Negative regulation of the SH2-homology containing protein-tyrosine phosphatase-1 (SHP-1) P2 promoter by the HTLV-1 Tax oncoprotein.
Expression of SH(2)-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-kappaB 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-kappaB dissociates from the SHP-1 P2 promoter following the binding of Tax and HDAC1. This is in agreement with coimmunoprecipitation studies where NF-kappaB 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-kappaB 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.
Cheng
Jihua
J
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA.
Kydd
Andre R
AR
Nakase
Koichi
K
Noonan
Kristin M
KM
Murakami
Akikazu
A
Tao
Hong
H
Dwyer
Markryan
M
Xu
Chen
C
Zhu
Quan
Q
Marasco
Wayne A
WA
D000107:Acetylation; D000328:Adult; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D015973:Gene Expression Regulation, Leukemic; D015967:Gene Expression Regulation, Viral; D016356:Gene Products, tax / Q000502:physiology*; D020868:Gene Silencing; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D007376:Interleukin-2 / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D008156:Luciferases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D054645:Protein Phosphatase 1; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D016356:Gene Products, tax; D007376:Interleukin-2; D016328:NF-kappa B; D008156:Luciferases; D054645:Protein Phosphatase 1; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases