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Peter J Thompson, Vered Dulberg, Kyung-Mee Moon, Leonard J Foster, Carol Chen, Mohammad M Karimi, Matthew C Lorincz
[This corrects the article DOI: 10.1371/journal.pgen.1004933.].
October 2016: PLoS Genetics
Caleb Sutherland, Yunxi Cui, Hanbin Mao, Laurence H Hurley
MYC is overexpressed in many different cancer types and is an intensively studied oncogene because of its contributions to tumorigenesis. The regulation of MYC is complex, and the NHE III1 and FUSE elements rely upon noncanonical DNA structures and transcriptionally induced negative superhelicity. In the NHE III1 only the G-quadruplex has been extensively studied, whereas the role of the i-motif, formed on the opposite C-rich strand, is much less understood. We demonstrate here that the i-motif is formed within the 4CT element and is recognized by hnRNP K, which leads to a low level of transcription activation...
October 11, 2016: Journal of the American Chemical Society
Yoshihiro Kawasaki, Mimon Komiya, Kosuke Matsumura, Lumi Negishi, Sakiko Suda, Masumi Okuno, Naoko Yokota, Tomoya Osada, Takeshi Nagashima, Masaya Hiyoshi, Mariko Okada-Hatakeyama, Joji Kitayama, Katsuhiko Shirahige, Tetsu Akiyama
Aberrant activation of Wnt/β-catenin signaling is a major driving force in colon cancer. Wnt/β-catenin signaling induces the expression of the transcription factor c-Myc, leading to cell proliferation and tumorigenesis. c-Myc regulates multiple biological processes through its ability to directly modulate gene expression. Here, we identify a direct target of c-Myc, termed MYU, and show that MYU is upregulated in most colon cancers and required for the tumorigenicity of colon cancer cells. Furthermore, we demonstrate that MYU associates with the RNA binding protein hnRNP-K to stabilize CDK6 expression and thereby promotes the G1-S transition of the cell cycle...
September 6, 2016: Cell Reports
Erica J Hutchins, Jamie L Belrose, Ben G Szaro
hnRNP K is a highly conserved nucleocytoplasmic shuttling protein, which associates with RNAs through synergistic binding via its three KH domains. hnRNP K is required for proper nuclear export and translational control of its mRNA targets, and these processes are controlled by hnRNP K's movement between subcellular compartments. Whereas the nuclear export and localization of hnRNP K that is associated with mRNP complexes has been well studied, the trafficking of hnRNP K that is unbound to mRNA has yet to be elucidated...
September 16, 2016: Biochemical and Biophysical Research Communications
Koichi Yamamoto, Mari T Furukawa, Kazuhiro Fukumura, Arisa Kawamura, Tomoko Yamada, Hitoshi Suzuki, Tetsuro Hirose, Hiroshi Sakamoto, Kunio Inoue
Pre-mRNA splicing is widely repressed upon heat shock in eukaryotic cells. However, it has been shown that HSP105 pre-mRNA is alternatively spliced in response to heat stress. Using RNAi screening in HeLa cells, we found that RNA-binding proteins hnRNP K and PSF/SFPQ are necessary for the exon 12 exclusion of HSP105 during heat stress. Moreover, exon array analyses showed that a group of genes is alternatively spliced during heat stress in an hnRNP K-dependent manner, whereas hnRNP K is not necessary for the stress-induced alternative splicing of the remaining genes...
September 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Gitte H Bruun, Thomas K Doktor, Jonas Borch-Jensen, Akio Masuda, Adrian R Krainer, Kinji Ohno, Brage S Andresen
BACKGROUND: Many pathogenic genetic variants have been shown to disrupt mRNA splicing. Besides splice mutations in the well-conserved splice sites, mutations in splicing regulatory elements (SREs) may deregulate splicing and cause disease. A promising therapeutic approach is to compensate for this deregulation by blocking other SREs with splice-switching oligonucleotides (SSOs). However, the location and sequence of most SREs are not well known. RESULTS: Here, we used individual-nucleotide resolution crosslinking immunoprecipitation (iCLIP) to establish an in vivo binding map for the key splicing regulatory factor hnRNP A1 and to generate an hnRNP A1 consensus binding motif...
2016: BMC Biology
Muralidhar L Hegde, Arijit Dutta, Chunying Yang, Anil K Mantha, Pavana M Hegde, Arvind Pandey, Shiladitya Sengupta, Yaping Yu, Patrick Calsou, David Chen, Susan P Lees-Miller, Sankar Mitra
Ionizing radiation (IR) induces highly cytotoxic double-strand breaks (DSBs) and also clustered oxidized bases in mammalian genomes. Base excision repair (BER) of bi-stranded oxidized bases could generate additional DSBs as repair intermediates in the vicinity of direct DSBs, leading to loss of DNA fragments. This could be avoided if DSB repair via DNA-PK-mediated nonhomologous end joining (NHEJ) precedes BER initiated by NEIL1 and other DNA glycosylases (DGs). Here we show that DNA-PK subunit Ku inhibits DGs via direct interaction...
June 9, 2016: Oncotarget
Kyu Young Song, Hack Sun Choi, Ping-Yee Law, Li-Na Wei, Horace H Loh
Expression of the mu-opioid receptor (MOR) protein is controlled by extensive transcriptional and post-transcriptional processing. MOR gene expression has previously been shown to be altered by a post-transcriptional mechanism involving the MOR mRNA untranslated region (UTR). Here, we demonstrate for the first time the role of heterogeneous nuclear ribonucleic acids (hnRNA)-binding protein (hnRNP) K and poly(C)-binding protein 1 (PCBP1) as post-transcriptional inducers in MOR gene regulation. In the absence of morphine, a significant level of MOR mRNA is sustained in its resting state and partitions in the translationally inactive polysomal fraction...
June 13, 2016: Journal of Cellular Physiology
Jing Lu, Feng-Hou Gao
Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a member of the hnRNP family, which exists in the nucleus and the cytoplasm simultaneously. It is a multifunctional protein that can participate in a variety of regulatory progressions of gene expression and signal transduction, such as chromatin remodeling, transcription, RNA alternative splicing and translation. hnRNP K not only directly binds to the kinases, but also recruits the associated factors regarding transcription, splicing and translation to control gene expression, and therefore, it serves as a docking platform for integrating transduction pathways to nucleic acid-directed processes...
June 2016: Biomedical Reports
Ruirui Yang, Ying Zeng, Haifan Xu, Zhuo Chen, Mengqin Xiang, Yun Fu, Yufang Yin, Jing Zhong, Min Zeng, Peihua Wang, Qin You, Xi Zeng
Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is one of the major pre-mRNA-binding proteins, that is involved in translational modifications. In our previous studies, we found that hnRNP K is associated with human gastric cancer. The protein levels of hnRNP K were detected in cell lines and tissue microarrays. The correlation between hnRNP K expression and patient survival rate was evaluated by Kaplan-Meier survival analysis. In addition, we also detected hnRNP K expression in preoperative and postoperative serum samples from patients with gastric cancer, and serum samples from healthy volunteers...
August 2016: Oncology Reports
R Singh, S C Gupta, W-X Peng, N Zhou, R Pochampally, A Atfi, K Watabe, Z Lu, Y-Y Mo
BC200 is a long non-coding RNA (lncRNA) that has been implicated in the regulation of protein synthesis, yet whether dysregulation of BC200 contributes to the pathogenesis of human diseases remains elusive. In this study, we show that BC200 is upregulated in breast cancer; among breast tumor specimens there is a higher level of BC200 in estrogen receptor (ER) positive than in ER-negative tumors. Further experiments show that activation of estrogen signaling induces expression of BC200. To determine the significance of ER-regulated BC200 expression, we knockout (KO) BC200 by CRISPR/Cas9...
2016: Cell Death & Disease
Eun Joo Jung, Ky Hyun Chung, Dong-Won Bae, Choong Won Kim
Nerve growth factor (NGF) is known to regulate both cancer cell survival and death signaling, depending on the cellular circumstances, in various cell types. In this study, we showed that NGF strongly upregulated the protein level of tropomyosin-related kinase A (TrkA) in TrkA-inducible SK-N-MC cancer cells, resulting in increases in various TrkA-dependent cellular processes, including the phosphorylation of c-Jun N-terminal kinase (JNK) and caspase-8 cleavage. In addition, NGF enhanced TrkA-induced morphological changes and cell death, and this effect was significantly suppressed by the JNK inhibitor SP600125, but not by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin...
2016: Experimental & Molecular Medicine
JinFang Zhang, XiaoLi Liu, YuDeng Lin, YuLing Li, JianWei Pan, Sa Zong, YongKang Li, Yang Zhou
The goal of this study was to explore the role of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in drug resistance through the regulation of autophagy in acute myeloid leukemia (AML). First, we used fluorescence quantitative polymerase chain reaction (PCR) to verify the connection between the expression level of hnRNP K and the level of drug resistance in AML. We then used Western blotting to determine the expression level of the autophagy-related proteins microtubule-associated protein light chain 3 I and II (LC3 I/II) after the modulation of hnRNP K by ribonucleic acid (RNA) interference...
September 2016: Experimental Hematology
Emily K Meredith, Maggie M Balas, Karla Sindy, Krystal Haislop, Aaron M Johnson
The human long noncoding RNA (lncRNA) HOTAIR acts in trans to recruit the Polycomb repressive complex 2 (PRC2) to the HOXD gene cluster and to promote gene silencing during development. In breast cancers, overexpression of HOTAIR increases metastatic potential via the repression of many additional genes. It has remained unclear what factors determine HOTAIR-dependent PRC2 activity at specific genomic loci, particularly when high levels of HOTAIR result in aberrant gene silencing. To identify additional proteins that contribute to the specific action of HOTAIR, we performed a quantitative proteomic analysis of the HOTAIR interactome...
July 2016: RNA
Y Mao, T Tamura, Y Yuki, D Abe, Y Tamada, S Imoto, H Tanaka, H Homma, K Tagawa, S Miyano, H Okazawa
In this study, we identify signaling network of necrotic cell death induced by transcriptional repression (TRIAD) by α-amanitin (AMA), the selective RNA polymerase II inhibitor, as a model of neurodegenerative cell death. We performed genetic screen of a knockdown (KD) fly library by measuring the ratio of transformation from pupa to larva (PL ratio) under TRIAD, and selected the cell death-promoting genes. Systems biology analysis of the positive genes mapped on protein-protein interaction databases predicted the signaling network of TRIAD and the core pathway including heterogeneous nuclear ribonucleoproteins (hnRNPs) and huntingtin (Htt)...
2016: Cell Death & Disease
Andrew S Brown, Bidyut K Mohanty, Philip H Howe
Non-canonical transforming growth factor β (TGFβ) signaling through protein kinase B (Akt2) induces phosphorylation of heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) at serine-43 (p-hnRNP E1). This post-translational modification (PTM) of hnRNP E1 promotes its dissociation from a 3' untranslated region (UTR) nucleic acid regulatory motif, driving epithelial to mesenchymal transition (EMT) and metastasis. We have identified an hnRNP E1 consensus-binding motif and genomically resolved a subset of genes in which it is contained...
July 8, 2016: Nucleic Acids Research
Miguel Gallardo, Marisa J Hornbaker, Xiaorui Zhang, Peter Hu, Carlos Bueso-Ramos, Sean M Post
The classification of a gene as an oncogene or a tumor suppressor has been a staple of cancer biology for decades. However, as we delve deeper into the biology of these genes, this simple classification has become increasingly difficult for some. In the case of heterogeneous nuclear ribonuclear protein K (hnRNP K), its role as a tumor suppressor has recently been described in acute myeloid leukemia and demonstrated in a haploinsufficient mouse model. In contrast, data from other clinical correlation studies suggest that hnRNP K may be more fittingly described as an oncogene, due to its increased levels in a variety of malignancies...
June 17, 2016: Cell Cycle
Zheying Zhang, Chang Zhou, Yaya Chang, Zuoyang Zhang, Yuhan Hu, Fan Zhang, Yanxia Lu, Lin Zheng, Wenjuan Zhang, Xiaomin Li, Xuenong Li
The abnormal expression of many long non-coding RNAs (lncRNAs) has been reported in the progression of various tumors, and these lncRNAs can be useful as diagnostic indicators and anti-tumor targets. Therefore, it is important to identify lncRNAs that can be used for the clinical prevention and treatment of colorectal cancer (CRC). Here, we report that cancer susceptibility candidate 11 (CASC11) was upregulated in CRC tissues; increased CASC11 expression in CRC was associated with tumor size, serosal invasion, lymph metastasis, and the tumor-node-metastasis (TNM) stage...
June 28, 2016: Cancer Letters
Youjin Na, Sunil C Kaul, Jihoon Ryu, Jung-Sun Lee, Hyo Min Ahn, Zeenia Kaul, Rajkumar S Kalra, Ling Li, Nashi Widodo, Chae-Ok Yun, Renu Wadhwa
Mortalin/mthsp70 (HSPA9) is a stress chaperone enriched in many cancers that has been implicated in carcinogenesis by promoting cell proliferation and survival. In the present study, we examined the clinical relevance of mortalin upregulation in carcinogenesis. Consistent with high mortalin expression in various human tumors and cell lines, we found that mortalin overexpression increased the migration and invasiveness of breast cancer cells. Expression analyses revealed that proteins involved in focal adhesion, PI3K-Akt and JAK-STAT signaling, all known to play key roles in cell migration and epithelial-to-mesenchymal transition (EMT), were upregulated in mortalin-expressing cancer cells...
March 9, 2016: Cancer Research
Samiran Mondal, Nasim A Begum, Wenjun Hu, Tasuku Honjo
Activation-induced cytidine deaminase (AID) is essential for the somatic hypermutation (SHM) and class-switch recombination (CSR) of Ig genes. Although both the N and C termini of AID have unique functions in DNA cleavage and recombination, respectively, during SHM and CSR, their molecular mechanisms are poorly understood. Using a bimolecular fluorescence complementation (BiFC) assay combined with glycerol gradient fractionation, we revealed that the AID C terminus is required for a stable dimer formation. Furthermore, AID monomers and dimers form complexes with distinct heterogeneous nuclear ribonucleoproteins (hnRNPs)...
March 15, 2016: Proceedings of the National Academy of Sciences of the United States of America
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