title: Involvement of HTLV-I Tax and CREB in aneuploidy: a bioinformatics approach.
abstract: BACKGROUND
  Adult T-cell leukemia (ATL) is a complex and multifaceted disease associated with human T-cell leukemia virus type 1 (HTLV-I) infection. Tax, the viral oncoprotein, is considered a major contributor to cell cycle deregulation in HTLV-I transformed cells by either directly disrupting cellular factors (protein-protein interactions) or altering their transcription profile. Tax transactivates these cellular promoters by interacting with transcription factors such as CREB/ATF, NF-kappaB, and SRF. Therefore by examining which factors upregulate a particular set of promoters we may begin to understand how Tax orchestrates leukemia development.
  
  
  RESULTS
  We observed that CTLL cells stably expressing wild-type Tax (CTLL/WT) exhibited aneuploidy as compared to a Tax clone deficient for CREB transactivation (CTLL/703). To better understand the contribution of Tax transactivation through the CREB/ATF pathway to the aneuploid phenotype, we performed microarray analysis comparing CTLL/WT to CTLL/703 cells. Promoter analysis of altered genes revealed that a subset of these genes contain CREB/ATF consensus sequences. While these genes had diverse functions, smaller subsets of genes were found to be involved in G2/M phase regulation, in particular kinetochore assembly. Furthermore, we confirmed the presence of CREB, Tax and RNA Polymerase II at the p97Vcp and Sgt1 promoters in vivo through chromatin immunoprecipitation in CTLL/WT cells.
  
  
  CONCLUSIONS
  These results indicate that the development of aneuploidy in Tax-expressing cells may occur in response to an alteration in the transcription profile, in addition to direct protein interactions.
authors.affiliation: The George Washington University Medical Center, Department of Biochemistry and Molecular Biology, Washington, DC 20037, USA. bcmclf@gwumc.edu
authors.forename: Cynthia
authors.initials: C
authors.lastname: de la Fuente
authors.forename: Madhur V
authors.initials: MV
authors.lastname: Gupta
authors.forename: Zachary
authors.initials: Z
authors.lastname: Klase
authors.forename: Katharine
authors.initials: K
authors.lastname: Strouss
authors.forename: Patrick
authors.initials: P
authors.lastname: Cahan
authors.forename: Timothy
authors.initials: T
authors.lastname: McCaffery
authors.forename: Anthony
authors.initials: A
authors.lastname: Galante
authors.forename: Patricia
authors.initials: P
authors.lastname: Soteropoulos
authors.forename: Anne
authors.initials: A
authors.lastname: Pumfery
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujii
authors.forename: Fatah
authors.initials: F
authors.lastname: Kashanchi
mesh_terms: D000782:Aneuploidy; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology / Q000379:methods*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D004257:DNA Polymerase II / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D016355:Genes, pX; D015368:Human T-lymphotropic virus 1 / Q000235:genetics; D006801:Humans; D018386:Kinetochores / Q000502:physiology; D015461:Leukemia, Prolymphocytic, T-Cell / Q000235:genetics / Q000821:virology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism / Q000502:physiology*; D014162:Transfection
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D016356:Gene Products, tax; D004257:DNA Polymerase II