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Lauren P Blair, Zongzhi Liu, Ramon Lorenzo D Labitigan, Lizhen Wu, Dinghai Zheng, Zheng Xia, Erica L Pearson, Fathima I Nazeer, Jian Cao, Sabine M Lang, Rachel J Rines, Samuel G Mackintosh, Claire L Moore, Wei Li, Bin Tian, Alan J Tackett, Qin Yan
The complexity by which cells regulate gene and protein expression is multifaceted and intricate. Regulation of 3' untranslated region (UTR) processing of mRNA has been shown to play a critical role in development and disease. However, the process by which cells select alternative mRNA forms is not well understood. We discovered that the Saccharomyces cerevisiae lysine demethylase, Jhd2 (also known as KDM5), recruits 3'UTR processing machinery and promotes alteration of 3'UTR length for some genes in a demethylase-dependent manner...
November 2016: Science Advances
Maciej Tarnowski, Michał Czerewaty, Anna Deskur, Krzysztof Safranow, Wojciech Marlicz, Elżbieta Urasińska, Mariusz Z Ratajczak, Teresa Starzyńska
Background. While cancer/testis antigens (CTAs) are restricted in postnatal tissues to testes and germ line-derived cells, their role in cancer development and the clinical significance of their expression still remain to be better defined. Objective. The aim of this study was to investigate the level of CTA expression in colon samples from patients with colorectal cancer (CRC) in relation to patient clinical status. Methods. Forty-five patients with newly diagnosed colorectal cancer were included in the study...
2016: Disease Markers
Molly Gale, Joyce Sayegh, Jian Cao, Michael Norcia, Peter Gareiss, Denton Hoyer, Jane S Merkel, Qin Yan
Lysine demethylase 5A (KDM5A/RBP2/JARID1A) is a histone lysine demethylase that is overexpressed in several human cancers including lung, gastric, breast and liver cancers. It plays key roles in important cancer processes including tumorigenesis, metastasis, and drug tolerance, making it a potential cancer therapeutic target. Chemical tools to analyze KDM5A demethylase activity are extremely limited as available inhibitors are not specific for KDM5A. Here, we characterized KDM5A using a homogeneous luminescence-based assay and conducted a screen of about 9,000 small molecules for inhibitors...
June 28, 2016: Oncotarget
John R Horton, Amanda Engstrom, Elizabeth L Zoeller, Xu Liu, John R Shanks, Xing Zhang, Margaret A Johns, Paula M Vertino, Haian Fu, Xiaodong Cheng
The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases remove methyl groups from tri- and dimethylated lysine 4 of histone H3. Accumulating evidence from primary tumors and model systems supports a role for KDM5A (JARID1A/RBP2) and KDM5B (JARID1B/PLU1) as oncogenic drivers. The KDM5 family is unique among the Jumonji domain-containing histone demethylases in that there is an atypical insertion of a DNA-binding ARID domain and a histone-binding PHD domain into the Jumonji domain, which separates the catalytic domain into two fragments (JmjN and JmjC)...
February 5, 2016: Journal of Biological Chemistry
Emeli M Nilsson, Kristian B Laursen, Jonathan Whitchurch, Andrew McWilliam, Niels Ødum, Jenny L Persson, David M Heery, Lorraine J Gudas, Nigel P Mongan
Androgens and the androgen receptor (AR) play crucial roles in male development and the pathogenesis and progression of prostate cancer (PCa). The AR functions as a ligand dependent transcription factor which recruits multiple enzymatically distinct epigenetic coregulators to facilitate transcriptional regulation in response to androgens. Over-expression of AR coregulators is implicated in cancer. We have shown that over-expression of KDM1A, an AR coregulator, contributes to PCa recurrence by promoting VEGFA expression...
November 3, 2015: Oncotarget
Jiaojiao Huang, Hongyong Zhang, Xianlong Wang, Kyle B Dobbs, Jing Yao, Guosong Qin, Kristin Whitworth, Eric M Walters, Randall S Prather, Jianguo Zhao
KDM5B (JARID1B/PLU1) is a H3K4me2/3 histone demethylase that is implicated in cancer development and proliferation and is also indispensable for embryonic stem cell self-renewal, cell fate, and murine embryonic development. However, little is known about the role of KDM5B during preimplantation embryo development. Here we show that KDM5B is critical to porcine preimplantation development. KDM5B was found to be expressed in a stage-specific manner, consistent with demethylation of H3K4me3, with the highest expression being observed from the 4-cell to the blastocyst stages...
March 2015: Biology of Reproduction
Peter Birk Rasmussen, Peter Staller
There is growing evidence for a causal role of the KDM5 family of histone demethylases in human cancer. In particular, KDM5A (JARID1A/RBP2) and KDM5B (JARID1B/PLU1) contribute to cancer cell proliferation, reduce the expression of tumor suppressor genes, promote the development of drug tolerance and maintain tumor-initiating cells. KDM5 enzymes remove tri- and di-methylations of lysine 4 of histone H3 - modifications that occur at the start site of transcription in actively transcribed genes. However, the importance of the histone demethylase activity of KDM5 proteins for cancer cells has not been resolved so far...
June 2014: Epigenomics
Mike Ran Zou, Jian Cao, Zongzhi Liu, Sung Jin Huh, Kornelia Polyak, Qin Yan
The JmjC domain-containing H3K4 histone demethylase jumonji AT-rich interactive domain 1B (JARID1B) (also known as KDM5B and PLU1) is overexpressed in breast cancer and is a potential target for breast cancer treatment. To investigate the in vivo function of JARID1B, we developed Jarid1b(-/-) mice and characterized their phenotypes in detail. Unlike previously reported Jarid1b(-/-) strains, the majority of these Jarid1b(-/-) mice were viable beyond embryonic and neonatal stages. This allowed us to further examine phenotypes associated with the loss of JARID1B in pubertal development and pregnancy...
June 20, 2014: Journal of Biological Chemistry
Louise Wolf, Chun S Gao, Karen Gueta, Qing Xie, Tiphaine Chevallier, Nikhil R Podduturi, Jian Sun, Ivan Conte, Peggy S Zelenka, Ruth Ashery-Padan, Jiri Zavadil, Ales Cvekl
MicroRNAs (miRNAs) and fibroblast growth factor (FGF) signaling regulate a wide range of cellular functions, including cell specification, proliferation, migration, differentiation, and survival. In lens, both these systems control lens fiber cell differentiation; however, a possible link between these processes remains to be examined. Herein, the functional requirement for miRNAs in differentiating lens fiber cells was demonstrated via conditional inactivation of Dicer1 in mouse (Mus musculus) lens. To dissect the miRNA-dependent pathways during lens differentiation, we used a rat (Rattus norvegicus) lens epithelial explant system, induced by FGF2 to differentiate, followed by mRNA and miRNA expression profiling...
December 9, 2013: G3: Genes—Genomes—Genetics
Mareike Albert, Sandra U Schmitz, Susanne M Kooistra, Martina Malatesta, Cristina Morales Torres, Jens C Rekling, Jens V Johansen, Iratxe Abarrategui, Kristian Helin
Embryonic development is tightly regulated by transcription factors and chromatin-associated proteins. H3K4me3 is associated with active transcription and H3K27me3 with gene repression, while the combination of both keeps genes required for development in a plastic state. Here we show that deletion of the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) results in major neonatal lethality due to respiratory failure. Jarid1b knockout embryos have several neural defects including disorganized cranial nerves, defects in eye development, and increased incidences of exencephaly...
April 2013: PLoS Genetics
Joyce Sayegh, Jian Cao, Mike Ran Zou, Alfonso Morales, Lauren P Blair, Michael Norcia, Denton Hoyer, Alan J Tackett, Jane S Merkel, Qin Yan
JARID1B (also known as KDM5B or PLU1) is a member of the JARID1 family of histone lysine demethylases responsible for the demethylation of trimethylated lysine 27 in histone H3 (H3K4me3), a mark for actively transcribed genes. JARID1B is overexpressed in several cancers, including breast cancer, prostate cancer, and lung cancer. In addition, JARID1B is required for mammary tumor formation in syngeneic or xenograft mouse models. JARID1B-expressing melanoma cells are associated with increased self-renewal character...
March 29, 2013: Journal of Biological Chemistry
Line H Kristensen, Anders L Nielsen, Charlotte Helgstrand, Michael Lees, Paul Cloos, Jette S Kastrup, Kristian Helin, Lars Olsen, Michael Gajhede
Dynamic methylations and demethylations of histone lysine residues are important for gene regulation and are facilitated by histone methyltransferases and histone demethylases (HDMs). KDM5B/Jarid1B/PLU1 is an H3K4me3/me2-specific lysine demethylase belonging to the JmjC domain-containing family of histone demethylases (JHDMs). Several studies have linked KDM5B to breast, prostate and skin cancer, highlighting its potential as a drug target. However, most inhibitor studies have focused on other JHDMs, and inhibitors for KDM5B remain to be explored...
June 2012: FEBS Journal
Sandra U Schmitz, Mareike Albert, Martina Malatesta, Lluis Morey, Jens V Johansen, Mads Bak, Niels Tommerup, Iratxe Abarrategui, Kristian Helin
H3K4 methylation is associated with active transcription and in combination with H3K27me3 thought to keep genes regulating development in a poised state. The contribution of enzymes regulating trimethylation of lysine 4 at histone 3 (H3K4me3) levels to embryonic stem cell (ESC) self-renewal and differentiation is just starting to emerge. Here, we show that the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) is dispensable for ESC self-renewal, but essential for ESC differentiation along the neural lineage...
November 16, 2011: EMBO Journal
Masakazu Yoshida, Akihiko Ishimura, Minoru Terashima, Zanabazar Enkhbaatar, Naohito Nozaki, Kenji Satou, Takeshi Suzuki
PLU1 is a candidate oncogene that encodes H3K4 (Lys(4) of histone H3) demethylase. In the present study, we found that ectopic expression of PLU1 enhanced the invasive potential of the weakly invasive cells dependent on its demethylase activity. PLU1 was shown to repress the expression of the KAT5 gene through its H3K4 demethylation on the promoter. The regulation of KAT5 by PLU1 was suggested to be responsible for PLU1-induced cell invasion. First, knockdown of KAT5 similarly increased the invasive potential of the cells...
August 1, 2011: Biochemical Journal
Jesper Christensen, Karl Agger, Paul A C Cloos, Diego Pasini, Simon Rose, Lau Sennels, Juri Rappsilber, Klaus H Hansen, Anna Elisabetta Salcini, Kristian Helin
Methylation of histones has been regarded as a stable modification defining the epigenetic program of the cell, which regulates chromatin structure and transcription. However, the recent discovery of histone demethylases has challenged the stable nature of histone methylation. Here we demonstrate that the JARID1 proteins RBP2, PLU1, and SMCX are histone demethylases specific for di- and trimethylated histone 3 lysine 4 (H3K4). Consistent with a role for the JARID1 Drosophila homolog Lid in regulating expression of homeotic genes during development, we show that RBP2 is displaced from Hox genes during embryonic stem (ES) cell differentiation correlating with an increase of their H3K4me3 levels and expression...
March 23, 2007: Cell
Hwa-Yong An, Harutoshi Tsuda, Taku Miyamoto
Recombinant vector pJLECit (8,232 bp) was constructed using citrate permease gene contained in the 3,919-bp fragment of plasmid pCM1 (8,280 bp) isolated from Lactococcus lactis subsp. lactis biovar diacetylactis NIAI N-7, repA and ori from pLU1, and pMB1 ori and the erythromycin resistance gene from pJIR418. Lactobacillus casei L-49-4 (plasmid-free mutant of strain L-49) harboring the constructed pJLECit converted citrate into diacetyl/acetoin. Citrate uptake rate of resting cells was the highest at pH 5.5 and 10 mM citrate concentration...
March 2007: Applied Microbiology and Biotechnology
I Lasa, M de Grado, M A de Pedro, J Berenguer
We describe the self-selection of replication origins of undescribed cryptic plasmids from Thermus aquaticus Y-VII-51B (ATCC 25105) and a Thermus sp. strain (ATCC 27737) by random insertion of a thermostable kanamycin adenyltransferase cartridge. Once selected, these autonomous replication origins were cloned into the Escherichia coli vector pUC9 or pUC19. The bifunctional plasmids were analyzed for their sizes, relationships, and properties as shuttle vectors for Thermus-Escherichia cloning. Seven different vectors with diverse kanamycin resistance levels, stabilities, transformation efficiencies, and copy numbers were obtained...
October 1992: Journal of Bacteriology
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