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Wang-Ching Lin, Jeng-Shyan Deng, Shyh-Shyun Huang, Sheng-Hua Wu, Chin-Chu Chen, Wan-Rong Lin, Hui-Yi Lin, Guan-Jhong Huang
Acute lung injury (ALI) is characterized by inflammation of the lung tissue and oxidative injury caused by excessive accumulation of reactive oxygen species. Studies have suggested that anti-inflammatory or antioxidant agents could be used for the treatment of ALI with a good outcome. Therefore, our study aimed to test whether the mycelium extract of Sanghuangporus sanghuang (SS-1), believed to exhibit antioxidant and anti-inflammatory properties, could be used against the excessive inflammatory response associated with lipopolysaccharides (LPS)-induced ALI in mice and to investigate its possible mechanism of action...
February 7, 2017: International Journal of Molecular Sciences
Barbara Hummel, Erik C Hansen, Aneliya Yoveva, Fernando Aprile-Garcia, Rebecca Hussong, Ritwick Sawarkar
Understanding how genotypes are linked to phenotypes is important in biomedical and evolutionary studies. The chaperone heat-shock protein 90 (HSP90) buffers genetic variation by stabilizing proteins with variant sequences, thereby uncoupling phenotypes from genotypes. Here we report an unexpected role of HSP90 in buffering cis-regulatory variation affecting gene expression. By using the tripartite-motif-containing 28 (TRIM28; also known as KAP1)-mediated epigenetic pathway, HSP90 represses the regulatory influence of endogenous retroviruses (ERVs) on neighboring genes that are critical for mouse development...
January 30, 2017: Nature Structural & Molecular Biology
Hongzhi He, An Ye, Hana Kim, Joomyeong Kim
Peg3 (Paternally Expressed Gene 3) is an imprinted gene that encodes a zinc finger DNA-binding protein. Peg3 itself is localized in the middle of a KRAB-A (Kruppel-Associated Box) zinc finger gene cluster. The amino acid sequence encoded by its exon 7 also shows sequence similarity to that of KRAB-A, suggesting Peg3 as a KRAB-containing zinc finger gene. As predicted, the PEG3 protein was co-immunoprecipitated with KAP1, a co-repressor that interacts with KRAB-A. A series of follow-up experiments further demonstrated that the exon 7 of PEG3 is indeed responsible for its physical interaction with KAP1...
2016: PloS One
Wang Jinlong, Wang Jian, Tian Chunyan
The C2H2 zinc finger protein family, one of the largest families of transcription factor/transcriptional regulator in mammal, arose from a small ancestral group of eukaryotic zinc finger transcription factors through many repeated gene duplications accompanied by functional divergence. As the biggest subfamily of C2H2 zinc finger protein family, Kruppel-associated box-containing zinc finger proteins (KRAB-ZFPs) appeared at the period oftetrapod, expand rapidly along with species evolution, and take about 60% of the total C2H2 zinc finger proteins in human...
November 20, 2016: Yi Chuan, Hereditas
Patrycja Czerwińska, Parantu K Shah, Katarzyna Tomczak, Marta Klimczak, Sylwia Mazurek, Barbara Sozańska, Przemysław Biecek, Konstanty Korski, Violetta Filas, Andrzej Mackiewicz, Jannik N Andersen, Maciej Wiznerowicz
The expression of Tripartite motif-containing protein 28 (TRIM28)/Krüppel-associated box (KRAB)-associated protein 1 (KAP1), is elevated in at least 14 tumor types, including solid and hematopoietic tumors. High level of TRIM28 is associated with triple-negative subtype of breast cancer (TNBC), which shows higher aggressiveness and lower survival rates. Interestingly, TRIM28 is essential for maintaining the pluripotent phenotype in embryonic stem cells. Following on that finding, we evaluated the role of TRIM28 protein in the regulation of breast cancer stem cells (CSC) populations and tumorigenesis in vitro and in vivo...
January 3, 2017: Oncotarget
Gary Z Wang, Stephen P Goff
: Embryonic carcinoma (EC) cells are malignant counterparts of embryonic stem (ES) cells and serve as useful models for investigating cellular differentiation and human embryogenesis. Though the susceptibility of murine EC cells to retroviral infection has been extensively analyzed, few studies of retrovirus infection of human EC cells have been performed. We tested the susceptibility of human EC cells to transduction by retroviral vectors derived from three different retroviral genera...
January 1, 2017: Journal of Virology
Paolo Mita, Jeffrey N Savas, Erica M Briggs, Susan Ha, Veena Gnanakkan, John R Yates, Diane M Robins, Gregory David, Jef D Boeke, Michael J Garabedian, Susan K Logan
URI (unconventional prefoldin RPB5 interactor protein) is an unconventional prefoldin, RNA polymerase II interactor that functions as a transcriptional repressor and is part of a larger nuclear protein complex. The components of this complex and the mechanism of transcriptional repression have not been characterized. Here we show that KAP1 (KRAB-associated protein 1) and the protein phosphatase PP2A interact with URI. Mechanistically, we show that KAP1 phosphorylation is decreased following recruitment of PP2A by URI...
December 2, 2016: Journal of Biological Chemistry
Melissa Resto, Bong-Hyun Kim, Alfonso G Fernandez, Brian J Abraham, Keji Zhao, Brian A Lewis
We describe here the identification and functional characterization of the enzyme O-GlcNAcase (OGA) as an RNA polymerase II elongation factor. Using in vitro transcription elongation assays, we show that OGA activity is required for elongation in a crude nuclear extract system, whereas in a purified system devoid of OGA the addition of rOGA inhibited elongation. Furthermore, OGA is physically associated with the known RNA polymerase II (pol II) pausing/elongation factors SPT5 and TRIM28-KAP1-TIF1β, and a purified OGA-SPT5-TIF1β complex has elongation properties...
October 21, 2016: Journal of Biological Chemistry
Y Jiang, H-C Chen, X Su, P A Thompson, X Liu, K-A Do, W Wierda, M J Keating, W Plunkett
Approximately 10-20% of chronic lymphocytic leukemia (CLL) patients exhibit del(11q22-23) before treatment, this cohort increases to over 40% upon progression following chemoimmunotherapy. The coding sequence of the DNA damage response gene, ataxia-telangiectasia-mutated (ATM), is contained in this deletion. The residual ATM allele is frequently mutated, suggesting a relationship between gene function and clinical response. To investigate this possibility, we sought to develop and validate an assay for the function of ATM protein in these patients...
September 2, 2016: Blood Cancer Journal
Chun-Ting Cheng, Ching-Ying Kuo, Ching Ouyang, Chien-Feng Li, Yiyin Chung, David C Chan, Hsing-Jien Kung, David K Ann
Mitochondrial dynamics during nutrient starvation of cancer cells likely exert profound effects on their capability for metastatic progression. Here, we report that KAP1 (TRIM28), a transcriptional coadaptor protein implicated in metastatic progression in breast cancer, is a pivotal regulator of mitochondrial fusion in glucose-starved cancer cells. Diverse metabolic stresses induced Ser473 phosphorylation of KAP1 (pS473-KAP1) in a ROS- and p38-dependent manner. Results from live-cell imaging and molecular studies revealed that during the first 6 to 8 hours of glucose starvation, mitochondria initially underwent extensive fusion, but then subsequently fragmented in a pS473-KAP1-dependent manner...
September 1, 2016: Cancer Research
Masayoshi Ikeuchi, Yasunori Fukumoto, Takuya Honda, Takahisa Kuga, Youhei Saito, Naoto Yamaguchi, Yuji Nakayama
An increase in Src activity is commonly observed in epithelial cancers. Aberrant activation of the kinase activity is associated with malignant progression. However, the mechanisms that underlie the Src-induced malignant progression of cancer are not completely understood. We show here that v-Src, an oncogene that was first identified from a Rous sarcoma virus and a mutant variant of c-Src, leads to an increase in the number of anaphase and telophase cells having chromosome bridges. v-Src increases the number of γH2AX foci, and this increase is inhibited by treatment with PP2, a Src kinase inhibitor...
June 2, 2016: International Journal of Molecular Sciences
Yvonne Lorat, Stefanie Schanz, Claudia E Ruebe
PURPOSE: Intensity-modulated radiotherapy (IMRT) enables the delivery of high doses to target volume while sparing surrounding non-targeted tissues. IMRT treatment, however, substantially increases the normal-tissue volume receiving low-dose irradiation, but the biological consequences are unclear. EXPERIMENTAL DESIGN: Using mouse strains that varied in genetic DNA repair capacity, we investigated the DNA damage response of cortical neurons during daily low-dose irradiation (0...
May 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Bryndon J Oleson, Katarzyna A Broniowska, Aaron Naatz, Neil Hogg, Vera L Tarakanova, John A Corbett
Nitric oxide, produced in pancreatic β cells in response to proinflammatory cytokines, plays a dual role in the regulation of β-cell fate. While nitric oxide induces cellular damage and impairs β-cell function, it also promotes β-cell survival through activation of protective pathways that promote β-cell recovery. In this study, we identify a novel mechanism in which nitric oxide prevents β-cell apoptosis by attenuating the DNA damage response (DDR). Nitric oxide suppresses activation of the DDR (as measured by γH2AX formation and the phosphorylation of KAP1 and p53) in response to multiple genotoxic agents, including camptothecin, H2O2, and nitric oxide itself, despite the presence of DNA damage...
August 1, 2016: Molecular and Cellular Biology
Iván D'Orso
RNA polymerase II (Pol II) pausing at promoter-proximal regions is a highly regulated step in the transcription cycle. Pause release is facilitated by the P-TEFb kinase, which phosphorylates Pol II and negative elongation factors. Recent studies suggest that P-TEFb (as part of the inhibitory 7SK snRNP) is recruited to promoter-proximal regions through interaction with KAP1/TRIM28/TIF1β to facilitate 'on-site' kinase activation and transcription elongation. Here, I discuss features of this model and future challenges to further hone our understanding of transcriptional regulation including Pol II pausing and pause release...
June 2, 2016: RNA Biology
Yanying Wang, Jianxin Jiang, Qun Li, Hong Ma, Zengguang Xu, Yong Gao
BACKGROUND: The transcriptional regulator in embryonic development, KAP1, has been proved could promote cell proliferation and metastatic progression in a variety of human cancers. However, the role of KAP1 in hepatocellular carcinoma (HCC) remains unclear. The purpose of this study is to investigate the relationship of KAP1 expression with the progression and prognosis of HCC. METHODS: We measured the expression level of KAP1 in both human hepatoma cell lines and HCC tissues obtained from HCC patients by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot...
October 2016: International Journal of Clinical Oncology
Haibo Zhang, Ji Luo
This review discusses our current understanding of the small ubiquitin-like modifier (SUMO) pathway and how it functionally intersects with Ras signaling in cancer. The Ras family of small GTPases are frequently mutated in cancer. The role of the SUMO pathway in cancer and in Ras signaling is currently not well understood. Recent studies have shown that the SUMO pathway can both regulate Ras/MAPK pathway activity directly and support Ras-driven oncogenesis through the regulation of proteins that are not direct Ras effectors...
April 2, 2016: Small GTPases
Gabriela Ecco, Marco Cassano, Annamaria Kauzlaric, Julien Duc, Andrea Coluccio, Sandra Offner, Michaël Imbeault, Helen M Rowe, Priscilla Turelli, Didier Trono
KRAB-containing zinc finger proteins (KRAB-ZFPs) are early embryonic controllers of transposable elements (TEs), which they repress with their cofactor KAP1 through histone and DNA methylation, a process thought to result in irreversible silencing. Using a target-centered functional screen, we matched murine TEs with their cognate KRAB-ZFP. We found the paralogs ZFP932 and Gm15446 to bind overlapping but distinguishable subsets of ERVK (endogenous retrovirus K), repress these elements in embryonic stem cells, and regulate secondarily the expression of neighboring genes...
March 21, 2016: Developmental Cell
Ryan P McNamara, Carlos Guzman, Jonathan E Reeder, Iván D'Orso
The transition of RNA polymerase II (Pol II) from transcription initiation into productive elongation in eukaryotic cells is regulated by the P-TEFb kinase, which phosphorylates the C-terminal domain of paused Pol II at promoter-proximal regions. Our recent study found that P-TEFb (in an inhibited state bound to the 7SK snRNP complex) interacts with the KAP1/TRIM28 transcriptional regulator, and that KAP1 and the 7SK snRNP co-occupy most gene promoters containing paused Pol II. Here we provide a detailed experimental description and analysis of the ChIP-seq datasets that have been deposited into Gene Expression Omnibus (GEO): GS72622, so that independent groups can replicate and expand upon these findings...
March 2016: Genomics Data
Gabriela Ecco, Helen M Rowe, Didier Trono
Deposition of epigenetic marks is an important layer of the transcriptional control of retrotransposons, especially during early embryogenesis. Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs) are one of the largest families of transcription factors, and collectively partake in this process by tethering to thousands of retroelement-containing genomic loci their cofactor KAP1, which acts as a scaffold for a heterochromatin-inducing machinery. However, while the sequence-specific DNA binding potential of the poly-zinc finger-containing KRAB-ZFPs is recognized, very few members of the family have been assigned specific targets...
2016: Methods in Molecular Biology
Lorenzo Alibardi
Hardening of the human hair shaft during cornification results from the bonding of keratins and keratin-associated proteins. In situ hybridization and light immunocytochemical studies have shown the general distribution of different keratins and some associated proteins but not determined their ultrastructural localization. I report here the localization of hair keratins, two high-sulfur keratin-associated proteins and sulfhydryl oxidase has been studied under the transmission electron microscope in the cornification zone of the human hair...
February 15, 2016: Anatomical Science International
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