specific Serf2 knockout mice, on the other hand, were viable, and showed no major behavioral or cognitive abnormalities. In a mouse model for amyloid-β aggregation, brain depletion of Serf2 altered the binding of structure-specific amyloid dyes, previously used to distinguish amyloid polymorphisms in the human brain. These results suggest that Serf2 depletion changed the structure of amyloid deposits, which was further supported by scanning transmission electron microscopy, but further study will be required to confirm this observation. Altogether, our data reveal the pleiotropic functions of SERF2 in embryonic development and in the brain and support the existence of modifying factors of amyloid deposition in mammalian brain, which offer possibilities for polymorphism-based interventions

The role of G protein-coupled receptors in the pathology of Alzheimer's disease

G protein-coupled receptors (GPCRs) are involved in numerous key neurotransmitter systems in the brain that are disrupted in Alzheimer's disease (AD). GPCRs also directly influence the amyloid cascade through modulation of the α-, β- and γ-secretases, proteolysis of the amyloid precursor protein (APP), and regulation of amyloid-β degradation. Additionally, amyloid-β has been shown to perturb GPCR function. Emerging insights into the mechanistic link between GPCRs and AD highlight the potential of this class of receptors as a therapeutic target for AD.status: publishe

G Protein-Coupled Receptors, Cholinergic Dysfunction, and A beta Toxicity in Alzheimer's Disease

The beta-amyloid (A beta) peptide is associated with the pathogenesis of Alzheimer's disease (AD). Evidence gathered over the last two decades suggests that the gradual accumulation of soluble and insoluble A beta peptide species triggers a cascade of events that leads to the clinical manifestation of AD. A beta accumulation has also been associated with the cholinergic dysfunction observed in AD, which is characterized by diminished acetylcholine release and impaired coupling of the muscarinic acetylcholine receptors (mAChRs) to heterotrimeric GTP-binding proteins (G proteins). Although the mechanism of A beta-mediated toxicity is not clearly understood, evidence shows that A beta accumulation has an effect on the oligomerization of the angiotensin II (AngII) AT(2) (angiotensin type 2) receptor and sequestration of the G alpha(q/11) family of G proteins. Sequestration of G alpha(q/11) results in dysfunctional coupling and signaling between M-1 mAChR and G alpha(q/11) and accompanies neurodegeneration, tau phosphorylation, and neuronal loss in an AD transgenic mouse model. Collectively, these results provide a putative link among A beta toxicity, AT(2) receptor oligomerization, and disruption of the signaling pathway through M-1 mAChR and G alpha(q/11) and potentially contribute to our understanding of the cholinergic deficit observed in AD.status: publishe

5-HT_4d receptor-stimulated APP shedding requires inositol polyphosphates and casein kinase 2.

<p>(A), (B) and (C) SH-SY5Y cells, transfected with pEAK12-AP-APP and pcDNA3.1-5-HT_4d, were treated with 1 µM prucalopride or 5-HT (5-HT₄ receptor agonists) in the absence or presence of 20 µM IP3K inhibitor (A), 80 µM CGA (IPMK inhibitor) (B) or 2.5 µM TBB (CK2 inhibitor) (C) and secretion of sAPPα was analyzed via measuring SEAP. (D) SEAP levels were measured in supernatants of SH-SY5Y cells, co-transfected with pEAK12-AP-APP, pcDNA3.1-5-HT_4d and 3 nM siRNA for knock-down of CK2 and treated with 1 µM prucalopride. (E) Cell lysates of (D) were analyzed for CK2 expression levels by western blotting. (F) Quantification of experiments in (E). Values shown are mean ± SEM of 6 individual wells and were normalized to vehicle control. * <i>P</i><0.05, ** <i>P</i><0.01, *** <i>P</i><0.001, one-way ANOVA with Tukey-Kramer's post-hoc test.</p

Single knock-down of ADAM9, ADAM10, ADAM17 and MMP9 does not affect 5-HT_4d receptor-stimulated APP shedding.

<p>(A) SH-SY5Y cells, transfected with pEAK12-AP-APP and pcDNA3.1-5-HT_4d, were treated with 1 µM prucalopride or 5-HT (5-HT₄ receptor agonists) in the absence or presence of 80 µM GM6001 (metalloproteinases inhibitor) and secretion of sAPPα was analyzed via measuring SEAP. (B) SEAP levels were measured in supernatants of SH-SY5Y cells, co-transfected with pEAK12-AP-APP, pcDNA3.1-5-HT_4d and 3 nM siRNA for knock-down of ADAM9 (A9), ADAM10 (A10), ADAM17 (A17) and MMP9 and treated with 1 µM prucalopride. (C) Cell lysates of (B) were analyzed for protein expression of ADAM9, 10, 17 and MMP9 by western blotting. The ADAM10 and ADAM17 immature precursor proteins are indicated by an x, whereas the mature catalytically active forms are indicated by an xx for ADAM9, 17 and MMP9. The immature ADAM9 and the mature ADAM10 proteins were not visible. (D) Quantification of experiments in (C). Values shown are mean ± SEM of 6 individual wells and were normalized to vehicle control. * <i>P</i><0.05, ** <i>P</i><0.01, *** <i>P</i><0.001, one-way ANOVA with Tukey-Kramer's post-hoc test.</p