Involvement of HTLV-I Tax and CREB in aneuploidy: a bioinformatics approach

Cynthia de la Fuente¹ , Madhur V Gupta¹ , Zachary Klase¹ , Katharine Strouss¹ , Patrick Cahan¹ , Timothy McCaffery¹ , Anthony Galante² , Patricia Soteropoulos² , Anne Pumfery¹ , Masahiro Fujii⁴^,5 and Fatah Kashanchi¹^,3

¹The George Washington University Medical Center, Department of Biochemistry and Molecular Biology, Washington, DC 20037, USA

²Center for Applied Genomics, Public Health Research Institute, Newark, NJ 07103, USA

³The Institute for Genomic Research (TIGR), Rockville, MD 20850, USA

⁴Department of Immunotherapeutics, Niigata University School of Medicine, Asahimachi-Dori, Niigata 951-8510, Japan

⁵Department of Virology, Niigata University School of Medicine, Asahimachi-Dori, Niigata 951-8510, Japan

author email corresponding author email

Retrovirology 2006, 3:43doi:10.1186/1742-4690-3-43


Published:	5 July 2006

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-κB, 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.

Conclusion

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.