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Christina Wei, Lauren Stock, Leila Valanejad, Zachary A Zalewski, Rebekah Karns, Jack Puymirat, David Nelson, David Witte, Jim Woodgett, Nikolai A Timchenko, Lubov Timchenko
Myotonic dystrophy type 1 (DM1) is a progressive neuromuscular disease caused by expanded CUG repeats, which misregulate RNA metabolism through several RNA-binding proteins, including CUG-binding protein/CUGBP1 elav-like factor 1 (CUGBP1/CELF1) and muscleblind 1 protein. Mutant CUG repeats elevate CUGBP1 and alter CUGBP1 activity via a glycogen synthase kinase 3β (GSK3β)-cyclin D3-cyclin D-dependent kinase 4 (CDK4) signaling pathway. Inhibition of GSK3β corrects abnormal activity of CUGBP1 in DM1 mice [human skeletal actin mRNA, containing long repeats ( HSALR ) model]...
January 5, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Ju-Ha Kim, Hee Young Kwon, Dong Hoon Ryu, Min-Ho Nam, Bum Sang Shim, Jin Han Kim, Jae Yeol Lee, Sung-Hoon Kim
Though piperazine derivative BK10007S was known to induce apoptosis in pancreatic cancer xenograft model as a T-type CaV3.1 a1G isoform calcium channel blocker, its underlying antitumor mechanism still remains unclear so far. Thus, in the present study, the antitumor mechanism of BK10007S was elucidated in hepatocellular carcinoma cells (HCCs). Herein, BK10007S showed significant cytotoxicity by 3-[4,5-2-yl]-2,5-diphenyltetra-zolium bromide (MTT) assay and anti-proliferative effects by colony formation assay in HepG2 and SK-Hep1 cells...
2017: PloS One
Yuan Zhang, Yun Zhang, Lan Xiao, Ting-Xi Yu, Jun-Zhe Li, Jaladanki N Rao, Douglas J Turner, Myriam Gorospe, Jian-Ying Wang
Insulin-like growth factor type 2 (IGF2) receptor (IGF2R) recognizes mannose 6-phosphate-containing molecules and IGF2 and plays an important role in many pathophysiological processes, including gut mucosal adaptation. However, the mechanisms that control cellular IGF2R abundance are poorly known. MicroRNAs (miRNAs) and RNA-binding proteins (RBPs) critically regulate gene expression programs in mammalian cells by modulating the stability and translation of target mRNAs. Here we report that miRNA 195 (miR-195) and RBP CUG-binding protein 1 (CUGBP1) jointly regulate IGF2R expression at the posttranscriptional level in intestinal epithelial cells...
October 1, 2017: Molecular and Cellular Biology
Vildan Betul Yenigun, Mario Sirito, Alla Amcheslavky, Tomek Czernuszewicz, Jordi Colonques-Bellmunt, Irma García-Alcover, Marzena Wojciechowska, Clare Bolduc, Zhihong Chen, Arturo López Castel, Ralf Krahe, Andreas Bergmann
The myotonic dystrophies are prototypic toxic RNA gain-of-function diseases. Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are caused by different unstable, noncoding microsatellite repeat expansions - (CTG)DM1 in DMPK and (CCTG)DM2 in CNBP Although transcription of mutant repeats into (CUG)DM1 or (CCUG)DM2 appears to be necessary and sufficient to cause disease, their pathomechanisms remain incompletely understood. To study the mechanisms of (CCUG)DM2 toxicity and develop a convenient model for drug screening, we generated a transgenic DM2 model in the fruit fly Drosophila melanogaster with (CCUG)n repeats of variable length ( n =16 and 106)...
August 1, 2017: Disease Models & Mechanisms
Kyle Lewis, Leila Valanejad, Ashley Cast, Mary Wright, Christina Wei, Polina Iakova, Lauren Stock, Rebekah Karns, Lubov Timchenko, Nikolai Timchenko
Despite intensive investigations, mechanisms of liver cancer are not known. Here, we identified an important step of liver cancer, which is the neutralization of tumor suppressor activities of an RNA binding protein, CUGBP1. The translational activity of CUGBP1 is activated by dephosphorylation at Ser302. We generated CUGBP1-S302A knock-in mice and found that the reduction of translational activity of CUGBP1 causes development of a fatty liver phenotype in young S302A mice. Examination of liver cancer in diethylnitrosamine (DEN)-treated CUGBP1-S302A mice showed these mice develop much more severe liver cancer that is associated with elimination of the mutant CUGBP1...
August 15, 2017: Molecular and Cellular Biology
Leila Valanejad, Kyle Lewis, Mary Wright, Yanjun Jiang, Amber D'Souza, Rebekah Karns, Rachel Sheridan, Anita Gupta, Kevin Bove, David Witte, James Geller, Gregory Tiao, David L Nelson, Lubov Timchenko, Nikolai Timchenko
The development of hepatoblastoma (HBL) is associated with failure of hepatic stem cells (HSC) to differentiate into hepatocytes. Despite intensive investigations, mechanisms of the failure of HSC to differentiate are not known. We found that oncogene Gankyrin (Gank) is involved in the inhibition of differentiation of HSC via triggering degradation of tumor suppressor proteins (TSPs) Rb, p53, C/EBPα and HNF4α. Our data show that the activation of a repressor of Gank, farnesoid X receptor, FXR, after initiation of liver cancer by Diethylnitrosamine (DEN) prevents the development of liver cancer by inhibiting Gank and rescuing tumor suppressor proteins...
July 1, 2017: Carcinogenesis
Aymeric Ravel-Chapuis, Guy Bélanger, Jocelyn Côté, Robin N Michel, Bernard J Jasmin
Myotonic Dystrophy type 1 (DM1) is caused by an expansion of CUG repeats in DMPK mRNAs. This mutation affects alternative splicing through misregulation of RNA-binding proteins. Amongst pre-mRNAs that are mis-spliced, several code for proteins involved in calcium homeostasis suggesting that calcium-handling and signaling are perturbed in DM1. Here, we analyzed expression of such proteins in DM1 mouse muscle. We found that the levels of several sarcoplasmic reticulum proteins (SERCA1, sarcolipin and calsequestrin) are altered, likely contributing to an imbalance in calcium homeostasis...
June 15, 2017: Human Molecular Genetics
Lei Gu, Huiwen Wang, Jun Wang, Yuting Guo, Yinglong Tang, Yang Mao, Lijuan Chen, Hua Lou, Guangju Ji
AIM: Myocardial infarction (MI) is one of the leading causes of death in elderly people. Expanding the knowledge of the molecular mechanisms underlying MI is of profound importance to developing a cure for MI. The CUGBP- and ETR-3-like factor (CELF) proteins, a family of RNA-binding proteins, play key roles in RNA metabolism. To determine the functions and molecular mechanisms of CELF proteins in MI, an animal model of acute myocardial infarction (AMI) was used in our study. RESULTS: We found that the CUG triplet repeat RNA-binding protein 1 (CUGBP1)/CELF1 expression levels were decreased in AMI-injured hearts, and further studies showed that two highly conserved adenylate-uridylate-rich (AU-rich) elements in the 3'UTR of CUGBP1 were responsible for the decreased CUGBP1 expression...
November 10, 2017: Antioxidants & Redox Signaling
Xianpeng Liu, Bo Zhao, Limin Sun, Karan Bhuripanyo, Yiyang Wang, Yingtao Bi, Ramana V Davuluri, Duc M Duong, Dhaval Nanavati, Jun Yin, Hiroaki Kiyokawa
Protein ubiquitination is mediated sequentially by ubiquitin activating enzyme E1, ubiquitin conjugating enzyme E2 and ubiquitin ligase E3. Uba1 was thought to be the only E1 until the recent identification of Uba6. To differentiate the biological functions of Uba1 and Uba6, we applied an orthogonal ubiquitin transfer (OUT) technology to profile their ubiquitination targets in mammalian cells. By expressing pairs of an engineered ubiquitin and engineered Uba1 or Uba6 that were generated for exclusive interactions, we identified 697 potential Uba6 targets and 527 potential Uba1 targets with 258 overlaps...
January 30, 2017: Nature Communications
Xingxin Wu, Xudong Wu, Yuxiang Ma, Fenli Shao, Yang Tan, Tao Tan, Liyun Gu, Yang Zhou, Beicheng Sun, Yang Sun, Xuefeng Wu, Qiang Xu
Excessive activation of hepatic stellate cells (HSCs) is a key step in liver fibrogenesis. Here we report that CUG-binding protein 1 (CUGBP1) expression is elevated in HSCs and positively correlates with liver fibrosis severity in human liver biopsies. Transforming growth factor-beta (TGF-β) selectively increases CUGBP1 expression in cultured HSCs in a p38 mitogen-activated protein kinase (MAPK)-dependent manner. Knockdown of CUGBP1 inhibits alpha smooth muscle actin (α-SMA) expression and promotes interferon gamma (IFN-γ) production in HSCs in vitro...
November 17, 2016: Nature Communications
Kui Zhai, Lei Gu, Zhiguang Yang, Yang Mao, Meng Jin, Yan Chang, Qi Yuan, Veronique Leblais, Huiwen Wang, Rodolphe Fischmeister, Guangju Ji
AIMS/HYPOTHESIS: CUG-binding protein 1 (CUGBP1) is a multifunctional RNA-binding protein that regulates RNA processing at several stages including translation, deadenylation and alternative splicing, as well as RNA stability. Recent studies indicate that CUGBP1 may play a role in metabolic disorders. Our objective was to examine its role in endocrine pancreas function through gain- and loss-of-function experiments and to further decipher the underlying molecular mechanisms. METHODS: A mouse model in which type 2 diabetes was induced by a high-fat diet (HFD; 60% energy from fat) and mice on a standard chow diet (10% energy from fat) were compared...
September 2016: Diabetologia
Bernd Rattenbacher, Daniel Beisang, Darin L Wiesner, Jonathan C Jeschke, Maximilian von Hohenberg, Irina A Vlasova-St Louis, Paul R Bohjanen
No abstract text is available yet for this article.
February 15, 2016: Molecular and Cellular Biology
Xiaofei Wang, Wenjie Jiao, Yandong Zhao, Liangdong Zhang, Ruyong Yao, Yongjie Wang, Mingzhao Wang, Yiren Luo, Jinpeng Zhao
BACKGROUND: The brain is a frequent site of metastases from non-small cell lung cancer (NSCLC). The purpose of this study was to detect the expression of CUG-binding protein 1 (CUGBP1) messenger ribonucleic acid (mRNA) and Ki-67 in metastasized brain tissue from NSCLC and determine the relationship between CUGBP1 and brain metastases. METHODS: The expression of CUGBP1 mRNA and Ki-67 in metastasized brain tissue from NSCLC was investigated by semiquantitative polymerase chain reaction and immunohistochemistry, respectively...
January 2016: Thoracic Cancer
Liang Xia, Caixing Sun, Qinglin Li, Fang Feng, Enqi Qiao, Limin Jiang, Bin Wu, Minghua Ge
BACKGROUND: As a member of the CELF family, CELF1 (CUG-binding protein 1, CUGBP1) is involved in cardiac and embryonic development, skeletal muscle differentiation and mammary epithelial cell proliferation. CELF1 is also observed in many kinds of cancer and may play a great role in tumorigenesis and deterioration. However, the expression and mechanism of its function in human glioma remain unclear. METHODS: We examined CELF1 expression in 62 glioma patients by immunohistochemistry and Western blot...
2015: International Journal of Biological Sciences
Ting-Xi Yu, Bei-Lin Gu, Jun-Kai Yan, Jie Zhu, Wei-Hui Yan, Jie Chen, Lin-Xi Qian, Wei Cai
The effectiveness and stability of epithelial barrier depend on apical junctional complexes, which consist of tight junctions (TJs) and adherens junctions (AJs). E-cadherin is the primary component of AJs, and it is essential for maintenance of cell-to-cell interactions and regulates the epithelial barrier. However, the exact mechanism underlying E-cadherin expression, particularly at the posttranscriptional level, remains largely unknown. RNA-binding proteins CUG-binding protein 1 (CUGBP1) and HU antigen R (HuR) are highly expressed in the intestinal epithelial tissues and modulate the stability and translation of target mRNAs...
January 1, 2016: American Journal of Physiology. Cell Physiology
Longfei Yang, Jinlong Zhang, Jiajia Chen, Huricha Jin, Jian Liu, Shen Huang, Zhiming Cui
CUG-binding protein 1, a member of the CELF (CUGBP and embryonic lethal abnormal vision-like factor) family of RNA-binding proteins, is shown to be multifunctional, regulating many posttranscriptional processes including alternative splicing, deadenylation, mRNA decay, and translation. Recently, CUGBP1 is found to represses p27 IRES activity and inhibits expression of endogenous p27 in cultured breast cancer cells. However, the roles of CUGBP1 in central nervous system injury remain unknown. In our study, we performed acute spinal cord injury (SCI) model in adult rats in order to research the expression changes of CUGBP1 in spinal cord...
September 2015: Neurochemical Research
Takayuki Katoh, Hiroaki Hojo, Tsutomu Suzuki
MicroRNA-122 (miR-122), which is expressed at high levels in hepatocytes, is selectively stabilized by 3'-adenylation mediated by the cytoplasmic poly(A) polymerase GLD-2. Here, we report that poly(A)-specific ribonuclease (PARN) is responsible for the deadenylation and destabilization of miR-122. The 3'-oligoadenylated variant of miR-122 was detected in Huh7 cells when PARN was down-regulated. In addition, both the steady-state level and stability of miR-122 were increased in PARN knockdown cells. We also demonstrate that CUG-binding protein 1 (CUGBP1) specifically interacts with miR-122 and other UG-rich miRNAs, and promotes their destabilization...
September 3, 2015: Nucleic Acids Research
Meghan Breaux, Kyle Lewis, Leila Valanejad, Polina Iakova, Fengju Chen, Qianxing Mo, Estela Medrano, Lubov Timchenko, Nikolai Timchenko
The histone acetyltransferase p300 has been implicated in the regulation of liver biology; however, molecular mechanisms of this regulation are not known. In this paper, we examined these mechanisms using transgenic mice expressing a dominant negative p300 molecule (dnp300). While dnp300 mice did not show abnormal growth within 1 year, these mice have many alterations in liver biology and liver functions. We found that the inhibition of p300 leads to the accumulation of heterochromatin foci in the liver of 2-month-old mice...
September 1, 2015: Molecular and Cellular Biology
Liam D Tryon, Matthew J Crilly, David A Hood
The purpose of this study was to determine how the expression of mitochondrial transcription factor A (Tfam), a protein that governs mitochondrial DNA (mtDNA) transcription and replication, is regulated during a state of reduced organelle content imposed by muscle disuse. We measured Tfam expression at 8 h, 16 h, 24 h, 3 days, or 7 days following denervation and hypothesized that decreases in Tfam expression would precede mitochondrial loss. Muscle mass was lowered by 13% and 38% at 3 and 7 days postdenervation, while cytochrome c oxidase activity fell by 33% and 39% at the same time points...
August 15, 2015: American Journal of Physiology. Cell Physiology
Eric T Wang, Amanda J Ward, Jennifer M Cherone, Jimena Giudice, Thomas T Wang, Daniel J Treacy, Nicole J Lambert, Peter Freese, Tanvi Saxena, Thomas A Cooper, Christopher B Burge
RNA binding proteins of the conserved CUGBP1, Elav-like factor (CELF) family contribute to heart and skeletal muscle development and are implicated in myotonic dystrophy (DM). To understand their genome-wide functions, we analyzed the transcriptome dynamics following induction of CELF1 or CELF2 in adult mouse heart and of CELF1 in muscle by RNA-seq, complemented by crosslinking/immunoprecipitation-sequencing (CLIP-seq) analysis of mouse cells and tissues to distinguish direct from indirect regulatory targets...
June 2015: Genome Research
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