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      CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer

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          Abstract

          Long non-coding RNA (lncRNA), highly up-regulated in liver cancer (HULC) plays an important role in tumorigenesis. Depletion of HULC resulted in a significant deregulation of several genes involved in liver cancer. Although up-regulation of HULC expression in hepatocellular carcinoma has been reported, the molecular mechanisms remain unknown. In this study, we used in vivo and in vitro approaches to characterize cancer-dependent alterations in the chromatin organization and find a CREB binding site (encompassing from −67 to −53 nt) in the core promoter. Besides, we also provided evidence that PKA pathway may involved in up-regulation of HULC. Furthermore, we demonstrated HULC may act as an endogenous ‘sponge’, which down-regulates a series of microRNAs (miRNAs) activities, including miR-372. Inhibition of miR-372 leads to reducing translational repression of its target gene, PRKACB, which in turn induces phosphorylation of CREB. Over-expression of miR-372 decreases the association of CREB with the proximal promoter, followed by the dissociation of P300, resulting in a change of the histone ‘code’, such as in deacetylation and methylation. The study elucidates that fine tuning of HULC expression is part of an auto-regulatory loop in which it’s inhibitory to expression and activity of miR-372 allows lncRNA up-regulated expression in liver cancer.

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          Most cited references25

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          An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans.

          Two small temporal RNAs (stRNAs), lin-4 and let-7, control developmental timing in Caenorhabditis elegans. We find that these two regulatory RNAs are members of a large class of 21- to 24-nucleotide noncoding RNAs, called microRNAs (miRNAs). We report on 55 previously unknown miRNAs in C. elegans. The miRNAs have diverse expression patterns during development: a let-7 paralog is temporally coexpressed with let-7; miRNAs encoded in a single genomic cluster are coexpressed during embryogenesis; and still other miRNAs are expressed constitutively throughout development. Potential orthologs of several of these miRNA genes were identified in Drosophila and human genomes. The abundance of these tiny RNAs, their expression patterns, and their evolutionary conservation imply that, as a class, miRNAs have broad regulatory functions in animals.
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            Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133.

            In this paper, we demonstrate that phosphorylation of CREB at Ser-133 is induced 6-fold in vivo, following treatment of PC12 cells with forskolin. By contrast, no such induction was observed in the kinase A-deficient PC12 line A126-1B2 (A126). Using F9 teratocarcinoma cells, which are unresponsive to cAMP, we initiated a series of transient expression experiments to establish a causal link between phosphorylation of CREB and trans-activation of cAMP-responsive genes. Inactivating the kinase A phosphorylation site by in vitro mutagenesis of the cloned CREB cDNA at Ser-133 completely abolished CREB transcriptional activity. As CREB mutants containing acidic residues in place of the Ser-133 phosphoacceptor were also transcriptionally inactive, these results suggest that phosphorylation of CREB may stimulate transcription by a mechanism other than by simply providing negative charge.
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              Phosphorylated CREB binds specifically to the nuclear protein CBP.

              Cyclic AMP-regulated gene expression frequently involves a DNA element known as the cAMP-regulated enhancer (CRE). Many transcription factors bind to this element, including the protein CREB, which is activated as a result of phosphorylation by protein kinase A. This modification stimulates interaction with one or more of the general transcription factors or, alternatively, allows recruitment of a co-activator. Here we report that CREB phosphorylated by protein kinase A binds specifically to a nuclear protein of M(r) 265K which we term CBP (for CREB-binding protein). Fusion of a heterologous DNA-binding domain to the amino terminus of CBP enables the chimaeric protein to function as a protein kinase A-regulated transcriptional activator. We propose that CBP may participate in cAMP-regulated gene expression by interacting with the activated phosphorylated form of CREB.
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                Author and article information

                Journal
                Nucleic Acids Res
                nar
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                September 2010
                September 2010
                27 April 2010
                27 April 2010
                : 38
                : 16
                : 5366-5383
                Affiliations
                1Department of Laboratory Medicine, Ruijin Hospital, 2Faculty of Medical Laboratory Science, 3Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, 4Department of Preventive Medicine, Tongji University, Shanghai 200092 and 5Institute of Bioengineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, People Republic of China
                Author notes
                *To whom correspondence should be addressed. Tel: +86 21 64370045; Fax: +86 21 64311744; Email: fan.qishi@ 123456yahoo.com
                Correspondence may also be addressed to Fenyong Sun. Tel: +86 20 85223266; Fax: +86 20 85221983; Email: sunfenyong@ 123456126.com

                The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

                Article
                gkq285
                10.1093/nar/gkq285
                2938198
                20423907
                997c0d7c-37a2-4a45-9125-0d537cf07081
                © The Author(s) 2010. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 January 2010
                : 1 April 2010
                : 6 April 2010
                Categories
                Gene Regulation, Chromatin and Epigenetics

                Genetics
                Genetics

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