Negative regulation of the SH2-homology–containing protein-tyrosine phosphatase-1 (SHP-1) P2 promoter by the HTLV-1 Tax oncoprotein

• Published in: Blood Vol. 110; no. 6; pp. 2110 - 2120
• Main Authors: Cheng, Jihua, Kydd, Andre R., Nakase, Koichi, Noonan, Kristin M., Murakami, Akikazu, Tao, Hong, Dwyer, Markryan, Xu, Chen, Zhu, Quan, Marasco, Wayne A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.09.2007; American Society of Hematology
• Series: Neoplasia
• Subjects: Acetylation; Adult; Blotting, Western; Chromatin Immunoprecipitation; Gene Expression Regulation, Leukemic; Gene Expression Regulation, Viral; Gene Products, tax - physiology; Gene Silencing; Histone Deacetylase 1; Histone Deacetylases - metabolism; Human T-lymphotropic virus 1 - genetics; Humans; Immunoprecipitation; Interleukin-2 - metabolism; Leukemia-Lymphoma, Adult T-Cell - genetics; Leukemia-Lymphoma, Adult T-Cell - metabolism; Leukemia-Lymphoma, Adult T-Cell - virology; Luciferases - metabolism; Mutagenesis, Site-Directed; Neoplasia; NF-kappa B - genetics; NF-kappa B - metabolism; Promoter Regions, Genetic - genetics; Protein Phosphatase 1; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; Transcriptional Activation; Transfection; Tumor Cells, Cultured
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-11-058388

Expression of SH2-homology–containing protein-tyrosine phosphatase-1 (SHP-1), a candidate tumor suppressor, is repressed in human T-cell leukemia virus type-1 (HTLV-1)–transformed lymphocyte cell lines, adult T-cell leukemia (ATL) cells, and in other hematologic malignancies. However, the mechanisms underlying regulation and repression of SHP-1 remain unclear. Herein, we cloned the putative full-length, hematopoietic cell–specific SHP-1 P2 promoter and identified the “core” promoter regions. HTLV-1 Tax profoundly represses P2 promoter activity and histone deacetylase-1 (HDAC1) potentiates such inhibition. NF-κB was implicated as both a rate-limiting factor for basal P2 promoter activity and important for Tax-induced promoter silencing (TIPS). Chromatin immunoprecipitation studies demonstrated that NF-κB dissociates from the SHP-1 P2 promoter following the binding of Tax and HDAC1. This is in agreement with coimmunoprecipitation studies where NF-κB competed with HDAC1 for association with Tax protein. We propose that in TIPS, Tax recruits HDAC1 to the SHP-1 P2 promoter and forms an inhibitory complex that results in deacetylation and dissociation of NF-κB from the promoter and attenuation of SHP-1 expression. TIPS provides a possible first step toward HTLV-1 leukemogenesis through its down-modulation of this key immediate early negative regulator of IL-2 signaling.