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Kaposin-B Enhances the PROX1 mRNA Stability during Lymphatic Reprogramming of Vascular Endothelial Cells by Kaposi's Sarcoma Herpes Virus

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      Abstract

      Kaposi's sarcoma (KS) is the most common cancer among HIV-positive patients. Histogenetic origin of KS has long been elusive due to a mixed expression of both blood and lymphatic endothelial markers in KS tumor cells. However, we and others discovered that Kaposi's sarcoma herpes virus (KSHV) induces lymphatic reprogramming of blood vascular endothelial cells by upregulating PROX1, which functions as the master regulator for lymphatic endothelial differentiation. Here, we demonstrate that the KSHV latent gene kaposin-B enhances the PROX1 mRNA stability and plays an important role in KSHV-mediated PROX1 upregulation. We found that PROX1 mRNA contains a canonical AU-rich element (ARE) in its 3′-untranslated region that promotes PROX1 mRNA turnover and that kaposin-B stimulates cytoplasmic accumulation of the ARE-binding protein HuR through activation of the p38/MK2 pathway. Moreover, HuR binds to and stabilizes PROX1 mRNA through its ARE and is necessary for KSHV-mediated PROX1 mRNA stabilization. Together, our study demonstrates that kaposin-B plays a key role in PROX1 upregulation during lymphatic reprogramming of blood vascular endothelial cells by KSHV.

      Author Summary

      Kaposi's sarcoma (KS) is the most common cancer in HIV-positive patients and KS-associated herpes virus (KSHV) was identified as its causing agent. We and others have discovered that when the virus infects endothelial cells of blood vessels, KSHV reprograms the cell type resembling endothelial cells in lymphatic vessels. Although endothelial cells of the blood vascular system and of the lymphatic system share functional similarities, the cell type-reprogramming does not occur under a normal physiological condition. Therefore, cell-fate reprogramming by the cancer-causing virus KSHV provides an important insight into the molecular mechanism for viral pathogenesis. Our current study investigates the molecular mechanism underlying the KSHV-mediated cell fate reprogramming. We identified that a KSHV latent gene kaposin-B plays an important role in KSHV-mediated regulation of PROX1 to promote PROX1 mRNA stability. This study will provide a better understanding on the tumorigenesis and pathogenesis of KS with a potential implication toward new KS therapy.

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      Most cited references 94

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      Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.

      Representational difference analysis was used to isolate unique sequences present in more than 90 percent of Kaposi's sarcoma (KS) tissues obtained from patients with acquired immunodeficiency syndrome (AIDS). These sequences were not present in tissue DNA from non-AIDS patients, but were present in 15 percent of non-KS tissue DNA samples from AIDS patients. The sequences are homologous to, but distinct from, capsid and tegument protein genes of the Gammaherpesvirinae, herpesvirus saimiri and Epstein-Barr virus. These KS-associated herpesvirus-like (KSHV) sequences appear to define a new human herpesvirus.
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        The UCSC Genome Browser Database: update 2006

        The University of California Santa Cruz Genome Browser Database (GBD) contains sequence and annotation data for the genomes of about a dozen vertebrate species and several major model organisms. Genome annotations typically include assembly data, sequence composition, genes and gene predictions, mRNA and expressed sequence tag evidence, comparative genomics, regulation, expression and variation data. The database is optimized to support fast interactive performance with web tools that provide powerful visualization and querying capabilities for mining the data. The Genome Browser displays a wide variety of annotations at all scales from single nucleotide level up to a full chromosome. The Table Browser provides direct access to the database tables and sequence data, enabling complex queries on genome-wide datasets. The Proteome Browser graphically displays protein properties. The Gene Sorter allows filtering and comparison of genes by several metrics including expression data and several gene properties. BLAT and In Silico PCR search for sequences in entire genomes in seconds. These tools are highly integrated and provide many hyperlinks to other databases and websites. The GBD, browsing tools, downloadable data files and links to documentation and other information can be found at .
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          AU-rich elements and associated factors: are there unifying principles?

          The control of mRNA stability is an important process that allows cells to not only limit, but also rapidly adjust, the expression of regulatory factors whose over expression may be detrimental to the host organism. Sequence elements rich in A and U nucleotides or AU-rich elements (AREs) have been known for many years to target mRNAs for rapid degradation. In this survey, after briefly summarizing the data on the sequence characteristics of AREs, we present an analysis of the known ARE-binding proteins (ARE-BP) with respect to their mRNA targets and the consequences of their binding to the mRNA. In this analysis, both the changes in mRNA stability and the lesser studied effects on translation are considered. This analysis highlights the multitude of mRNAs bound by one ARE-BP and conversely the large number of ARE-BP that associate with any particular ARE-containing mRNA. This situation is discussed with respect to functional redundancies or antagonisms. The potential relationship between mRNA stability and translation is also discussed. Finally, we present several hypotheses that could unify the published data and suggest avenues for future research.
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            Author and article information

            Affiliations
            [1]Departments of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
            [2]Max-von-Pettenkofer Institut, Ludwig-Maximilians-Universität München, München, Germany
            [3]Division of Pediatric Urology, Childrens Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
            University of California San Francisco, United States of America
            Author notes

            Conceived and designed the experiments: JY JK BA DK SL IC JL SR YKH. Performed the experiments: JY JK HNL BA DK SL IC JL SR YKH. Analyzed the data: YKH. Contributed reagents/materials/analysis tools: JH CJK YKH. Wrote the paper: YKH.

            Contributors
            Role: Editor
            Journal
            PLoS Pathog
            plos
            plospath
            PLoS Pathogens
            Public Library of Science (San Francisco, USA)
            1553-7366
            1553-7374
            August 2010
            August 2010
            12 August 2010
            : 6
            : 8
            2921153
            20730087
            09-PLPA-RA-2154R2
            10.1371/journal.ppat.1001046
            (Editor)
            Yoo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 14
            Categories
            Research Article
            Cell Biology/Gene Expression
            Infectious Diseases/HIV Infection and AIDS
            Virology/Effects of Virus Infection on Host Gene Expression
            Virology/Viral Replication and Gene Regulation
            Virology/Viruses and Cancer
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