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Yi-Zi Zheng, Meng-Zhu Xue, Hong-Jie Shen, Xiao-Guang Li, Ding Ma, Yue Gong, Yi-Rong Liu, Feng Qiao, Hong-Yan Xie, Bi Lian, Wei-Li Sun, Hai-Yun Zhao, Ling Yao, Wen-Jia Zuo, Da-Qiang Li, Peng Wang, Xin Hu, Zhi-Ming Shao
Alternative splicing (AS) and its regulation play critical roles in cancer, yet the dysregulation of AS and its molecular bases in breast cancer development have not yet been elucidated. Using an in vivo CRISPR screen targeting RNA-binding proteins, we identified PHD finger protein 5A (PHF5A) as a key splicing factor involved in tumor progression. PHF5A expression was frequently upregulated in breast cancer and correlated with poor survival, and knockdown of PHF5A significantly suppressed cell proliferation, migration, and tumor formation...
April 26, 2018: Cancer Research
Yan Yang, Jian Zhu, Tiantian Zhang, Jing Liu, Yumei Li, Yue Zhu, Lingjie Xu, Rui Wang, Fang Su, Yurong Ou, Qiong Wu
BACKGROUND: PHD-finger domain protein 5A (PHF5A) is a highly conserved small transcriptional regulator also involved in pre-mRNA splicing; however, its biological functions and molecular mechanisms in non-small cell lung cancer (NSCLC) have not yet been investigated. The purpose of this study was to determine the functional relevance and therapeutic potential of PHF5A in lung adenocarcinoma (LAC). METHODS: The expression of PHF5A in LAC tissues and adjacent non-tumor (ANT) tissues was investigated using immunohistochemistry of a tissue microarray, qRT-PCR, western blot and bioinformatics...
March 22, 2018: Journal of Experimental & Clinical Cancer Research: CR
Lorenzo I Finci, Xiaofeng Zhang, Xiuliang Huang, Qiang Zhou, Jennifer Tsai, Teng Teng, Anant Agrawal, Betty Chan, Sean Irwin, Craig Karr, Andrew Cook, Ping Zhu, Dominic Reynolds, Peter G Smith, Peter Fekkes, Silvia Buonamici, Nicholas A Larsen
Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a variety of cancers. These genetic aberrations may offer a potential intervention point for targeted therapeutics. SF3B1, part of the U2 small nuclear RNP (snRNP), is targeted by splicing modulators, including E7107, the first to enter clinical trials, and, more recently, H3B-8800. Modulating splicing represents a first-in-class opportunity in drug discovery, and elucidating the structural basis for the mode of action opens up new possibilities for structure-based drug design...
February 1, 2018: Genes & Development
Teng Teng, Jennifer Hc Tsai, Xiaoling Puyang, Michael Seiler, Shouyong Peng, Sudeep Prajapati, Daniel Aird, Silvia Buonamici, Benjamin Caleb, Betty Chan, Laura Corson, Jacob Feala, Peter Fekkes, Baudouin Gerard, Craig Karr, Manav Korpal, Xiang Liu, Jason T Lowe, Yoshiharu Mizui, James Palacino, Eunice Park, Peter G Smith, Vanitha Subramanian, Zhenhua Jeremy Wu, Jian Zou, Lihua Yu, Agustin Chicas, Markus Warmuth, Nicholas Larsen, Ping Zhu
Pladienolide, herboxidiene and spliceostatin have been identified as splicing modulators that target SF3B1 in the SF3b subcomplex. Here we report that PHF5A, another component of this subcomplex, is also targeted by these compounds. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074 and SF3B1-V1078 confer resistance to these modulators, suggesting a common interaction site. RNA-seq analysis reveals that PHF5A-Y36C has minimal effect on basal splicing but inhibits the global action of splicing modulators. Moreover, PHF5A-Y36C alters splicing modulator-induced intron-retention/exon-skipping profile, which correlates with the differential GC content between adjacent introns and exons...
May 25, 2017: Nature Communications
Alexandros Strikoudis, Charalampos Lazaris, Thomas Trimarchi, Antonio L Galvao Neto, Yan Yang, Panagiotis Ntziachristos, Scott Rothbart, Shannon Buckley, Igor Dolgalev, Matthias Stadtfeld, Brian D Strahl, Brian D Dynlacht, Aristotelis Tsirigos, Iannis Aifantis
Pluripotent embryonic stem cells (ESCs) self-renew or differentiate into all tissues of the developing embryo and cell-specification factors are necessary to balance gene expression. Here we delineate the function of the PHD-finger protein 5a (Phf5a) in ESC self-renewal and ascribe its role in regulating pluripotency, cellular reprogramming and myoblast specification. We demonstrate that Phf5a is essential for maintaining pluripotency, since depleted ESCs exhibit hallmarks of differentiation. Mechanistically, we attribute Phf5a function to the stabilization of the Paf1 transcriptional complex and control of RNA polymerase II elongation on pluripotency loci...
November 2016: Nature Cell Biology
Claire A Schreiber, Toshie Sakuma, Yoshihiro Izumiya, Sara J Holditch, Raymond D Hickey, Robert K Bressin, Upamanyu Basu, Kazunori Koide, Aravind Asokan, Yasuhiro Ikeda
Adeno-associated viruses (AAV) have evolved to exploit the dynamic reorganization of host cell machinery during co-infection by adenoviruses and other helper viruses. In the absence of helper viruses, host factors such as the proteasome and DNA damage response machinery have been shown to effectively inhibit AAV transduction by restricting processes ranging from nuclear entry to second-strand DNA synthesis. To identify host factors that might affect other key steps in AAV infection, we screened an siRNA library that revealed several candidate genes including the PHD finger-like domain protein 5A (PHF5A), a U2 snRNP-associated protein...
August 2015: PLoS Pathogens
Chengcheng Zhang, Lei He, Kai Kang, Heng Chen, Lei Xu, Yanming Zhang
Classical swine fever virus (CSFV), the pathogen of classical swine fever (CSF), causes severe hemorrhagic fever and vascular necrosis in domestic pigs and wild boar. A large number of evidence has proven that non-structural 5A (NS5A) is not only a very important part of viral replication complex, but also can regulate host cell's function; however, the underlying mechanisms remain poorly understood. In the current study, aiming to find more clues in understanding the molecular mechanisms of CSFV NS5A's function, the yeast two-hybrid (Y2H) system was adopted to screen for CSFV NS5A interactive proteins in the cDNA library of the swine umbilical vein endothelial cell (SUVEC)...
March 2014: Journal of Biosciences
(no author information available yet)
PHF5A-mediated exon recognition is selectively required for GSC viability and tumor formation.
July 2013: Cancer Discovery
Eva Falck, Karin Klinga-Levan
Endometrial adenocarcinoma is the most frequently diagnosed cancer of the female genital tract in the western world. Studies of complex diseases can be difficult to perform on human tumor samples due to the high genetic heterogeneity in human. The use of rat models is preferable since rat has similarities in pathogenesis and histopathological properties to that of human.A genomic region including the highly conserved Phf5a gene associated to development of EAC has previously been identified in an association study...
2013: Cancer Cell International
Christopher G Hubert, Robert K Bradley, Yu Ding, Chad M Toledo, Jacob Herman, Kyobi Skutt-Kakaria, Emily J Girard, Jerry Davison, Jason Berndt, Philip Corrin, Justin Hardcastle, Ryan Basom, Jeffery J Delrow, Thomas Webb, Steven M Pollard, Jeongwu Lee, James M Olson, Patrick J Paddison
To identify key regulators of human brain tumor maintenance and initiation, we performed multiple genome-wide RNAi screens in patient-derived glioblastoma multiforme (GBM) stem cells (GSCs). These screens identified the plant homeodomain (PHD)-finger domain protein PHF5A as differentially required for GSC expansion, as compared with untransformed neural stem cells (NSCs) and fibroblasts. Given PHF5A's known involvement in facilitating interactions between the U2 snRNP complex and ATP-dependent helicases, we examined cancer-specific roles in RNA splicing...
May 1, 2013: Genes & Development
Jung-hua Steven Kuo, Meng-jie Liou, Hsueh-chen Chiu
Using dendrimers in cancer therapy as nonviral vectors for gene delivery seems promising. The biological performance of a dendrimer-based gene delivery system depends heavily on its molecular architecture. The transfection activity of dendrimers is significantly improved by processes activated in the heat degradation treatment of solvolysis. However, very little is known about the molecular mechanisms that dendrimers produce in cancer cells. We studied the changes in global gene-expression profiles in human cervical cancer HeLa cells exposed to nonactivated and activated poly(amidoamine) (PAMAM) dendrimers, alone or in complexes with plasmid DNA (dendriplexes)...
June 7, 2010: Molecular Pharmaceutics
T Rzymski, P Grzmil, A Meinhardt, S Wolf, P Burfeind
PHF5A is a highly conserved protein from yeast to man, and based on studies in yeast, it was suggested that the homologous protein RDS3P in S. cerevisiae takes part in the organization of U2 snRNP particles. By using the yeast two-hybrid assay we could demonstrate that PHF5A interacted both with ATP-dependent helicases EP400 and DDX1 and with arginine-serine (RS)-rich domains of splicing factors U2AF1 and SFRS5 in mouse. Furthermore, domain interaction studies revealed that PHF5A interaction with EP400 and DDX1 is restricted to the N-terminal part of PHF5A, whereas the C-terminal region of PHF5A was found to be responsible for the association with U2AF1 and SFRS5...
2008: Cytogenetic and Genome Research
R Trappe, E Schulze, T Rzymski, S Fröde, W Engel
We have recently described a novel human and murine multigene-family that is highly conserved during evolution and shows a PHD-finger-like domain present in the deduced protein sequences. Here, we describe the cloning and characterization of the Caenorhabditis elegans ortholog of human PHF5a. Transgenic phf-5::yfp-reporter techniques in C. elegans identified temporal C. elegans phf-5 expression being restricted to late C. elegans development. The phf-5::yfp expression starts within the morphogenetic phase of embryonic development and lasts to the stage of adult worms...
October 4, 2002: Biochemical and Biophysical Research Communications
R Trappe, M Ahmed, B Gläser, C Vogel, S Tascou, P Burfeind, W Engel
The genes Phf5a and Phf5b-ps are the first two members of a novel murine multigene family that is highly conserved during evolution and belongs to the superfamily of PHD-finger genes. The Phf5 gene family contains an active locus on mouse chromosome 15, region E and several processed pseudogenes on different chromosomes. The active locus, Phf5a, is expressed ubiquitously in pre- and postnatal murine tissues and encodes a protein of 110 amino acids. The protein is localized in the nucleus in a non-homogenous pattern as the nucleolar subcompartment is almost free of Phf5a...
May 3, 2002: Biochemical and Biophysical Research Communications
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