The antioncogenic Chk2 kinase plays a crucial role in DNA damage-induced cell-cycle checkpoint regulation. Here we show that Chk2 associates with the oncogenic protein Wip1 (wild-type p53-inducible phosphatase 1) (PPM1D), a p53-inducible protein phosphatase. Phosphorylation of Chk2 at threonine68 (Thr68), a critical event for Chk2 activation, which is normally induced by DNA damage or overexpression of Chk2, is inhibited by expression of wild-type (WT), but not a phosphatase-deficient mutant (D314A) of Wip1 in cultured cells. Furthermore, an in vitro phosphatase assay revealed that Wip1 (WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C. Moreover, inhibition of Wip1 expression by RNA interference results in abnormally sustained Thr68 phosphorylation of Chk2 and increased susceptibility of cells in response to DNA damage, indicating that Wip1 acts as a negative regulator of Chk2 in response to DNA damage.

A B S T R A C T Background:Having support from an informal carer is important for heart failure patients. Carers have the potential to improve patient self-care. At the same time, it should be acknowledged that caregiving could affect the carer negatively and cause emotional reactions of burden and stress. Dyadic (patient and informal carer) heart failure self-care interventions seek to improve patient self-care such as adherence to medical treatment, exercise training, symptom monitoring and symptom management when needed. Currently, no systematic assessment of dyadic interventions has been conducted with a focus on describing components, examining physical and delivery contexts, or determining the effect on patient and/or carer outcomes.Objective: To examine the components, context, and outcomes of dyadic self-care interventions.Design: A systematic review registered in PROSPERO, following PRISMA guidelines with a narrative analysis and realist synthesis. Data Sources: PubMed, EMBASE, Web of Science, PsycINFO, and Cochrane Central Register of Controlled Trials were searched using MeSH, EMTREE terms, keywords, and keyword phrases for the following concepts: dyadic, carers, heart failure and intervention. Eligible studies were original research, written in English, on dyadic self-care interventions in adult samples. Review methods:We used a two-tiered analytic approach including both completed studies with power to determine outcomes and ongoing studies including abstracts, small pilot studies and protocols to forecast future directions.Results: Eighteen papers -12 unique, completed intervention studies (two quasi-and ten experimental trials) from 2000 to 2016 were reviewed.Intervention components fell into three groups -education, support, and guidance. Interventions were implemented in 5 countries, across multiple settings of care, and involved 3 delivery modes -face to face, telephone or technology based. Dyadic intervention effects on cognitive, behavioral, affective and health services utilization outcomes were found within studies. However, findings across studies were inconclusive as some studies reported positive and some non-sustaining outcomes on the same variables. All the included papers had methodological limitations including insufficient sample size, mixed intervention effects and counter-intuitive outcomes. Conclusions:We found that the evidence from dyadic interventions to promote heart failure selfcare, while growing, is still very limited. Future research needs to involve advanced sample size justification, innovative solutions to increase and sustain behavior change, and use of mixed methods for capturing a more holistic picture of effects in clinical practice. Contribution of the paper:What is already known about the topic?• Having support from an informal carer is important for heart failure (HF) patients • Dyadic (patient and informal carer) HF self-care interventions seek to improve patient self-care such as adherence to medical treatment, exercise training, symptom monitoring and symptom...

Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins, designated Alc ␣ , Alc ␤ , and Alc ␥ . The Alcs express in neurons dominantly and largely colocalize with the Alzheimer amyloid precursor protein (APP) in the brain. Alcs and APP show an identical function as a cargo receptor of kinesin-1. Moreover, proteolytic processing of Alc proteins appears highly similar to that of APP. We found that APP ␣-secretases ADAM 10 and ADAM 17 primarily cleave Alc proteins and trigger the subsequent secondary intramembranous cleavage of Alc C-terminal fragments by a presenilin-dependent ␥-secretase complex, thereby generating "APP p3-like" and non-aggregative Alc peptides (p3-Alcs). We determined the complete amino acid sequence of p3-Alc ␣ , p3-Alc ␤ , and p3-Alc ␥ , whose major species comprise 35, 37, and 31 amino acids, respectively, in human cerebrospinal fluid. We demonstrate here that variant p3-Alc C termini are modulated by FAD-linked presenilin 1 mutations increasing minor ␤-amyloid species A␤42, and these mutations alter the level of minor p3-Alc species. However, the magnitudes of C-terminal alteration of p3-Alc ␣ , p3-Alc ␤ , and p3-Alc ␥ were not equivalent, suggesting that one type of ␥-secretase dysfunction does not appear in the phenotype equivalently in the cleavage of type I membrane proteins. Because these C-terminal alterations are detectable in human cerebrospinal fluid, the use of a substrate panel, including Alcs and APP, may be effective to detect ␥-secretase dysfunction in the prepathogenic state of Alzheimer disease subjects. Alcadein (Alc)5 proteins comprise a family of evolutionarily conserved, type I membrane proteins that are predominantly expressed in neuronal tissues. Alc has been independently identified as a binding protein for the neuron-specific adaptor protein X11L (X11-like) (1) and as a postsynaptic Ca 2ϩ -binding protein, where it is known by the name calsyntenin (2). Alc functions as a cargo-receptor for the kinesin-1 motor that mediates anterograde transport of APP (3, 4), and a mutation in a nematode ortholog of the Alc gene is reported to cause a defect in associative learning (5, 6). Thus, Alc plays important roles in vesicular transport at the subcellular level and in learning behavior at the organismal level. Alc exists as four isoforms in mammals: Alc ␣1 (971 amino acids in humans), Alc ␣2 (981 amino acids in humans), Alc ␤ (956 amino acids in humans), and Alc ␥ (955 amino acids in humans) (1). Alc ␣ , Alc ␤ , and Alc ␥ are * This work was supported, in whole or in part, by National Institutes of Health, NIA, Grants R01 AG23611, P01 AG10491, and P50 AG005138 (to S. G.). This work was also supported in part by Grants-in-aid for Scientific Research on Priority Areas 20023001 (to T. S.) from the Ministry of Education, Science, Culture, Sports, and Technology, Japan. □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental

The Alcadeins (Alcs)/calsyntenins and the amyloid ␤-protein precursor (APP) associate with each other in the brain by binding via their cytoplasmic domains to X11L (the X11-like protein). We previously reported that the formation of this APP-X11L-Alc tripartite complex suppresses the metabolic cleavages of APP. We show here that the metabolism of the Alcs markedly resembles that of APP. The Alcs are subjected to a primary cleavage event that releases their extracellular domain. Alcs then undergo a secondary presenilin-dependent ␥-cleavage that leads to the secretion of the amyloid ␤-protein-like peptide and the liberation of an intracellular domain fragment (AlcICD). However, when Alc is in the tripartite complex, it escapes from these cleavages, as does APP. We also found that AlcICD suppressed the FE65-dependent gene transactivation activity of the APP intracellular domain fragment, probably because AlcICD competes with the APP intracellular domain fragment for binding to FE65. We propose that the Alcs and APP are coordinately metabolized in neurons and that their cleaved cytoplasmic fragments are reciprocally involved in the regulation of FE65-dependent gene transactivation. Any imbalance in the metabolism of Alcs and APP may influence the FE65-dependent gene transactivation, which together with increased secretion of amyloid ␤-protein may contribute to neural disorders.The deposition and accumulation of amyloid ␤-protein (A␤) 1 in the human brain are hallmarks of Alzheimer's disease (AD)(1). Amyloid ␤-protein precursor (APP) is the precursor of A␤. It has a receptor-like transmembrane protein structure that consists of an extracellular domain, a transmembrane domain, and a short carboxyl-terminal cytoplasmic domain (2). The cytoplasmic domain of APP controls its metabolism and various physiological functions by interacting with cytoplasmic adaptor proteins (3-8). One of these adaptor proteins is X11L (the X11-like protein), which associates with the cytoplasmic domain of APP and stabilizes APP metabolism (5, 9). During our previous research that aimed to reveal the molecular mechanism by which X11L regulates APP metabolism, we found that the Alcadeins, which form cadherin-related membrane protein family, are X11-and X11L-binding proteins (9). These proteins are also known as calsyntenins, which were originally isolated as postsynaptic Ca 2ϩ -binding membrane proteins, but whose functions were not identified (10, 11). The Alcadeins (Alcs) consist of two Alc␣ isoforms (Alc␣1 and Alc␣2) and Alc␤ and Alc␥, all of which are type I transmembrane proteins and contain a conserved X11L-binding motif in their single cytoplasmic domains, similar to APP (9).Alc does not directly interact with the cytoplasmic domain of APP. Rather, the association between the two molecules is bridged by the phosphotyrosine interaction domain of X11L. This results in the formation of a tripartite complex in the brain (9). The formation of this complex enhances the X11L-mediated stabilization of APP metabolism and suppresses the generation...

Innate immune cells such as natural killer (NK) cells play a crucial role in antitumor immune responses. NKG2D is a major activating immunoreceptor expressed in not only NK cells but also CD8þ T cells and shows cytotoxicity against tumors by recognizing its ligands major histocompatibility complex class I-related chain A and B (MICA and MICB) on tumor cells. Recently, it has been suggested that NKG2D-mediated cytotoxicity correlates with the expression levels of NKG2D ligands on target cells. In this study, we were able to increase the expression levels of MICA and MICB on leukemic cell lines and patients' leukemic cells by treatment with trichostatin A (TsA), a histone deacetylase (HDAC) inhibitor. Chromatin immunoprecipitation (ChIP) assays revealed that treatment with TsA resulted in increased acetylation of histone H3 and decreased association with HDAC1 at the promoters of MICA and MICB. Intriguingly, upregulation of MICA and MICB by treatment with TsA led to enhancement of the susceptibility of leukemic cells to the cytotoxicity of NKG2D-expressing cells. Our results suggest that regulation of the expression of NKG2D ligands by treatment with chromatin-remodeling drugs may be an attractive strategy for immunotherapy.