155: STAT5 regulation of TOX: Its dependence on IL-2 and role in cancer

Abstract

The Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway represents a rapid membrane to nucleus signaling system used by cytokines, hormones and growth factors. STAT5 is one of the seven STATs and is a key signaling protein which binds to chromatin at IFN-γ activation site (GAS motifs) and leads to the activation or repression of target genes involved in cell differentiation, proliferation and survival. In this study, several genes directly regulated by STAT5 were identified using chromatin immunoprecipitation in human CD8 + T lymphocytes. Mapping of the genomic fragments revealed that approximately 50% of the target sites were either in the proximal promoter region or introns of genes. Of the 183 STAT5 responsive binding sites identified in CD8 + T cells, almost a fourth contained the canonical GAS motif. Bioinformatic analyses, identified several target-genes whose aberrant functions are associated with malignant transformation of cells, consistent with the frequent dysregulation of STAT5 noted in various cancers. We have identified two other genes regulated by STAT5 and an interesting gene gene identified here is TOX: which is a differentiation program of developing T-cells [1] , [2] . The STAT5 binding site identified here, mapped to an internal intron within the TOX gene. The histone methylation marks too were indicative of an active enhancer region. Mining for information about promoter/TSS on the UCSC genome browser, revealed the presence of a typical GAS motif. An upregulation of TOX was observed in activated CD8 + T cells upon stimulation with IL-2. Although its role is T cell development is well studied, its role in cancers is less known. Various studies have shown the association between TOX subfamily of genes and cancer [3] , [4] . Due to its role in cellular proliferation and differentiation, TOX could have implications in cancer therapeutics. In conclusion, this study identified a role for STAT5 in the regulation of TOX in human T lymphocytes. Its role in cancer is under investigation. TOX (Thymocyte Selection-Associated High Mobility Group Box).