Identifying the immunodeficiency gateway proteins in humans and their involvement in microRNA regulation.

Very little is known to date about the regulation protocol between transcription factors (TFs), genes and microRNAs (miRNAs) associated with diseases in various organisms. In this paper, we focus on finding the activity of miRNAs through the HIV-1 regulatory pathway in humans at the systems level. For this, we integrate and study the characteristics of the interaction information between HIV-1 and human proteins obtained from literature and prediction analysis. This information, realized in the form of a bipartite network, is subsequently mined with an exhaustive graph search technique to identify the strong significant biclusters, which are effectively the bicliques. They are unified further to form the core bipartite subnetwork. Many of the known HIV-1 associated kinase proteins (including LCK) are found in this core module. From this, the secondary significant proteins are identified by mapping these gateway proteins to the human protein-protein interaction network. Finally, these proteins are mapped onto the TF-to-miRNA and miRNA-to-gene regulatory networks derived from a couple of current studies to obtain a global view of the HIV-1 mediated TF-gene-miRNA inter-regulatory network. Interestingly, a few miRNAs participating in this pathway at the secondary level are found to have oncogenic involvement.

[1]  David L Robertson,et al.  Cataloguing the HIV type 1 human protein interaction network. , 2008, AIDS research and human retroviruses.

[2]  Susumu Goto,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 2000, Nucleic Acids Res..

[3]  Andy M. Yip,et al.  Gene network interconnectedness and the generalized topological overlap measure , 2007, BMC Bioinformatics.

[4]  Michelle R. Arkin,et al.  Small-molecule inhibitors of protein–protein interactions: progressing towards the dream , 2004, Nature Reviews Drug Discovery.

[5]  B. Clotet,et al.  A clathrin-dynamin-dependent endocytic pathway for the uptake of HIV-1 by direct T cell-T cell transmission. , 2008, Antiviral research.

[6]  David L. Robertson,et al.  Patterns of HIV-1 Protein Interaction Identify Perturbed Host-Cellular Subsystems , 2010, PLoS Comput. Biol..

[7]  S. Chellappan,et al.  Raf-1 Physically Interacts with Rb and Regulates Its Function: a Link between Mitogenic Signaling and Cell Cycle Regulation , 1998, Molecular and Cellular Biology.

[8]  Lyle Ungar,et al.  Prediction of HIV-1 virus-host protein interactions using virus and host sequence motifs , 2009, BMC Medical Genomics.

[9]  A. Rice,et al.  miR-198 Inhibits HIV-1 Gene Expression and Replication in Monocytes and Its Mechanism of Action Appears To Involve Repression of Cyclin T1 , 2009, PLoS pathogens.

[10]  T. de Oliveira,et al.  BioAfrica's HIV-1 Proteomics Resource: Combining protein data with bioinformatics tools , 2005, Retrovirology.

[11]  J. Skolnick,et al.  Prediction of physical protein–protein interactions , 2005, Physical biology.

[12]  J. Parker,et al.  A feed-forward loop involving protein kinase Calpha and microRNAs regulates tumor cell cycle. , 2009, Cancer research.

[13]  P. Michael Conn,et al.  Trafficking of G-protein-coupled receptors to the plasma membrane: insights for pharmacoperone drugs , 2010, Trends in Endocrinology & Metabolism.

[14]  I. Chen,et al.  Human Immunodeficiency Virus Type 1 Vpr Induces Apoptosis through Caspase Activation , 2000, Journal of Virology.

[15]  Chris H. Q. Ding,et al.  Biclustering Protein Complex Interactions with a Biclique Finding Algorithm , 2006, Sixth International Conference on Data Mining (ICDM'06).

[16]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[17]  Donna R. Maglott,et al.  Human immunodeficiency virus type 1, human protein interaction database at NCBI , 2008, Nucleic Acids Res..

[18]  Lothar Thiele,et al.  A systematic comparison and evaluation of biclustering methods for gene expression data , 2006, Bioinform..

[19]  Shawn M Gomez,et al.  Structural similarity-based predictions of protein interactions between HIV-1 and Homo sapiens , 2010, Virology Journal.

[20]  Jason Weston,et al.  Semi-supervised multi-task learning for predicting interactions between HIV-1 and human proteins , 2010, Bioinform..

[21]  Yitzhak Pilpel,et al.  Global and Local Architecture of the Mammalian microRNA–Transcription Factor Regulatory Network , 2007, PLoS Comput. Biol..

[22]  Jin-Wu Nam,et al.  miR-29 miRNAs activate p53 by targeting p85α and CDC42 , 2009, Nature Structural &Molecular Biology.

[23]  V. Hughes The outlook for a cure , 2010, Nature.

[24]  Sumeet Gupta,et al.  Association of Tat with Promoters of PTEN and PP2A Subunits Is Key to Transcriptional Activation of Apoptotic Pathways in HIV-Infected CD4+ T Cells , 2010, PLoS pathogens.

[25]  Joaquín Dopazo,et al.  FatiGO: a web tool for finding significant associations of Gene Ontology terms with groups of genes , 2004, Bioinform..

[26]  Ujjwal Maulik,et al.  Development of the human cancer microRNA network , 2010 .

[27]  S. Deweerdt Dancing with an escape artist , 2010, Nature.

[28]  A. Hatzigeorgiou,et al.  TarBase: A comprehensive database of experimentally supported animal microRNA targets. , 2005, RNA.

[29]  Ming Lu,et al.  TransmiR: a transcription factor–microRNA regulation database , 2009, Nucleic Acids Res..

[30]  Vinod Scaria,et al.  Targets for human encoded microRNAs in HIV genes. , 2005, Biochemical and biophysical research communications.

[31]  Huating Wang,et al.  NF-kappaB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma. , 2008, Cancer cell.

[32]  Sanghamitra Bandyopadhyay,et al.  PuTmiR: A database for extracting neighboring transcription factors of human microRNAs , 2010, BMC Bioinformatics.

[33]  P. Stein,et al.  Lck Mediates Th2 Differentiation through Effects on T-bet and GATA-3 , 2010, The Journal of Immunology.

[34]  J. Lieberman,et al.  Identification of Host Proteins Required for HIV Infection Through a Functional Genomic Screen , 2007, Science.

[35]  D. Weiner,et al.  HIV-1 viral genes and mitochondrial apoptosis , 2008, Apoptosis.

[36]  Stuart Maudsley,et al.  The Origins of Diversity and Specificity in G Protein-Coupled Receptor Signaling , 2005, Journal of Pharmacology and Experimental Therapeutics.

[37]  J. Sedivy,et al.  Raf-1 protein kinase activates the NF-kappa B transcription factor by dissociating the cytoplasmic NF-kappa B-I kappa B complex. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[38]  S. Bohlander,et al.  The leukemogenic CALM/AF10 fusion protein alters the subcellular localization of the lymphoid regulator Ikaros , 2008, Oncogene.

[39]  Q. Cui,et al.  An Analysis of Human MicroRNA and Disease Associations , 2008, PloS one.

[40]  Sandhya Rani,et al.  Human Protein Reference Database—2009 update , 2008, Nucleic Acids Res..

[41]  Xuehua Zhong,et al.  HIV-1 Tat RNA silencing suppressor activity is conserved across kingdoms and counteracts translational repression of HIV-1 , 2009, Proceedings of the National Academy of Sciences.

[42]  Tongbin Li,et al.  miRecords: an integrated resource for microRNA–target interactions , 2008, Nucleic Acids Res..

[43]  B. Cullen Five Questions about Viruses and MicroRNAs , 2010, PLoS pathogens.

[44]  Sanghamitra Bandyopadhyay,et al.  TargetMiner: microRNA target prediction with systematic identification of tissue-specific negative examples , 2009, Bioinform..