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Jennifer F Knight, Vanessa Y C Sung, Elena Kuzmin, Amber L Couzens, Danielle A de Verteuil, Colin D H Ratcliffe, Paula P Coelho, Radia M Johnson, Payman Samavarchi-Tehrani, Tina Gruosso, Harvey W Smith, Wontae Lee, Sadiq M Saleh, Dongmei Zuo, Hong Zhao, Marie-Christine Guiot, Ryan R Davis, Jeffrey P Gregg, Christopher Moraes, Anne-Claude Gingras, Morag Park
Triple-negative breast cancers (TNBCs) display a complex spectrum of mutations and chromosomal aberrations. Chromosome 5q (5q) loss is detected in up to 70% of TNBCs, but little is known regarding the genetic drivers associated with this event. Here, we show somatic deletion of a region syntenic with human 5q33.2-35.3 in a mouse model of TNBC. Mechanistically, we identify KIBRA as a major factor contributing to the effects of 5q loss on tumor growth and metastatic progression. Re-expression of KIBRA impairs metastasis in vivo and inhibits tumorsphere formation by TNBC cells in vitro...
March 20, 2018: Cell Reports
Ting Lin, Li Zhang, Shuangxin Liu, Yuanhan Chen, Hong Zhang, Xingchen Zhao, Ruizhao Li, Qianmei Zhang, Ruyi Liao, Zongshun Huang, Bin Zhang, Wenjian Wang, Xinling Liang, Wei Shi
Previous studies have indicated that glomerular podocyte injury serves a crucial role in proteinuria during the process of chronic kidney disease. The slit diaphragm of podocytes forms the final barrier to proteinuria. Dendrin, a constituent of the slit diaphragm protein complex, has been observed to relocate from the slit diaphragm to the nuclei in injured podocytes and promote podocyte apoptosis. However, the exact mechanism for nuclear relocation of dendrin remains unclear. The expression of WWC1 in podocyte injury induced by lipopolysaccharides (LPS) or adriamycin (ADR) was detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), western blotting and the immunofluorescence assay...
December 2017: Molecular Medicine Reports
Kristin Meliambro, Jenny S Wong, Justina Ray, Rhodora C Calizo, Sara Towne, Beatriz Cole, Fadi El Salem, Ronald E Gordon, Lewis Kaufman, John C He, Evren U Azeloglu, Kirk N Campbell
Kidney podocytes represent a key constituent of the glomerular filtration barrier. Identifying the molecular mechanisms of podocyte injury and survival is important for better understanding and management of kidney diseases. KIBRA (<u>ki</u>dney <u>bra</u>in protein), an upstream regulator of the Hippo signaling pathway encoded by the Wwc1 gene, shares the pro-injury properties of its putative binding partner dendrin and antagonizes the pro-survival signaling of the downstream Hippo pathway effector YAP (Yes-associated protein) in Drosophila and MCF10A cells...
December 22, 2017: Journal of Biological Chemistry
Yijun Zhang, Shumei Yan, Jiewei Chen, Caixia Gan, Dong Chen, Yan Li, Jiahuai Wen, Joachim Kremerskothen, Shilu Chen, Jiangbo Zhang, Yun Cao
WWC family proteins negatively regulate HEK293 cell proliferation and organ growth by suppressing the transcriptional activity of Yes-associated protein (YAP), a major effector of the Hippo pathway. The function of the scaffolding protein WWC1 (also called KIBRA) has been intensively studied in cells and animal models. However, the expression and clinicopathologic significance of WWC2 in cancer are poorly characterized. This study aimed to clarify the biological function and mechanism of action of WWC2 in hepatocellular carcinoma (HCC)...
December 2017: Journal of Cellular and Molecular Medicine
A Jeremy Willsey, Thomas V Fernandez, Dongmei Yu, Robert A King, Andrea Dietrich, Jinchuan Xing, Stephan J Sanders, Jeffrey D Mandell, Alden Y Huang, Petra Richer, Louw Smith, Shan Dong, Kaitlin E Samocha, Benjamin M Neale, Giovanni Coppola, Carol A Mathews, Jay A Tischfield, Jeremiah M Scharf, Matthew W State, Gary A Heiman
Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2...
May 3, 2017: Neuron
Ignazio S Piras, Jonida Krate, Isabelle Schrauwen, Jason J Corneveaux, Geidy E Serrano, Lucia Sue, Thomas G Beach, Matthew J Huentelman
The rs17070145-T variant of the WWC1 gene, coding for the KIBRA protein, has been associated with both increased episodic memory performance and lowered risk for late onset Alzheimer's disease, although the mechanism behind this protective effect has not been completely elucidated. To achieve a better understanding of the pathways modulated by rs17070145 and its associated functional variant(s), we used laser capture microdissection (LCM) and RNA-sequencing to investigate the effect of rs17070145 genotypes on whole transcriptome expression in the human hippocampus (HP) of 22 neuropathologically normal individuals, with a specific focus on the dentate gyrus (DG) and at the pyramidal cells (PC) of CA1 and CA3 sub-regions...
July 2017: Hippocampus
Agnieszka Paziewska, Andrzej Habior, Agnieszka Rogowska, Włodzimierz Zych, Krzysztof Goryca, Jakub Karczmarski, Michalina Dabrowska, Filip Ambrozkiewicz, Bozena Walewska-Zielecka, Marek Krawczyk, Halina Cichoz-Lach, Piotr Milkiewicz, Agnieszka Kowalik, Krzysztof Mucha, Joanna Raczynska, Joanna Musialik, Grzegorz Boryczka, Michal Wasilewicz, Irena Ciecko-Michalska, Malgorzata Ferenc, Maria Janiak, Alina Kanikowska, Rafal Stankiewicz, Marek Hartleb, Tomasz Mach, Marian Grzymislawski, Joanna Raszeja-Wyszomirska, Ewa Wunsch, Tomasz Bobinski, Michal Mikula, Jerzy Ostrowski
BACKGROUND: Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are forms of hepatic autoimmunity, and risk for both diseases has a strong genetic component. This study aimed to define the genetic architecture of PBC and PSC within the Polish population. METHODS: Subjects were 443 women with PBC, 120 patients with PSC, and 934 healthy controls recruited from Gastroenterology Departments in various Polish hospitals. Allelotyping employed a pooled-DNA sample-based genome-wide association study (GWAS) approach, using Illumina Human Omni2...
January 6, 2017: BMC Medical Genomics
Srinivas Vinod Saladi, Kenneth Ross, Mihriban Karaayvaz, Purushothama R Tata, Hongmei Mou, Jayaraj Rajagopal, Sridhar Ramaswamy, Leif W Ellisen
Loss-of-function mutations in SWI/SNF chromatin-remodeling subunit genes are observed in many cancers, but an oncogenic role for SWI/SNF is not well established. Here, we reveal that ACTL6A, encoding an SWI/SNF subunit linked to stem cell and progenitor cell function, is frequently co-amplified and highly expressed together with the p53 family member p63 in head and neck squamous cell carcinoma (HNSCC). ACTL6A and p63 physically interact, cooperatively controlling a transcriptional program that promotes proliferation and suppresses differentiation, in part through activation of the Hippo-YAP pathway via regulators including WWC1...
January 9, 2017: Cancer Cell
Monika Talarowska, Janusz Szemraj, Małgorzata Kowalczyk, Piotr Gałecki
BACKGROUND: Genes participating in synaptic signalling or plasticity in brain regions such as the prefrontal cortex (PFC) and the hippocampus have been implicated in cognition. Recently, a new gene (KIBRA, WWC1) has been added to this group due to its impact on memory performance. Recurrent depressive disorder (rDD) is a multifactorial disease, that one of the typical features is cognitive impairment. The main objective of this study was to perform an analysis of the KIBRA gene on both mRNA and protein levels in patients suffering from rDD and to investigate the relationship between KIBRA expression and cognitive performance...
2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Mark Z Kos, Melanie A Carless, Juan Peralta, August Blackburn, Marcio Almeida, David Roalf, Michael F Pogue-Geile, Konasale Prasad, Ruben C Gur, Vishwajit Nimgaonkar, Joanne E Curran, Ravi Duggirala, David C Glahn, John Blangero, Raquel E Gur, Laura Almasy
Schizophrenia is a mental disorder characterized by impairments in behavior, thought, and neurocognitive performance. We searched for susceptibility loci at a quantitative trait locus (QTL) previously reported for abstraction and mental flexibility (ABF), a cognitive function often compromised in schizophrenia patients and their unaffected relatives. Exome sequences were determined for 134 samples in 8 European American families from the original linkage study, including 25 individuals with schizophrenia or schizoaffective disorder...
March 2016: Schizophrenia Bulletin
Mac B Robinson, Deepak A Deshpande, Jeffery Chou, Wei Cui, Shelly Smith, Carl Langefeld, Annette T Hastie, Eugene R Bleecker, Gregory A Hawkins
Genetic data suggest that IL-6 trans-signaling may have a pathogenic role in the lung; however, the effects of IL-6 trans-signaling on lung effector cells have not been investigated. In this study, human airway smooth muscle (HASM) cells were treated with IL-6 (classical) or IL-6+sIL6R (trans-signaling) for 24 h and gene expression was measured by RNAseq. Intracellular signaling and transcription factor activation were assessed by Western blotting and luciferase assay, respectively. The functional effect of IL-6 trans-signaling was determined by proliferation assay...
July 15, 2015: American Journal of Physiology. Lung Cellular and Molecular Physiology
Upal Basu-Roy, N Sumru Bayin, Kirk Rattanakorn, Eugenia Han, Dimitris G Placantonakis, Alka Mansukhani, Claudio Basilico
The repressive Hippo pathway has a profound tumour suppressive role in cancer by restraining the growth-promoting function of the transcriptional coactivator, YAP. We previously showed that the stem cell transcription factor Sox2 maintains cancer stem cells (CSCs) in osteosarcomas. We now report that in these tumours, Sox2 antagonizes the Hippo pathway by direct repression of two Hippo activators, Nf2 (Merlin) and WWC1 (Kibra), leading to exaggerated YAP function. Repression of Nf2, WWC1 and high YAP expression marks the CSC fraction of the tumor population, while the more differentiated fraction has high Nf2, high WWC1 and reduced YAP expression...
2015: Nature Communications
Diego A Ojeda, Diego A Forero
BACKGROUND: Non-synonymous single nucleotide polymorphisms (nsSNPs) in brain-expressed genes represent interesting candidates for genetic research in neuropsychiatric disorders. PURPOSE: To study novel nsSNPs in brain-expressed genes in a sample of Colombian subjects. METHODS: We applied an approach based on in silico mining of available genomic data to identify and select novel nsSNPs in brain-expressed genes. We developed novel genotyping assays, based in allele-specific PCR methods, for these nsSNPs and genotyped them in 171 Colombian subjects...
October 2014: Annals of Neurosciences
Dirk Oliver Wennmann, Jürgen Schmitz, Michael C Wehr, Michael P Krahn, Nora Koschmal, Sascha Gromnitza, Ulf Schulze, Thomas Weide, Anil Chekuri, Boris V Skryabin, Volker Gerke, Hermann Pavenstädt, Kerstin Duning, Joachim Kremerskothen
The scaffolding protein KIBRA (also called WWC1) is involved in the regulation of important intracellular transport processes and the establishment of cell polarity. Furthermore, KIBRA/WWC1 is an upstream regulator of the Hippo signaling pathway that controls cell proliferation and organ size in animals. KIBRA/WWC1 represents only one member of the WWC protein family that also includes the highly similar proteins WWC2 and WWC3. Although the function of KIBRA/WWC1 was studied intensively in cells and animal models, the importance of WWC2 and WWC3 was not yet elucidated...
July 2014: Molecular Biology and Evolution
Igor Martianov, Emilie Cler, Isabelle Duluc, Serge Vicaire, Muriel Philipps, Jean-Noel Freund, Irwin Davidson
Collagen 6A3 (Col6a3), a component of extracellular matrix, is often up-regulated in tumours and is believed to play a pro-oncogenic role. However the mechanisms of its tumorigenic activity are poorly understood. We show here that Col6a3 is highly expressed in densely growing mouse embryonic fibroblasts (MEFs). In MEFs where the TAF4 subunit of general transcription factor IID (TFIID) has been inactivated, elevated Col6a3 expression prevents contact inhibition promoting their 3 dimensional growth as foci and fibrospheres...
2014: PloS One
John Muse, Matthew Emery, Fabio Sambataro, Herve Lemaitre, Hao-Yang Tan, Qiang Chen, Bhaskar S Kolachana, Saumitra Das, Joseph H Callicott, Daniel R Weinberger, Venkata S Mattay
BACKGROUND: Episodic memory (EM) declines with age and the rate of decline is variable across individuals. A single nucleotide polymorphism (rs17070145) in the WWC1 gene that encodes the KIBRA protein critical for long-term potentiation and memory consolidation has previously been associated with EM performance, as well as differences in hippocampal engagement during EM tasks using functional magnetic resonance imaging (fMRI). In the current study, we explore the effect of this polymorphism on EM-related activity and cognitive performance across the adult life span using fMRI...
May 1, 2014: Biological Psychiatry
Angela Vogt-Eisele, Carola Krüger, Kerstin Duning, Daniela Weber, Robert Spoelgen, Claudia Pitzer, Christian Plaas, Gisela Eisenhardt, Annette Meyer, Gerhard Vogt, Markus Krieger, Eva Handwerker, Dirk Oliver Wennmann, Thomas Weide, Boris V Skryabin, Matthias Klugmann, Hermann Pavenstädt, Matthew J Huentelmann, Joachim Kremerskothen, Armin Schneider
The WWC1 gene has been genetically associated with human episodic memory performance, and its product KIdney/BRAin protein (KIBRA) has been shown to interact with the atypical protein kinase protein kinase M ζ (PKMζ). Although recently challenged, PKMζ remains a candidate postsynaptic regulator of memory maintenance. Here, we show that PKMζ is subject to rapid proteasomal degradation and that KIBRA is both necessary and sufficient to counteract this process, thus stabilizing the kinase and maintaining its function for a prolonged time...
March 2014: Journal of Neurochemistry
Sarah Wilker, Thomas Elbert, Iris-Tatjana Kolassa
A good memory for emotionally arousing experiences may be intrinsically adaptive, as it helps the organisms to predict safety and danger and to choose appropriate responses to prevent potential harm. However, under conditions of repeated exposure to traumatic stressors, strong emotional memories of these experiences can lead to the development of trauma-related disorders such as posttraumatic stress disorder (PTSD). This syndrome is characterized by distressing intrusive memories that can be so intense that the survivor is unable to discriminate past from present experiences...
July 2014: Neurobiology of Learning and Memory
Nicolas W Schuck, Christian F Doeller, Brit-Maren M Schjeide, Julia Schröder, Peter A Frensch, Lars Bertram, Shu-Chen Li
Spatial navigation relies on multiple mnemonic mechanisms and previous work in younger adults has described two separate types of spatial memory. One type uses directional as well as boundary-related information for spatial memory and mainly implicates the hippocampal formation. The other type has been linked to directional and landmark-related information and primarily involves the striatum. Using a virtual reality navigation paradigm, we studied the impacts of aging and a single nucleotide polymorphism (SNP rs17070145) of the KIBRA gene (official name: WWC1) on these memory forms...
October 2013: Hippocampus
Sarah Wilker, Stephan Kolassa, Christian Vogler, Birke Lingenfelder, Thomas Elbert, Andreas Papassotiropoulos, Dominique J-F de Quervain, Iris-Tatjana Kolassa
BACKGROUND: Posttraumatic stress disorder (PTSD) results from the formation of a strong memory for the sensory-perceptual and affective representations of traumatic experiences, which is detached from the corresponding autobiographical context information. Because WWC1, the gene encoding protein KIBRA, is associated with long-term memory performance, we hypothesized that common WWC1 alleles influence the risk for a lifetime diagnosis of PTSD. METHODS: Traumatic load and diagnosis of current and lifetime PTSD were assessed in two independent African samples of survivors from conflict zones who had faced severe trauma (n = 392, Rwanda, and n = 399, Northern Uganda, respectively)...
November 1, 2013: Biological Psychiatry
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